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Dulaglutide.nxml
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Dulaglutide
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2019-04-10
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Dulaglutide is a recombinant DNA produced polypeptide analogue of human glucagon-like peptide-1 (GLP-1) which is used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other antidiabetic agents. There have been no published reports of hepatotoxicity attributed to dulaglutide therapy.
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Dulaglutide (doo" la gloo' tide) is a glucagon-like peptide-1 (GLP-1) analogue that acts like the native gastrointestinal hormone (incretin) to increase insulin secretion. Dulaglutide reproduces the activity of GLP-1, binding to specific receptors on pancreatic beta cells and increasing insulin secretion, which can lead to improvement of glycemic control in patients with type 2 diabetes. Dulaglutide, like other GLP-1 analogues, also causes weight loss which may contribute to its clinical effects. Dulaglutide is a recombinant DNA produced polypeptide that shares 97% homology to endogenous human GLP-1(7-37), but has an amino acid substitution which makes it resistant to DPP-4 degradation and thus extends its half-life in serum. In addition, the GLP-1 like polypeptide is linked to an Fc fragment of human IgG4 which further prolongs its serum half-life and duration of activity. Dulaglutide, like other GLP-1 analogues, must be given parenterally. Dulaglutide was approved for use in the United States in 2014 and current indications are for management of glycemic control in adults with type 2 diabetes in combination with diet and exercise, with or without other oral hypoglycemic agents. Dulaglutide is available under the brand name Trulicity in solution for subcutaneous injection in prefilled, single dose pens or syringes (0.75 and 1.5 mg/0.5 mL). The typical initial dose is 0.75 mg once weekly, which can be increased to 1.5 mg weekly. Dulaglutide is generally well tolerated, but side effects can be dose limiting and include nausea [~20%], vomiting [~5%], diarrhea [~12%], abdominal pain, decreased appetite, dyspepsia and fatigue. Rare side effects include pancreatitis [0.1-0.3%], hypoglycemia and hypersensitivity reactions.
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In large clinical trials, serum enzyme elevations were no more common with dulaglutide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Since licensure, there have been no published case reports of hepatotoxicity due to dulaglutide and the product label does not list liver injury as an adverse event. Thus, liver injury due to dulaglutide must be rare, if it occurs at all.
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Dulaglutide is a polypeptide and is metabolized to amino acids by serum and tissue proteases, and is unlikely to have any direct hepatotoxic potential. Dulaglutide acts through the incretin pathway to affect glucose metabolism and, thus, is often grouped with other incretin-based antidiabetic mediations such as the DPP-4 inhibitors, sitagliptin, saxagliptin and linagliptin, and other GLP-1 analogues such as exenatide, liraglutide and albiglutide which are also discussed in LiverTox.\n\nReferences regarding the hepatotoxicity and safety of dulaglutide are given with the Overview section of the GLP-1 Analogues.\n\nDrug Class: Antidiabetic Agents\n\nOther Drugs in the Subclass, Incretin-Based Drugs, Glucagon-Like Peptide-1 (GLP-1) Analogues: Albiglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide
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Dulaglutide – Trulicity®
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Antidiabetic Agents
| null |
Piroxicam.nxml
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Piroxicam
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2020-03-20
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Piroxicam is a commonly used nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and is used in therapy of chronic arthritis. Piroxicam can cause mild serum aminotransferase elevations and, in rare instances, leads to clinically apparent acute liver injury that can be severe and even fatal.
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Piroxicam (pir ox' i kam) belongs to the oxicam family, which is a class of enolic acids structurally unrelated to other NSAIDs. Piroxicam, like other NSAIDs, acts through inhibition of tissue cyclooxygenases (Cox-1 and -2) leading to a decrease in synthesis of pro-inflammatory prostaglandins, which are potent mediators of pain and inflammation. Piroxicam has analgesic as well as antipyretic and antiinflammatory activities. Piroxicam was approved for use in the United States in 1982 and is still widely used, with several million prescriptions filled yearly. Current indications include rheumatoid arthritis and osteoarthritis. Piroxicam is available as capsules of 10 and 20 mg in several generic forms as well as under brand names such as Feldene, Novo-Pirocam and Nu-Pirox. The recommended dose is 10 to 20 mg orally once daily. Piroxicam is available by prescription only. Other oxicam NSAIDs include meloxicam, tenoxicam, and droxicam, the latter two being available in other countries, but not the United States. As with other NSAIDs, piroxicam is generally well tolerated, but side effects can include headache, dizziness, somnolence, dyspepsia, abdominal discomfort, diarrhea, peripheral edema and hypersensitivity reactions. Rare but serious adverse events from NSAIDs include gastrointestinal ulceration and bleeding, increased risk for cardiovascular disease, renal dysfunction and hypersensitivity reactions including anaphylaxis, exfoliative dermatitis and Stevens Johnson syndrome.
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Elevated serum aminotransferase levels have been reported in 3% to 18% of patients taking piroxicam, but symptomatic liver disease with jaundice is rare (estimated at 1 to 5 cases per 100,000 prescriptions). The latency to onset of symptoms of clinically apparent liver injury due to piroxicam is variable from a few days to several months, but is generally within the first 1 to 6 weeks of treatment. The pattern of injury is predominantly cholestatic, although cases presenting with mixed or hepatocellular patterns have been reported (Case 1). Eosinophilia, rash and fever can occur, but are not always present and are usually not prominent. Autoantibodies are rarely found. The injury is usually self-limited and recovery occurs within 1 to 2 months. Rare cases of acute liver failure have been reported.\n\nLikelihood score: B (rare but likely cause of clinically apparent liver injury).
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The mechanism of piroxicam induced liver injury is not known, but may be due to a toxic metabolic intermediate of piroxicam metabolism, which occurs largely in the liver. Cases with allergic manifestations (fever, rash, eosinophilia) may also have a component of hypersensitivity.
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Severity of the liver injury from piroxicam ranges from asymptomatic elevations in serum aminotransferase levels to severe hepatitis with acute liver failure. Several instances of chronic vanishing bile duct syndrome have been attributed to other oxicam NSAIDs, but not specifically to piroxicam. In most instances, however, complete recovery is expected after stopping the drug and usually takes one to two months. Cross sensitivity to liver injury among the various NSAIDs has not been well studied or described. Due to the wide availability of alternative medications, rechallenge with piroxicam and other oxicam forms of NSAIDs (meloxicam, droxicam, tenoxicam) should be avoided.\n\nDrug Class: Nonsteroidal Antiinflammatory Drugs, see also Meloxicam
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Piroxicam – Generic, Feldene®
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Nonsteroidal Antiinflammatory Drugs
| null |
Ertapenem.nxml
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Ertapenem
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2017-01-17
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Ertapenem is a broad spectrum carbapenem antibiotic used primarily for the treatment of aerobic gram-negative bacterial infections. Ertapenem, like other carbapenems, is associated with transient and asymptomatic elevations in serum enzymes. The carbapenems have also been linked to rare instances of clinically apparent, acute cholestatic liver injury.
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Ertapenem (er" ta pen' em) is a broad spectrum beta-lactam antibiotic used predominantly for treatment of severe aerobic gram-negative infections. Ertapenem, like other carbapenems, binds to bacterial penicillin binding proteins and interferes with bacterial cell wall integrity and synthesis. It is a broad spectrum antibiotic with activity against many aerobic and anaerobic gram-positive and gram-negative organisms, including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, viridans group streptococci, Enterococcus faecalis, Escherichia coli, Proteus mirabilis, Bacteroides fragilis and Peptostreptococcus species. Ertapenem was approved for use in the United States in 2001, and its use is largely restricted to serious infections in hospitalized patients. Ertapenem is indicated for the treatment of severe or complicated skin, tissue, joint, respiratory tract, intraabdominal, urinary tract and urogenital infections as well as endocarditis and sepsis due to susceptible organisms. The recommended dosage is 1 gram given intramuscularly once daily for 5 to 28 days. It is currently available as Invanz. The most common side effects of ertapenem are infusion site pain and phlebitis, diarrhea, nausea, rash, pruritus and headache.
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Mild, transient, asymptomatic elevations in serum aminotransferase levels occur in about 5% of patients receiving parenteral ertapenem for 5 to 14 days. These abnormalities are usually self-limited and asymptomatic. In the limited period that it has been available, no cases of hepatitis with jaundice have been reported. Nevertheless, several instances of cholestatic jaundice arising during or shortly after therapy have been reported with other carbapenems. The latency to onset has been within 1 to 3 weeks and the pattern of enzyme elevations is usually cholestatic. Immunoallergic features can occur but autoantibodies are rare. The course is usually self-limiting, but at least one case of vanishing bile duct syndrome related to a carbapenem has been reported. Ertapenem and other carbapenems have not been linked to cases of acute liver failure.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
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The liver injury due to the carbapenems is usually mild, asymptomatic and self-limited. Rarely, the carbapenems can cause a clinically apparent acute cholestatic hepatitis that is usually self-limiting and not requiring therapy or intervention. There is little information on possible cross sensitivity to liver injury among the different beta-lactam antibiotics, but patients with clinically apparent liver injury due to ertapenem should probably avoid the other carbapenems.\n\nReferences to the safety and potential hepatotoxicity of ertapenem are given in the Overview section on Carbapenems.\n\nDrug Class: Antiinfective Agents, Carbapenems\n\nOther Drugs in the Subclass, Carbapenems: Doripenem, Imipenem, Meropenem
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Ertapenem – Invanz®
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Antiinfective Agents
| null |
Captopril.nxml
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Captopril
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2018-02-11
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Captopril is an angiotensin-converting enzyme (ACE) inhibitor used in the therapy of hypertension and heart failure. Captopril is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury.
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Captopril (kap' toe pril) was the first ACE inhibitor to be approved for use in the United States and is still widely used for therapy of hypertension and heart failure. Like other ACE inhibitors, captopril inhibits the conversion of angiotensin I, a relatively inactive molecule, to angiotensin II which is the major mediator of vasoconstriction and volume expansion induced by the renin-angiotensin system. Other enzymes besides that which converts angiotensin I to II may also be inhibited, which may account for some of the side effects of the ACE inhibitors. Captopril was approved for use in the United States in 1981 and current indications are for hypertension, congestive heart failure, left ventricular dysfunction after myocardial infarction, and treatment and prevention of diabetic nephropathy. Captopril is available in 12.5, 25, 50 and 100 mg tablets in many generic forms and formerly under the trade name Capoten. The typical dose of captopril in adults in 25 to 50 mg two or three times daily, and it is administered long term. Captopril is also available in several fixed combinations with hydrochlorothiazide (Capozide and others). Common side effects of captopril and ACE inhibitors in general include dizziness, fatigue, headache, cough, gastrointestinal upset and skin rash.
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Captopril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (<2%) that, in controlled trials, was no higher than with placebo therapy. These elevations were transient and rarely required dose modification. While rare, several dozen cases of clinically apparent liver injury have been reported with captopril therapy. The onset is usually within 2 to 12 weeks of starting therapy and the serum enzyme pattern is typically cholestatic (Case 1). In some instances, cholestasis has been prolonged and relapsing and associated with persistent elevations in serum alkaline phosphatase, suggestive of vanishing bile duct syndrome. Immunoallergic manifestations (rash, fever, eosinophilia) are infrequent and most patients do not develop autoantibodies. Rare instances of captopril injury with a hepatocellular pattern and cases with a long latency (one or more years) have been described as well, a distinctly unusual pattern of drug induced liver injury.\n\nLikelihood score: B (likely but rare cause of clinically apparent liver injury).
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The cause of the minor serum aminotransferase associated with captopril is not known. The clinically apparent acute liver injury from captopril is likely an idiosyncratic reaction to a metabolite. Captopril is hydrolyzed by the liver to its active metabolite captoprilat and has little further hepatic metabolism.
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Most instances of acute liver injury reported with captopril use have been self limited, but there have been rare reports of acute liver failure due to captopril and several reports of cholestatic hepatitis leading to prolonged jaundice. Patients with severe captopril induced acute liver injury and hypersensitivity reactions should avoid use of other ACE inhibitors, although cross sensitivity to liver injury among the members of this class of agents has not always been shown.\n\nReferences to the safety and potential hepatotoxicity of captopril are given in the Overview section on the Angiotensin-Converting Enzyme (ACE) Inhibitors.\n\nDrug Class: Antihypertensive Agents, Angiotensin-Converting Enzyme Inhibitors
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Captopril – Generic, Capoten®
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Angiotensin-Converting Enzyme Inhibitors
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SawPalmetto.nxml
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Saw Palmetto
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2020-04-02
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Saw palmetto is a popular herbal medication and extract derived from the fruit of the low growing, small palm, Serenoa repens, which has fan shaped leaves and is native to Florida and the Southeast United States. Currently, saw palmetto is used mostly for symptoms of benign prostatic hypertrophy. Saw palmetto has been implicated in rare cases of clinically apparent liver injury, but its specific role in causing liver injury remains uncertain.
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Saw palmetto (saw pal met’ toe) is a widely used herbal derived from the fruit of the low growing bushy palm of the same name (Serenoa repens). Native Americans used saw palmetto fruit both as a food as well as an herbal remedy with multiple uses, including as a sedative, diuretic, sleeping aid, expectorant and cough suppressant, aid to lactation, infertility, indigestion and urinary problems. Currently, saw palmetto is one of the most widely used herbal medications and is used largely for symptomatic benign prostatic hypertrophy. Saw palmetto is available in multiple formulations including liquid extracts, tablets, capsules, and as an herbal tea. The active components of palmetto extracts are believed to be the volatile oils and free fatty acids which have activity in inhibiting 5-alpha-reductase and the conversion of testosterone to dihydrotesterone, which has been demonstrated in vitro, but not in human studies. In short term clinical trials, saw palmetto appeared to be beneficial in improving symptoms of prostatic hypertrophy, but it had no effects on prostate size or serum prostatic specific antigen (PSA) levels. In longer term studies, the benefit of saw palmetto in improving urinary symptoms of benign prostatic hypertrophy was less clear. Saw palmetto is available in multiple over-the-counter preparations often in combination with other herbals or dietary supplements, and most commonly for symptoms of urinary hesitancy, urgency or burning. Side effects of saw palmetto are uncommon and mild and may include dizziness, headache, nausea, vomiting, constipation and diarrhea. In most randomized controlled clinical trials, side effects were no more frequent with saw palmetto than with placebo therapy.
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Chronic therapy with saw palmetto has not been linked to serum enzyme elevations and prospective trials found little or no evidence of liver injury from its administration. However, there have been rare case reports of clinically apparent liver injury attributed to saw palmetto, although in some instances, other possible causes of liver disease were present. In the reported cases, the latency to onset was within 1 to 2 weeks of starting therapy, and clinical features resembled acute viral hepatitis with a hepatocellular pattern of serum enzyme elevations and resolution within 1 to 3 months. Immunoallergic and autoimmune features were not present.\n\nLikelihood score: D (possible, rare cause of clinically apparent liver injury).
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Saw palmetto extracts have many components, but none of them has been shown to be particularly hepatotoxic. The rare cases of liver injury reported with saw palmetto use have had idiosyncratic features. Saw palmetto has few herb-drug interactions and is not affected by inducers or inhibitors of the cytochrome P450 enzyme system.
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Hepatotoxicity from saw palmetto is very rare and cases have been self-limiting upon stopping the herbal. There have been no instances leading to fatalities, liver transplantation, chronic hepatitis, or vanishing bile duct syndrome. Studies of rechallenge have not been reported.\n\nOther Names: Cabbage palm, Sabal\n\nDrug Class: Herbal and Dietary Supplements
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Saw Palmetto – Generic
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Herbal and Dietary Supplements
| null |
Histrelin.nxml
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Histrelin
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2023-05-28
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Histrelin is a gonadotropin releasing hormone (GnRH) agonist that is a potent inhibitor of production of testosterone (in men) and estrogen (in women) and is used predominantly to treat advanced prostate cancer. Histrelin is associated with a low rate of transient serum enzyme elevations during therapy, but has not been linked convincingly to cases of clinically apparent acute liver injury.
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Histrelin (his trel' in) is a nonapeptide analogue of gonadotropin releasing hormone that acts on the pituitary to cause the synthesis and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH), two gonadotropins that act on the male testes to stimulate the production of testosterone and on the female ovaries to induce synthesis of estrogen. Histrelin and other GnRH agonists cause an initial surge of gonadotropin release, but then lead to down-regulation of their synthesis and secretion which results in a decline in testosterone and estrogen production. Histrelin, alone or in combination with other antiandrogens, has been found to be palliative in advanced prostate cancer and as effective as surgical castration. Histrelin was approved for use in the United States in 1991 and as a once-yearly implant formulation in 2004. The major indications for histrelin are advanced prostate cancer and precocious puberty. The GnRH agonists have also been used off label for precocious puberty, infertility, and as a part of gender affirming therapy. Histrelin is available under the brand names Supprelin (for precocious puberty) and Vantas (for prostate cancer; discontinued September 2021) in solution as implants of 50 mg, which are inserted subcutaneously in the inner aspect of the upper arm at 12 month intervals. Histrelin and the other GnRH analogues cause a profound hypogonadism ("chemical castration") and its common side effects are typical of androgen deprivation, including hot flashes, loss of libido, erectile dysfunction, depression, nausea, diarrhea, weight gain and fluid retention. Rare, but potentially severe adverse events include hypersensitivity reactions and transient tumor flare with the first injection.
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Histrelin has been associated with serum enzyme elevations during therapy in rates similar to those of other GnRH analogues. The serum enzyme elevations are generally mild, asymptomatic and resolve even without dose adjustment or drug discontinuation. ALT elevations above 3 times the upper limit of normal occur in less than 1% of recipients. Histrelin has been linked to a single case of acute liver injury, but it was unclear from the report whether the episode was associated with jaundice or symptoms and other diagnoses remained possible. Thus, clinically apparent liver injury from histrelin may occur, but it is extremely rare and usually self-limited in course. There have been no episodes of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with histrelin or other GnRH analogue therapy.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
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The cause of the minor serum enzyme elevations that can occur during histrelin therapy is unknown. Histrelin is a short peptide similar to GnRH and is metabolized locally in tissue and not by the hepatic cytochrome P450 system. Some serum enzyme elevations may be caused by nonalcoholic fatty liver arising because of weight gain or metabolic changes caused by the androgen deprivation state induced by the GnRH agonist.
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The serum enzyme elevations during histrelin therapy rarely require dose modification or drug discontinuation and should instead lead to investigation of other possible causes of liver injury. There is no evidence for cross sensitivity to liver injury among the various GnRH analogues, despite their similarity in chemical structure.\n\nDrug Class: Antineoplastic Agents, GnRH Analogues\n\nOther Drugs in the Subclass, GnRH Analogues: Degarelix, Goserelin, Leuprolide, Relugolix, Triptorelin
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Histrelin – Supprelin®
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Antineoplastic Agents
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Apoaequorin.nxml
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Apoaequorin
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2019-12-11
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Apoaequorin is a recombinant protein used as a dietary supplement that is purported to improve memory and verbal learning. Apoaequorin has not been associated with serum enzyme elevations during therapy nor with clinically apparent liver injury.
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Apoaequorin is a calcium binding protein found in luminescent jellyfish (Aequorea victoria). When the natural (apo) form of the protein is conjugated with coelenterazine, the resulting protein aequorin has natural bioluminescence when exposed to calcium. For this reason, it has been used as a research molecule to study intracellular physiology and regulation of calcium flux. Recombinant apoaequorin, developed for use in research studies, was subsequently evaluated for its potential to improve memory. The basis for this use of aequorin was its calcium binding characteristics which resembled those of calmodulin, an intracellular protein complex which appears to play a central role in memory. A single trial of oral apoaequorin in patients with memory problems found no overall differences in changes in measures of verbal learning in comparison to placebo, but slightly greater improvements were reported in a subset of patients with normal cognitive test values at baseline. These findings were questioned later because of the lack of evidence that apoaequorin is absorbed orally or can cross the blood-brain barrier. Nevertheless, apoaequorin is marketed as a dietary supplement that supports brain health and helps with aging-related memory loss. It has been used off label in patients with amyotrophic lateral sclerosis and multiple sclerosis. Apoaequorin is available in tablets of 10, 20 and 40 mg under the brand name Prevagen. It has not been approved by the FDA as therapy of memory loss or neurologic illnesses. Side effects were not reported in the few prospective studies that have been published. Adverse events reported to the sponsor have been rare but have included headache, nausea, constipation, edema and hypertension. There have been anecdotal reports of serious adverse events in persons with multiple sclerosis taking apoaequorin including hypotension and depression with suicidal ideation.
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Apoaequorin is considered generally safe and without major adverse effects. In the human studies that have been published there were no reports of serum enzyme elevations occurring during therapy and no mention of serious adverse events or hepatotoxicity.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nMechanism of Injury\n\nThe mechanism by which apoaequorin might cause hepatotoxicity is unclear. Indeed, there is little evidence that apoaequorin is absorbed orally, most proteins being broken down in the stomach and intestines to individual amino acids or short polypeptides. Allergic reactions can occur with proteins taken orally but have not been reported with apoaequorin. The possibility of mislabeling or adulteration with hepatotoxic natural products is always an issue in commercial supplements.\n\nDrug Class: Herbal and Dietary Supplements
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Apoaequorin – Prevagen®
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Herbal and Dietary Supplements
| null |
Givosiran.nxml
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Givosiran
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2020-02-27
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Givosiran is synthetic small interfering RNA (siRNA) molecule directed against 5-aminolevulinic acid synthase that is used to treat acute hepatic porphyria. Givosiran has been linked to mild-to-moderate ALT elevations during therapy, but has not been linked to instances of idiosyncratic acute liver injury with symptoms and jaundice.
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Givosiran (giv” oh sir’ an) is a synthetic double stranded, small interfering RNA (siRNA) directed against 5-aminolevulinic acid synthase 1, which results in decreases in serum delta aminolevulinic acid (ALA) and porphobilinogen (PBG), intermediates in porphyrin metabolism which accumulate in patients with acute hepatic porphyrias and are believed to cause the neurologic and visceral symptoms of acute attacks. The siRNA molecule is covalently linked to three N-acetylgalactosamine residues which directs it to specific receptors found largely on hepatocytes. Once taken up by the hepatocyte, the siRNA is cleaved into smaller fragments and separated into single strands that bind and silence the mRNA of ALA synthase. In animal models, givosiran reduced ALA synthase mRNA levels in liver that was accompanied by a corresponding decline in urine and plasma ALA and PBG. In placebo controlled trials of givosiran in patients with recurring acute attacks, single infusions of givosiran resulted in dose related reductions in urinary ALA and PBG levels and, with monthly injections, annualized rates of attacks were reduced by 75% to 90%. Givosiran was approved for use in the United States for adults with acute hepatic porphyria in 2019. Current indications are limited to adults. Givosiran is available in solution in single dose vials of 189 mg/mL under the brand name Givlaari. The recommended regimen is 2.5 mg per kg body weight once monthly by subcutaneous injection. Givosiran is generally well tolerated but side effects can include nausea, injection site reactions, rash, fatigue and creatinine and serum aminotransferase elevations. Less common, but more severe side effects include severe injection reactions, anaphylaxis and recall reactions. In registration studies, immunogenicity was uncommon; only 1% of givosiran treated patients developed anti-drug antibodies.
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The acute hepatic porphyrias are rare, and the pivotal trials of givosiran were conducted in rather small numbers of patients, so the full spectrum of hepatotoxicity may not be fully known. Nevertheless, in the registration controlled trials, serum aminotransferase elevations arose in 13% of givosiran- versus 2% of placebo-recipients, but rose to levels above 5 times the upper limit of normal only rarely. One patient was reported as discontinuing givosiran therapy because of aminotransferase elevations, but no patient developed concurrent elevations in serum bilirubin or symptoms suggestive of hepatitis. Thus, givosiran has not been linked to instances of acute hepatitis or jaundice, but it has had limited clinical use.\n\nLikelihood score: E* (unproven but suspected cause of clinically apparent liver injury).
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The cause of hepatic injury from the givosiran and other siRNA therapeutics is unknown. One possibility is that suppression of 5-aminolevulinic acid synthase may cause cell damage in some hepatocytes. The mRNA suppression appears to lower but not completely eliminate enzyme activity, but individual hepatocytes may vary in the sensitivity to the enzyme inhibition and effects of its loss. Givosiran is metabolized intracellularly by nucleases and is not a substrate of cytochrome P450 enzymes. On the other hand, the chronic inhibition of ALA synthase can result in decreases in CYP 1A2 and 2D6 synthesis and lead to supra-therapeutic or toxic levels of drugs that are metabolized by these enzymes.
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The liver injury associated with givosiran therapy has invariably been mild, not associated with jaundice and rapidly resolving often without discontinuation or even dose adjustment. In prelicensure clinical trials, subjects received hemin therapy for acute attacks without evidence of liver injury, and there is no reason to suspect cross reactivity of hepatic injury with other therapies of acute porphyria. Monitoring of liver tests during therapy is recommended during givosiran therapy as well as interruption or discontinuation for significant elevations in serum aminotransferases.\n\nDrug Class: Genetic Disorder Agents\n\nOther Therapeutic siRNA and Antisense Agents: Eteplirsen, Golodirsen, Patisiran
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Givosiran – Givlaari®
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Genetic Disorder Agents
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Anagrelide.nxml
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Anagrelide
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2017-07-05
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Anagrelide is an antithrombotic and platelet reducing agent that is used to treat the thrombocythemia associated with myeloproliferative diseases. Anagrelide has had limited clinical use, but has not been linked to significant serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury.
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Anagrelide (an ag' re lide) is platelet reducing agent that is used to treat thrombocytosis due to myeloproliferative diseases. Its mechanism of action is not well defined, but it appears to inhibit the maturation and differentiation of megakaryocytes, and both synthesis and release of platelets as well as subsequent platelet aggregation. In addition, anagrelide inhibits phosphodiesterase-3 which causes vasodilation and may account for many of its side effects. In several open label trials, anagrelide was shown to reduce platelet counts in patients with thrombocythemia due to essential thrombocytosis and other myeloproliferative diseases. Severe thrombocythemia is associated with an increased risk of arterial and venous thromboses including transient ischemic attacks, stroke, myocardial infarction and other thrombotic ischemic conditions. Less commonly, thrombocytosis is associated with venous thromboses including deep vein thrombosis, pulmonary embolus and portal or splanchnic vein thrombosis. Anagrelide was approved for use in thrombocythemia due to myeloproliferative diseases in 1997, but is considered a second line agent, appearing to be less effective and less well tolerated than hydroxyurea. Anagrelide is available in capsules of 0.5 mg generically and under the brand name Agrylin. The typical initial dose is 0.5 mg daily, with subsequent gradual and monitored dose escalation based upon platelet counts and tolerance, not to exceed 10 mg daily or 2.5 mg in a single dose. It is often given in combination with aspirin. Side effects can include headache, dizziness, palpitations, fatigue, nausea, abdominal pain, dyspnea, cough, fever, edema, rash, chest pain and tachycardia. Rare, but potentially severe adverse reactions include arrhythmias, prolongation of the QTc interval, excessive bleeding and interstitial nephritis.
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In preregistration studies, anagrelide was not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. Since its approval, there has been a single published abstract reporting progressive, ultimately fatal cholestasis after liver transplantation and use of anagrelide, but there have been no other published reports of anagrelide hepatotoxicity in the literature. In large, long term follow up studies there have been occasional instances of transient serum enzyme elevations without jaundice or symptoms. The product label for anagrelide mentions abnormal enzymes as an adverse event but not clinically apparent liver injury, hepatitis or jaundice. However, the general clinical experience with anagrelide has been limited.\n\nLikelihood score: E* (unlikely, but suspected rare cause of clinically apparent liver injury).
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The mechanism by which anagrelide might cause serum aminotransferase elevations or liver injury is not known. The typical daily dose is low (1 to 10 mg), which may account for its relative lack of hepatotoxicity.\n\nDrug Class: Antithrombotic Agents\n\nOther Drugs in the Subclass (Primary Thrombocythemia): Hydroxyurea, Interferon alfa, Aspirin
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Anagrelide – Generic, Agrylin®
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Antithrombotic Agents
| null |
ThrombopoietinRecept.nxml
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Thrombopoietin Receptor Agonists
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2018-12-30
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The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches to activating the thrombopoietin receptor were sought.\n\nSeveral thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for raising platelet counts in persons with thrombocytopenia undergoing surgical procedures or other thrombocytopenic conditions. Eltrombopag, lusutrombopag and avatrombopag are peptide-like, small molecular weight agonists of the thrombopoietin receptor. These agents are given by mouth and result in significant increases in platelet counts in normal persons as well as patients with thrombocytopenia due to hematologic and liver diseases. Romiplostim, in contrast, is a recombinant polypeptide that binds to and activates the thrombopoietin receptor despite having no amino acid homology to native thrombopoietin. It also increases platelet counts in normal subjects as well as patients with chronic ITP but has not been associated with induction of anti-thrombopoietin antibodies.
| null | null | null | null |
Avatrombopag – Doptelet®
|
Hematologic Growth Factors
|
[
{
"cas_registry_number": "570406-98-3",
"molecular_formula": "C29-H34-Cl2-N6-O3-S2",
"name": "Avatrombopag"
},
{
"cas_registry_number": "496775-61-2",
"molecular_formula": "C25-H22-N4-O4",
"name": "Eltrombopag"
},
{
"cas_registry_number": "1110766-97-6",
"molecular_formula": "C29-H32-Cl2-N2-O5-S",
"name": "Lusutrombopag"
},
{
"cas_registry_number": "267639-76-9",
"molecular_formula": "Protein",
"name": "Romiplostim"
},
{
"cas_registry_number": "9014-42-0",
"molecular_formula": "Protein",
"name": "Thrombopoietin"
}
] |
Romidepsin.nxml
|
Romidepsin
|
2020-09-25
|
Romidepsin is an intravenously administered histone deacetylase inhibitor and antineoplastic agent that is approved for use in refractory or relapsed cutaneous and peripheral T cell lymphomas. Romidepsin is associated with modest rate of minor serum enzyme elevations during therapy but has not been linked to cases of clinically apparent liver injury, although it has been reported to cause reactivation of hepatitis B.
|
Romidepsin (roe" mi dep' sin) is an intravenously administered antineoplastic agent which acts by inhibition of histone deacetylases, thereby preventing removal of acetyl groups from histones. The accrual of acetyl groups on histones causes cell cycle arrest and apoptotic cell death. Malignant cells and particularly malignant T cells are particularly sensitive to the effects of inhibition of histone deacetylases. Romidepsin was initially isolated from a bacterium Chromobacterium violaceum and found to have antineoplastic activity. Elucidation of its molecular structure and analysis of its in vitro effects demonstrated that it was a histone deacetylase. Romidepsin has been evaluated as therapy of several malignancies and found to have greatest activity in T cell lymphomas. Romidepsin was approved for use in the United States in 2009 as monotherapy for refractory or relapsing cutaneous T cell lymphoma (CTCL) and indications were expanded in 2011 to include refractory or relapsing peripheral T cell lymphoma (PTCL). Romidepsin is available as a powder for reconstitution in 10 mg vials under the commercial name Istodax. The recommended dose is 14 mg/m2 given intravenously on days 1, 8 and 15 of a 28 day cycle. Side effects are common, but usually mild-to-moderate in severity, and include nausea, fatigue, fever, anemia, neutropenia, thrombocytopenia, constipation and rash. Side effects lead to early discontinuation in up to 15% of patients. Severe adverse events can include marked neutropenia, thrombocytopenia, serious infections, sepsis, tumor lysis syndrome and cardiac arrhythmias.
|
In clinical trials of romidepsin in patients with CTLC and PTLC, the rates of serum enzyme elevations during therapy ranged from 7% to 20%, but the abnormalities were usually transient and mild and did not require dose modifications. Serum ALT elevations above 5 times ULN occurred in 6% of patients. In the preregistration clinical trials of romidepsin, there were no reports of hepatitis, jaundice or clinically apparent liver injury among the treated subjects. Romidepsin has had limited clinical use, but there is no evidence that it is associated with significant liver injury.\n\nRomidepsin also has immunomodulatory activities and has been reported to cause reactivation of latent DNA viruses including Epstein-Barr, varicella zoster and hepatitis B virus. Reactivation of hepatitis B occurred in a patient who was initially negative for HBsAg, but reactive for anti-HBc and anti-HBs. Nevertheless, the clinical features of hepatitis B reactivation were mild and responded to oral antiviral therapy. In patients with EBV associated lymphoma, romidepsin has been associated with severe reactivation of EBV infection and acute hepatitis that can be severe and even fatal.\n\nLikelihood score: C (probable cause of clinically apparent liver injury, which can be due to reactivation of hepatitis B or EBV infection).
|
The reason why romidepsin might cause serum enzyme elevations is not known, but may be a direct toxicity to hepatocytes caused by inhibition of histone deacetylase or other enzyme activities. Romidepsin is metabolized in the liver by cytochrome P450 system, predominantly CYP 3A4 and is susceptible to drug-drug interactions. Reactivation of hepatitis B and EBV is likely due to the immunomodulatory actions of romidepsin.
|
Serum enzyme elevations during romidepsin therapy are usually mild and rarely dose limiting. Romidepsin should be held if ALT or AST values rise above 5 times the ULN and should be permanently discontinued if elevations exceed 20 times the ULN, or with the appearance of jaundice or symptoms of liver injury. There is no known cross sensitivity to hepatic injury among the different histone deacetylase inhibitors. Patients who are to receive romidepsin should be screened for evidence of hepatitis B and monitored carefully or given prophylaxis against HBV reactivation if they have evidence on ongoing or previous infection. Patients with active EBV infection should be treated with caution and with prophylaxis against reactivation.\n\nDrug Class: Antineoplastic Agents, Histone Deacetylase Inhibitors
|
Romidepsin – Istodax®
|
Antineoplastic Agents
| null |
Zolpidem.nxml
|
Zolpidem
|
2018-02-20
|
Zolpidem is a benzodiazepine receptor agonist that is used for the treatment of insomnia. Zolpidem has rarely been implicated in causing serum enzyme elevations and has not been reported to cause clinically apparent liver injury.
|
Zolpidem (zol' pi dem) is a non-benzodiazepine, benzodiazepine receptor agonist of the imidazopyridine class that acts by binding to the benzodiazepine (BZ) site on the GABA receptor complex, causing neural inhibition and helping to induce sleep. Zolpidem has selectivity for certain BZ receptor subtypes and does not have the neuromuscular relaxation or anticonvulsant effects of the standard benzodiazepines. Zolpidem has a short half life and rapid onset of action. In multiple placebo controlled trials, zolpidem was shown to decrease the latency to onset of sleep and improve perceived sleep quality with minimal next day residual somnolence or rebound insomnia after withdrawal. Zolpidem was approved for use in the United States in 1992 for the short term treatment of insomnia and is the most commonly prescribed medication for insomnia with more than 10 million prescriptions filled yearly. Zolpidem is available in 5 and 10 mg tablets generically and under the brand name Ambien. The recommended dose is 5 mg taken orally immediately before bedtime. Higher doses should be used with caution as they may result in next-morning impairment in motor activity that may affect driving. Zolpidem is also available in an extended release and in a low dose sublingual form (3.5 mg) for middle-of-the-night awakening. Like the other benzodiazepine receptor agonists, zolpidem is classified as a Schedule IV controlled substance (low potential for abuse and limited physical or psychological dependence). Side effects are uncommon, usually mild and may include headache, nausea, dizziness and drowsiness.
|
In multiple premarketing randomized controlled trials, zolpidem was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy. A single instance of clinically apparent liver injury has been reported. The onset of injury was 2 days after a single dose of zolpidem and was accompanied by abdominal pain, but no jaundice. The pattern of liver enzyme elevations was hepatocellular and the abnormalities were self-limited, although they seemed to recur on reexposure. Zolpidem is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4) and can cause drug-drug interactions, although such interactions are rare. Thus, zolpidem has not been linked to cases of liver injury with jaundice, but rarely may cause transient, mild-to-moderate serum enzyme elevations with or without symptoms.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nDrug Class: Sedatives and Hypnotics\n\nOther Drugs in the Subclass, Benzodiazepine Receptor Agonists: Eszopiclone, Zaleplon
| null | null |
Zolpidem – Generic, Ambien®
|
Sedatives and Hypnotics
| null |
Tofacitinib.nxml
|
Tofacitinib
|
2022-08-30
|
Tofacitinib is an oral, small molecule inhibitor of Janus kinases that is used to treat moderate-to-severe rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Tofacitinib is associated with transient and usually mild elevations in serum aminotransferase levels during therapy, but has yet to be linked to cases of clinically apparent acute liver injury.
|
Tofacitinib (tow" fa sye' ti nib) is an orally available, specific inhibitor of Janus-associated kinases (mainly JAK1 and JAK3) that is used to treat moderate-to-severe rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. The Janus kinases are critical steps in immune activation as well as in hematopoiesis. The immunomodulatory effects of tofacitinib led to its evaluation in several autoimmune conditions including rheumatoid arthritis and psoriasis. In multiple, randomized controlled trials, tofacitinib was found to improve symptoms and signs of severe rheumatoid arthritis and psoriatic arthritis when used alone or in combination with other disease modifying antirheumatologic drugs (DMARDs). Tofacitinib was approved for use in rheumatoid arthritis in the United States in 2012. Subsequently, indications were expanded to psoriatic arthritis and inflammatory bowel disease. The Janus kinase inhibitors including tofacitinib are also being evaluated as therapy of the COVID-19, focusing upon alleviating the hyperinflammatory stages of advanced COVID-19 infection. At present, indications for tofacitinib are limited to moderate-to-severe rheumatoid arthritis and active psoriatic arthritis after failure or intolerance to methotrexate or other non-biological DMARDs, juvenile idiopathic arthritis with a polyarticular course, and moderately to severely active ulcerative colitis after failure of tumor necrosis factor (TNF) inhibitors. Tofacitinib is available in tablets of 5 and 10 mg under the brand name Xeljanz. The recommended dose is rheumatoid arthritis and psoriatic arthritis is 5 mg twice daily. For patients with active ulcerative colitis, an induction dose of 10 mg twice daily is recommended for the first three months. More recently, an extended release formulation of tofacitinib (Xeljanz XR, 11 and 22 mg tablets) that allows for once daily dosing has been made available. Common side effects of tofacitinib are neutropenia, headaches, diarrhea, fatigue, hypertension and symptoms of upper respiratory tract infection. Severe adverse events may include severe infections, reactivation of latent tuberculosis or herpes zoster, gastrointestinal perforation, venous and arterial thromboses, and de novo malignancies including Epstein-Barr virus related lymphoproliferative disorder.
|
In large registration clinical trials, serum aminotransferase elevations occurred in 28% to 34% of tofacitinib treated subjects compared to 25% in comparator arms and 10% in placebo recipients. These elevations were typically mild and transient, but values above 3 times the upper limit of normal (ULN) occurred in 1% to 2% of patients on tofacitinib compared to less than 1% on placebo. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to tofacitinib. Since approval and more wide scale availability of tofacitinib, there have been no published reports of hepatotoxicity associated with its use but a proportion of patients do develop serum aminotransferase elevations which in some cases leads to drug discontinuation. While other Janus kinase inhibitors such as ruxolitinib have been associated with episodes of reactivation of hepatitis B, spontaneous reports of clinically apparent reactivation of hepatitis during tofacitinib therapy have not been reported. On the other hand, retrospective studies on patients with HBsAg and inactive liver disease who were treated with tofacitinib have been reported to develop rising levels of HBV DNA and modest elevations in serum aminotransferase levels without symptoms. In contrast, studies of patients with anti-HBc without HBsAg in serum have shown no evidence of HBV DNA rises and appearance of HBsAg. Thus, reactivation of hepatitis B during therapy can occur, although it is generally mild and self-limited in course. Whether reactivation of hepatitis B can arise after therapy of susceptible patients with tofacitinib for severe COVID-19 pneumonia is unknown, but there have been no such reports to date.\n\nLikelihood score: E* (suspected but unproven rare cause of clinically apparent liver injury with the potential to cause reactivation of hepatitis B).
|
The causes of serum enzyme elevations during tofacitinib therapy are not known. Tofacitinib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic or immunogenic intermediate. Because it is a substrate for CYP 3A4, tofacitinib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity. Tofacitinib is a potent immunomodulatory agent and appears to be capable of causing reactivation of hepatitis B.
|
Monitoring of serum aminotransferase levels is recommended for patients starting tofacitinib. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There are no data to suggest a cross reactivity in risk for hepatic injury between tofacitinib and other kinase inhibitors or biologic or nonbiologic DMARDs. Because tofacitinib is capable of inducing reactivation of hepatitis B, patients starting long term therapy with tofacitinib should be screened for HBsAg and anti-HBc. Patients with preexisting HBsAg in serum should undergo evaluation and prophylaxis against reactivation of HBV using potent oral antiviral agents, such as tenofovir or entecavir. Those with anti-HBc without HBsAg or HBV DNA should be monitored for evidence of infection and treated if there is de novo appearance of HBsAg or HBV DNA.\n\nDrug Class: Antirheumatic Agents, Protein Kinase Inhibitors, COVID-19 Drugs
|
Tofacitinib – Xeljanz®
|
Antirheumatic Agents
|
[
{
"cas_registry_number": "941678-49-5",
"molecular_formula": "C17-H18-N6",
"name": "Ruxolitinib"
},
{
"cas_registry_number": "477600-75-2",
"molecular_formula": "C16-H20-N6-O",
"name": "Tofacitinib"
}
] |
Acalabrutinib.nxml
|
Acalabrutinib
|
2021-03-21
|
Acalabrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of B cell malignancies including refractory mantle cell lymphoma and chronic lymphocytic leukemia. Acalabrutinib has been associated with mild-to-moderate serum enzyme elevations during therapy but has not been linked to instances of idiosyncratic acute liver injury, although it has been associated with cases of reactivation of hepatitis B which can be severe and even fatal.
|
Acalabrutinib (a kal" a broo' ti nib) is an orally available, small molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is an essential component in the B cell receptor signaling pathway. Inhibition of this pathway prevents B cell activation, differentiation and proliferation. Deficiency of BTK is the cause of X linked (Bruton’s) agammaglobulinemia, and B cell receptor signaling through BTK has been shown to be critical for proliferation and survival of malignant B lymphocytes in mantle cell lymphoma and chronic lymphocytic leukemia (CLL). Unlike ibrutinib, another BTK inhibitor, acalabrutinib has a high degree of specificity for BTK and has little or no activity against other tyrosine kinases. Acalabrutinib was approved for use in the United States as therapy for refractory mantle cell lymphoma in 2017 and for CLL and small lymphocytic lymphoma in 2019. It is under evaluation in other malignancies such as Waldenstrӧm’s macroglobulinemia, pancreatic and non-small cell lung cancer. Acalabrutinib is available in capsules of 100 mg under the brand name Calquence. The recommended dose is 100 mg twice daily. Side effects are common, but usually mild-to-moderate in severity; they include myelosuppression, fatigue, diarrhea, nausea, headache, arthralgia, myalgia, bruising and rash. Uncommon, but potentially serious side effects include severe bone marrow suppression, severe or opportunistic infections, bleeding episodes, hypertension, cardiac arrhythmias and secondary malignancies.
|
In open label clinical trials of acalabrutinib in patients with CLL and mantle cell lymphoma, serum aminotransferase elevations occurred in 19% to 23% of patients during therapy and rose to above 5 times ULN in 2% to 3%. These elevations were transient and resolved spontaneously but occasionally led to early drug discontinuation. Among the 610 patients treated with acalabrutinib in pre-registration trials, there were no instances of clinically apparent liver injury attributed to its use, but there was a single instance of acute liver failure and death due to reactivation of hepatitis B. Similar cases of reactivation have been reported with ibrutinib, another small molecule inhibitor of Bruton's tyrosine kinase. Experience with acalabrutinib has been limited and the frequency of clinically apparent liver injury and reactivation of hepatitis B are not known. The majority of cases have occurred in patients taking multiple immunosuppressive agents and not just acalabrutinib alone.\n\nLikelihood score: D (possible rare cause of reactivation of hepatitis B).
|
The mechanism by which acalabrutinib might cause liver injury is unknown but may be due to off-target inhibition of tyrosine kinases. Acalabrutinib is metabolized in the liver largely by the CYP 3A4 and is susceptible to drug-drug interactions with inhibitors or inducers of this enzyme reactivity. Reactivation of hepatitis B from acalabrutinib is probably the result of profound B cell suppression, which can lead to increases in viral replication, which can result in severe hepatitis upon immune reconstitution.
|
Liver injury due to acalabrutinib is generally mild and asymptomatic. Reactivation of hepatitis B, however, can result in severe hepatitis and even acute hepatic failure. Patients who are to receive B cell inhibitors such as acalabrutinib, ibrutinib, rituximab and usteokinumab should be screened for serologic markers of hepatitis B infection, including HBsAg and anti-HBc before starting chemotherapy, and those who are positive given prophylaxis against reactivation using oral antiviral agent with activity against HBV such as tenofovir or entecavir. Alternatively, patients can be monitored carefully for changes in HBV DNA levels during therapy. If HBV DNA levels appear de novo or increase significantly (by 10-fold or greater; at least one log increase in HBV DNA), initiation of antiviral therapy is appropriate. Therapy should be continued for at least six months after immunosuppressive therapy has been completed.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors
|
Acalabrutinib – Calquence®
|
Antineoplastic Agents
|
[
{
"cas_registry_number": "1420477-60-6",
"molecular_formula": "C26-H23-N7-O2",
"name": "Acalabrutinib"
},
{
"cas_registry_number": "936563-96-1",
"molecular_formula": "C25-H24-N6-O2",
"name": "Ibrutinib"
}
] |
Selegiline.nxml
|
Selegiline
|
2017-07-21
|
Selegiline is an inhibitor of monamine oxidase used in the treatment of depression and as adjunctive therapy in combination with levodopa and carbidopa in the therapy of Parkinson disease. Selegiline has been associated with a low rate of serum enzyme elevations during treatment, but has not been linked to instances of clinically apparent acute liver injury.
|
Selegiline (se le' ji leen) is a specific inhibitor of monamine oxidase (MAO) type B, which is a major enzyme in the pathway of dopamine and levodopa metabolism. As a result, selegiline results in an increase in the bioavailability of levodopa, enhancing and increasing the duration of its effects in Parkinson disease. Selegiline is also an antidepressant, its mechanism of action being inhibition of dopamine reuptake from the synaptic cleft. Selegiline was approved for use in the United States in 2006, the first MAO-B inhibitor approved for use in the therapy of Parkinson disease as an adjunct to levodopa therapy. Selegiline is available in capsules and tablets of 5 mg generically and under the brand name Eldepryl, the typical dose being 10 mg daily in two divided doses. It is also available in oral disintegrating tablets of 1.25 mg under the brand name Zelapar, which is given once or twice daily. Transdermal patches of selegiline in amounts of 6, 9 and 12 mg/24 hours are available under the brand name Emsam for treatment of depresssion, the usual dose being 6 to 12 mg daily. Common side effects include headache, nausea, dizziness, agitation, delusions, insomnia, orthostatic hypotension, dry mouth, headache and gastrointestinal upset – most of which are attributable to enhanced dopaminergic effects. In higher doses, selegiline can also inhibit MAO-A and, similar to the nonspecific MAO inhibitors, cause increased susceptibility to dietary tyramine inducing hypertensive crises (“cheese effect”).
|
Selegiline has been reported to cause serum enzyme elevations in up to 40% of patients treated long term. Although the abnormalities were usually mild and self-limiting, they were persistent with continuation of treatment in some patients, ultimately requiring drug discointuation. Selegiline has not been implicated in cases of clinically apparent acute liver injury, but such instances have been reported with other less specific MAO inhibitors.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).
|
Selegiline is extensively removed from the blood by the liver (first pass metabolism) and undergoes hepatic conjugation and elimination. The pathways of selegiline metabolism have not been well defined.
|
The only liver abnormalities that have attributed to selegiline have been mild and self-limiting elevations in serum enzymes. No instances of acute hepatitis, acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been linked to selegiline use.\n\nDrug Class: Antiparkinson Agents\n\nOther Drugs in the Subclass, Selective MAO-B Inhibitors: Rasagiline, Safinamide
|
Selegiline – Generic, Atapryl®, Eldepryl®
|
Antiparkinson Agents
| null |
Chlorzoxazone.nxml
|
Chlorzoxazone
|
2017-01-30
|
Chlorzoxazone is a centrally acting muscle relaxant commonly used for low back pain. Chlorzoxazone has been linked to rare instances of acute liver injury, a few of which have been fatal.
|
Chlorzoxazone (klor zox' a zone) acts centrally rather than directly on muscles to relieve muscle spasms, either through its sedative effects or other unknown mechanisms. Chlorzoxazone is indicated for therapy of low back pain and muscle spasms, although its overall efficacy is considered only fair. Chlorzoxazone was approved for use in the United States in 1958 and is still widely used. It is available in various generic forms as well as under the brand names of Parafon Forte and Remular in tablets of 250 or 500 mg. The usual recommended dose in adults is 250 to 750 mg orally three to four times daily, reducing the dose to lowest effective level once a response occurs. Chlorzoxazone is typically given for 1 to 4 weeks only. Common side effects of chlorzoxazone include dizziness, drowsiness, headache, fatigue and tremor.
|
There have been no adequate prospective studies demonstrating the rates of ALT or AST elevations on chlorzoxazone therapy. Rare instances of clinical apparent liver disease possibly attributable to chlorzoxazone have appeared, including fatal cases. Such cases must be very rare, as this agent is widely used. While case reports have been few, in many instances chlorzoxazone was clearly implicated; furthermore, a related muscle relaxant with similar structure (zoxazolamine) was withdrawn from use in 1961, largely because of hepatotoxicity. The usual latency period is 1 to 4 weeks and the pattern of disease typically hepatocellular with marked elevations in ALT levels and jaundice, with minimal increases in alkaline phosphatase. Cholestatic enzyme elevations after exposure to chlorzoxazone have also been described. Allergic manifestations (rash and fever) are common, particularly in cases with a short latency (Case 1); autoantibodies are rare. Recovery is rapid once chlorzoxazone is stopped, but fatal cases have been reported, with disease progression despite early discontinuation of the agent (Case 2). There is rapid recurrence of injury with reexposure, often accompanied by fever.\n\nLikelihood score: B (Highly likely cause of clinically apparent liver injury).
|
The cause of acute hepatic injury from chlorzoxazone is unknown, but is clearly idiosyncratic and likely due to hypersensitivity.
|
The idiosyncratic liver injury due to chlorzoxazone ranges from mild, self-limited hepatitis to severe, protracted liver injury leading to death or need for liver transplantation. Rechallenge leads to rapid return of hepatic injury and should be avoided. No cross reactivity with other muscle relaxants has been identified.\n\nDrug Class: Muscle Relaxants
|
Chlorzoxazone – Generic, Parafon Forte®
|
Autonomic Agents: Muscle Relaxants, Central
| null |
SerotoninRcptAgonist.nxml
|
Serotonin Receptor Agonists (Triptans)
|
2018-02-10
|
The triptans are a group of serotonin receptor agonists that are useful in the therapy of vascular headaches and migraine. The triptans are generally used in low doses for a limited period of time and have not been associated with serum enzyme elevations, but some have been implicated in rare instances of clinically apparent, acute cholestatic hepatitis.
|
The triptans (trip' tans) are synthetic serotonin receptor agonists that are used in the therapy of migraine and vascular headache. Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine that has multiple actions, acting as a neurotransmitter and bioactive amine. The diversity of actions of serotonin is partially due to the multitude of different serotonin receptors and their tissue location. There are at least 15 classes of serotonin receptors which have overlapping actions, but variable distribution and intracellular pathways of response to stimulation and inhibition. The triptans are serotonin agonists with high affinity for the 5-HT1B and 5-HT1D receptors which are found on smooth-muscle cells of blood vessels. Simulation of the 5-HT1D receptor results in constriction of intracranial blood vessels. The triptans may also block the release of vasoactive peptides from perivascular trigeminal neurons through their action at presynaptic 5-HT1D receptors on nerve terminals. Regardless, the triptans have been found to be effective in preventing or aborting migraine headaches with shortening of the period of pain and symptoms. The triptans are considered “first line” agents for patients whose vascular headaches do not reliably respond to conventional analgesics. They generally have a more rapid onset of action and fewer side effects than the ergot alkaloids. Seven triptans are approved for use in the United States including almotriptan (al" moe trip' tan), eletriptan (el" e), forvatriptan (froe" va), naratriptan (nar"' a), rizatriptan (rye" za, sumatriptan (soo" ma) and zolmitriptan (zole" ma). Generic formulations are available for most agents. The short acting triptans include sumatriptan, almotriptan, eletriptan, rizatriptan and rolmitriptan and generally provide relief within 30 to 60 minutes. The longer activing oral triptans include naratriptan and frovatriptan which have a slower onset of action but may be better tolerated. Intranasal formulations may have a more rapid onset of action as do subcutaneous administered forms. Brand names, year approved, tablet or wafer size, usual dose and maximum daily recommended doses are shown in the Table.\n\n* Also available as nasal spray, transdermal patch and solution for injection.\n\n** Also available in orally disintegrating tablets and as nasal spray.\n\nEarly therapy is recommended in patients with recurrent migraine, and typically the dose is repeated in 2 to 4 hours if relief has not occurred. However, the total dosage should be limited to 2 to 3 doses per 24 hour period. Parenteral and intranasal administration is helpful in patients with nausea and vomiting. Chronic, long term use of triptans to prevent migraines has been studied, but is not currently approved. The seven triptans have similar side effect profiles which include “triptan sensations” characterized by tightening of the throat, chest, neck and limbs with paresthesias and hot or cold sensations. Triptans may also cause flushing, headache, somnolence and fatigue. Rare but potentially severe adverse events include medication overuse syndrome, cerebrovascular and cardiovascular events such as myocardial infarction and stroke, serotonin syndrome and anaphylaxis.
|
In large prospective controlled trials, the different triptans have not been associated with serum enzyme elevations or hepatotoxicity; however, the frequency of monitoring in most studies was limited and rates of ALT elevations not reported. There have been rare individual reports of cholestatic hepatitis after the use of triptans, largely associated with zolmitriptan. Typically, the onset of injury was within 1 to 2 weeks of taking several doses of the zolmitriptan for a protracted and severe migraine attack. Recurrent jaundice with intermittent therapy has also been reported (Case 1). The pattern of serum enzyme elevations was mixed or cholestatic, and recovery was complete within 1 to 2 months. Allergic manifestations (rash, fever, eosinophilia) were not present and autoantibodies did not develop.\n\nLikelihood score, zolmitriptan: D (probable rare cause of clinically apparent liver injury).\n\nLikelihood score, rizatriptan: E* (suspected but unproven cause of liver injury).\n\nLikelihood score, other triptans: E (unlikely cause of clinically apparent liver injury).
|
The cause of idiosyncratic liver injury after triptan use is not known, but is likely due to a toxic metabolite causing an acute, cholestatic hepatitis-like injury. An intriguing hypothesis is that the serotonin agonist activity causes biliary dyskinesis and functional obstruction.
| null |
Almotriptan – Generic, Almogran®, Axert®
|
Migraine Headache Agents
|
[
{
"cas_registry_number": "154323-57-6",
"molecular_formula": "C17-H25-N3-O2-S",
"name": "Almotriptan"
},
{
"cas_registry_number": "177834-92-3",
"molecular_formula": "C22-H26-N2-O2-S.Br-H",
"name": "Eletriptan"
},
{
"cas_registry_number": "158930-17-7",
"molecular_formula": "C14-H17-N3-O.C4-H6-O4.H2-O",
"name": "Frovatriptan"
},
{
"cas_registry_number": "121679-13-8",
"molecular_formula": "C17-H25-N3-O2-S",
"name": "Naratriptan"
},
{
"cas_registry_number": "144034-80-0",
"molecular_formula": "C15-H19-N5",
"name": "Rizatriptan"
},
{
"cas_registry_number": "103628-46-2",
"molecular_formula": "C14-H21-N3-O2-S",
"name": "Sumatriptan"
},
{
"cas_registry_number": "139264-17-8",
"molecular_formula": "C16-H21-N3-O2",
"name": "Zolmitriptan"
}
] |
Thioguanine.nxml
|
Thioguanine
|
2017-08-17
|
Thioguanine (also referred to as 6-thioguanine and as tioguanine) is a purine analogue that is used in the therapy of acute and chronic myelogenous leukemias. Thioguanine therapy is associated with minor, usually transient and asymptomatic elevations in serum aminotransferase levels and has also been linked to rare instances of cholestatic acute liver injury and to chronic liver injury, resulting in portal hypertension due to nodular regenerative hyperplasia.
|
Thioguanine (thye" oh gwa' neen) is a thiopurine, a purine analogue and antimetabolite. It is a derivative of mercaptopurine (2-amino-6-mercaptopurine) and, like its parent molecule, inhibits purine metabolism, thus blocking DNA, RNA and subsequent protein synthesis. Thioguanine also has antiinflammatory activity. Thioguanine was approved for use in the United States in 1966 and is commonly used in the therapy of acute and chronic myelogenous (nonlymphocytic) leukemias. Thioguanine has also been used off-label to treat autoimmune diseases as a steroid sparing agent. Thioguanine is available generically and under the brand name of Tabloid as tablets of 40 mg. The usual dose is 1 to 3 mg per kilogram or 40 to 120 mg daily and it is typically given long term. Common side effects include nausea, abdominal upset, rash, aphthous ulcers and dose related bone marrow suppression.
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As with other thiopurines, thioguanine has been associated with several forms of hepatotoxicity, including mild, transient and asymptomatic rises in serum aminotransferase levels, an acute hepatic injury developing during the first year of starting therapy, and a chronic hepatic injury marked by variable degrees of peliosis hepatis, veno-occlusive disease and/or nodular regenerative hyperplasia. Chronic injury typically arises 1 to 5 years after starting thioguanine and can present insidiously with signs and symptoms of portal hypertension.\n\nMild serum aminotransferase elevations can occur during thioguanine therapy, particularly with high doses during the first 12 weeks of therapy. These elevations are generally asymptomatic, benign and self-limited, resolving rapidly either with stopping therapy, decreasing the dose and often even with continuing treatment without modifications. ALT elevations during thioguanine therapy may be due to a direct toxic effect of the drug; ALT elevations as well as myelotoxicity have been linked to higher levels of methyl-mercaptopurine, a product of one of the metabolic pathways of thioguanine metabolism.\n\nThe acute hepatic injury due to thioguanine usually presents with fatigue and jaundice and with a mixed hepatocellular-cholestatic pattern of serum enzyme elevations after 2 to 12 months of starting therapy. Rash, fever and eosinophilia are uncommon and autoantibodies are generally not found. Liver biopsy typically shows intrahepatic cholestasis with focal hepatocellular necrosis and scant inflammation. The liver injury usually resolves rapidly on stopping, but prolonged cholestasis has been reported and some cases have been fatal. This form of hepatotoxicity appears to be idiosyncratic and a class effect of the thiopurines, although more typical of azathioprine than thioguanine or mercaptopurine.\n\nThe chronic thioguanine hepatotoxicity typically presents with fatigue and signs and symptoms of portal hypertension with mild liver enzyme abnormalities and minimal jaundice arising 6 months to many years after starting thioguanine. Liver biopsy shows nodular regenerative hyperplasia and varying amounts of sinusoidal dilation and central vein injury. This syndrome can progress to hepatic failure, particularly if thioguanine is continued, but improvement on stopping therapy is typical. The onset of this syndrome may be acute with abdominal pain and ascites, in which situation liver biopsy usually shows sinusoidal dilation, central congestion and injury to sinusoidal endothelial cells suggestive of veno-occlusive disease, which is currently referred to as sinusoidal obstructive syndrome. Typically, serum aminotransferase levels and alkaline phosphatase levels are minimally elevated, even in the presence of hyperbilirubinemia and other manifestations of hepatic dysfunction and portal hypertension. Many cases of nodular regenerative hyperplasia due to the thiopurines present initially with thrombocytopenia of unknown cause, and a gradual decrease in platelet count is probably the most reliable marker for the development of non-cirrhotic portal hypertension. Among the thiopurines, this syndrome is more frequent with thioguanine than azathioprine, and appears to be least frequent with mercaptopurine.\n\nFinally, long term therapy with thiopurines has been implicated in leading to the development of malignancies, including hepatocellular carcinoma (HCC) and hepatosplenic T cell lymphoma (HSTCL). Both of these complications are rare, but have been reported in several dozen case reports and small case series, most frequently with azathioprine. In neither instance, has the role of thiopurine therapy in causing the malignacies been proven, and similar cases have been described in patients with autoimmune conditions or after solid organ transplantation who have not received thiopurines. Hepatocellular carcinoma typically arises after years of thiopurine therapy and in the absence of accompanying liver disease (although sometimes with focal hepatic glycogenosis). The HCC is most frequently found on an imaging study done of an unrelated condition. The prognosis is more favorable than that of HCC associated with cirrhosis. Hepatosplenic T cell lymphoma has been reported largely among young men with inflammatory bowel disease and long term immunosuppression with a thiopurine with or without anti-tumor necrosis factor therapy. The typical presentation is with fatigue, fever, hepatosplenomegaly and pancytopenia. The diagnosis is made by bone marrow or liver biopsy showing marked infiltration with malignant T cells. HSTCL is poorly responsive to antineoplastic therapy and has a high mortality rate.\n\nLikelihood score: A (well known cause of clinically apparent liver injury).
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The mechanism by which thioguanine causes idiosyncratic acute liver injury is not known, but is likely due to an immunological response to a metabolic byproduct of its metabolism. Thioguanine undergoes extensive hepatic metabolism to 6-mercaptopurine and thereafter to other thiopurines via three different pathways. Patients with deficiency in thiopurine methyltransferase which mediates one of these metabolic pathways have a higher rate of complications of thioguanine use, particularly bone marrow suppression. but do not appear to be at higher rise of acute cholestasis or nodular regeneration. The cause of the nodular regenerative hyperplasia that develops after long term thioguanine therapy is not well defined, but it appears to be due to injury to endothelial cells that causes variable degrees of venous outflow obstruction or vascular damage that promotes the nodular transformation. This form of injury is more likely to be a direct toxic effect of the antimetabolite.
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The serum aminotransferase elevations that occur during thioguanine therapy may improve spontaneously or with dose reduction and generally resolve rapidly with discontinuation. In patients who have aberrant metabolism of thiopurines to 6-methylmercaptopurine (6-MMP) as shown by elevated plasma levels, lowering the dose of thiopurine and adding allopurinol (100 mg daily) may lower 6-MMP levels, reverse aminotransferase elevations while maintaining 6-thioguanine (6-TGN) levels and clinical response. Both the acute cholestasis and the chronic nodular regeneration caused by thioguanine improve upon stopping the medication, but instances of progression to hepatic failure despite discontinuation of thioguanine have been reported with both syndromes. Rechallenge with thioguanine usually results in recurrence of the injury (within days to weeks) and should be avoided. Some patients have tolerated switching therapy to mercaptopurine or azathioprine, but substitution with a structurally unrelated antimetabolite may be more appropriate.\n\nDrug Class: Antineoplastic Agents, Antimetabolites\n\nOther Drugs in the Subclass, Purine Analogues: Azathioprine, Cladribine, Clofarabine, Fludarabine, Mercaptopurine, Nelarabine, Pentostatin\n\nSee also: Transplant Drugs\n\nOther Drugs in the Subclass, Purine Analogues/Thiopurines: Azathioprine, Mercaptopurine
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Thioguanine – Generic, Tabloid®
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Antineoplastic Agents
| null |
disclaimer.nxml
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Disclaimer
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2019-09-03
| null | null | null | null | null | null | null | null |
Famotidine.nxml
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Famotidine
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2018-01-25
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Famotidine is a histamine type 2 receptor antagonist (H2 blocker) which is commonly used for treatment of acid-peptic disease and heartburn. Famotidine has been linked to rare instances of clinically apparent acute liver injury.
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Famotidine (fam oh' ti deen) was the third H2 blocker introduced into clinical practice in the United States and is a commonly used agent for treatment of duodenal and gastric ulcer and gastroesophageal reflux disease. The H2 blockers are specific antagonists of the histamine type 2 receptor, which is found on the basolateral (antiluminal) membrane of gastric parietal cells. The binding of famotidine to the H2 receptor results in inhibition of acid production and secretion, and improvement in symptoms and signs of acid-peptic disease. The H2 blockers inhibit an early, “upstream” step in gastric acid production and are less potent that the proton pump inhibitors, which inhibit the final common step in acid secretion. Nevertheless, the H2 blockers inhibit 24 hour gastric acid production by about 70% and are most effective in blocking basal and nocturnal acid production. Famotidine was first approved for use in the United States in 1986 and more than 3 million prescriptions for it are filled yearly. Famotidine is now available both by prescription and over-the-counter. The listed indications for famotidine are duodenal and gastric ulcer disease, gastroesophageal reflux and prevention of stress ulcers. Famotidine is available in tablets of 20 and 40 mg in several generic forms and in parenteral forms under the brand name Pepcid. Over-the-counter formulations are typically gelcaps or tablets of 10 or 20 mg. Liquid solutions are also available for intravenous use. The typical recommended dose for therapy of peptic ulcer disease in adults is 40 mg once daily for 4 to 8 weeks and maintenance therapy of 20 mg daily. Lower, chronic and intermittent doses of famotidine are used for therapy of heartburn and indigestion. Side effects are uncommon, usually minor, and include diarrhea, constipation, fatigue, drowsiness, headache and muscle aches. Famotidine is metabolized by the hepatic cytochrome P450 system, but has minimal inhibitory effects on the metabolism of other drugs, making it less likely to cause drug-drug interactions than cimetidine.
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Chronic therapy with famotidine has been associated with minor elevations in serum aminotransferase levels in 1% to 4% of patients, but similar rates were reported in placebo recipients. The ALT elevations are usually asymptomatic and transient, and may resolve without dose modification. Rare instances of clinically apparent liver injury have been reported in patients receiving famotidine, but few cases have been reported and clinical characteristics in published cases have varied in the time to onset and pattern of injury. Onset has ranged from 1 to 14 weeks and serum enzyme pattern has typically been hepatocellular. The injury resolves within 4 to 12 weeks of stopping famotidine. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation.\n\nLikelihood score: C (probable rare cause of clinically apparent liver injury).
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Famotidine is metabolized by the microsomal P450 drug metabolizing enzymes and injury may be the result of its activation to a toxic intermediate.
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The hepatic injury caused by famotidine is usually rapidly reversible with stopping the medication (Case 1). Famotidine has not been definitively linked to cases of acute liver failure, chronic hepatitis, prolonged cholestasis or vanishing bile duct syndrome. The results of rechallenge have not been reported. There appears to be cross reactivity in hepatic injury with cimetidine (Case 2). If acid suppression is required, use of an unrelated proton pump inhibitor is probably prudent for patients with clinically apparent famotidine induced liver injury.\n\nThe H2 receptor blockers include cimetidine, famotidine, nizatidine, and ranitidine. Combined general references on the H2 receptor blockers are given together after this overview section, while specific references are provided in the separate section on each drug. See also the Proton Pump Inhibitors.\n\nDrug Class: Antiulcer Agents\n\nOther Drugs in the Subclass, Histamine Type 2 Receptor Antagonists: Cimetidine, Nizatidine, Ranitidine
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Famotidine – Generic, Pepcid®
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Antiulcer Agents
| null |
Oliceridine.nxml
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Oliceridine
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2024-07-05
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Oliceridine is an intravenously administered, synthetic opioid that is used to treat moderate-to-severe pain not responsive to nonsteroidal antiinflammatory agents. Oliceridine is associated with a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent liver injury.
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Oliceridine (oh” li ser’ i deen) is an intravenously administered, synthetic opioid approved for use in moderate-to-severe acute pain in adults after surgery or painful procedures. Oliceridine is an agonist of the μ-opioid receptor with a potency similar to that of morphine, but with post-receptor actions that are biased to G protein signaling and with less β-arrestin2 recruitment and receptor internalization. This bias in μ-opioid receptor agonism was associated with fewer adverse effects in animal models, but this selectivity has been less well shown in humans. In several controlled trials, intravenous oliceridine was shown to be superior to placebo in controlling postoperative pain, but responses were numerically less than with morphine. Oliceridine was approved in the United States in 2020 for management of adults with acute pain severe enough to require intravenous opioid analgesia. Oliceridine is available in 1 and 2 mg single dose vials (1 mg/mL) and as a 30 mg single patient use vial of 30 mL (1 mg/mL) for patient-controlled analgesia. The common adverse events of oliceridine are similar to other opiates and include nausea, vomiting, headache, dizziness, constipations, pruritus, and respiratory depression with hypoxia. The gastrointestinal adverse events appear to be less frequent and milder with oliceridine than with morphine. Severe adverse events include serious, life threatening or fatal respiratory depression particularly in patients with chronic pulmonary disease, the elderly, debilitated patients, and those on other CNS depressants. High doses of oliceridine may cause prolongation of the QTc interval and dosing should be limited to less than 27 mg daily. Oliceridine, like other opioid drugs, has a boxed warning for addiction, abuse, and misuse. Use of oliceridine during pregnancy may cause fetal harm and can result in neonatal opioid withdrawal syndrome.
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Serum ALT elevations developed in 1% to 3% of patients receiving oliceridine and in a similar proportion (2.4%) receiving morphine after abdominal surgery. However, the aminotransferase elevations were not associated with jaundice and were usually considered unrelated to therapy. Since approval of oliceridine, there have been no published reports of clinically apparent liver injury attributed to its use.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).
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Oliceridine like other opioid analgesics has not been associated with significant liver injury. The reasons for its lack of hepatotoxicity may relate to the short duration of therapy and the low doses used. Oliceridine is metabolized in the liver predominantly by cytochrome P450 enzymes (CYP 2D6 and 3A4).
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The product label for oliceridine does not recommend screening or monitoring for routine liver tests before or during therapy.\n\nDrug Class: Opioids, Opioid Antagonists\n\nOther Drugs in this Class: Alfentanil, Fentanyl, Morphine, Remifentanil, Sufentanil
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Oliceridine – Olinvyk®
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Opioids
| null |
Eplerenone.nxml
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Eplerenone
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2021-10-13
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Eplerenone is an aldosterone receptor antagonist and potassium-sparing diuretic used in the therapy of hypertension. Eplerenone therapy has been associated with transient elevations in serum aminotransferase levels, but has yet to be linked to cases of clinically apparent drug induced liver disease.
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Eplerenone (e pler' e none) is a competitive antagonist of aldosterone at the mineralocorticoid receptor. The aldosterone receptor in the late distal tubules and collecting ducts of the kidneys induces sodium reabsorption and potassium excretion in the distal tubule. Inhibition of this receptor promotes a sodium diuresis, but maintains body potassium levels. Eplerenone has a higher affinity for the aldosterone receptor than spironolactone and is claimed to have fewer anti-androgenic effects (gynecomastia, hair loss). However, the two molecules are structurally quite similar. Eplerenone was approved for use in the United States in 2002 for treatment of hypertension and later for improving survival of stable patients with heart failure after myocardial infarction. Eplerenone is available in 25 and 50 mg tablets generically and under the brand name of Inspra. The typical dose of eplerenone is 25 or 50 mg once daily initially, with modification of the dose based upon blood pressure response and tolerance, maintenance doses ranging from 25 to 100 mg daily in one or two divided doses. Eplerenone is well tolerated and the most common side effects are hyperkalemia and increases in serum creatinine.
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Eplerenone therapy has been associated with a low rate of serum aminotransferase elevations which are typically mild and transient. ALT elevations of greater than 3 times the ULN occurred in 0.7% and greater than 5 times in 0.2% of eplerenone treated compared to 0.3% and 0.3% of placebo treated subjects. Idiosyncratic, clinically apparent liver injury from eplerenone has yet to be reported. The similarity in structure to spironolactone suggests that it may share susceptibility to the acute liver injury reported rarely with that agent.\n\nLikelihood score: E* (unproven but suspect rare cause of clinically apparent liver injury).
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Eplerenone is metabolized in the liver by the cytochrome P450 system (CYP 3A4) and hepatic reactions may be generated by intermediates in its metabolism.
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The mild serum aminotransferase elevations that have been reported with eplerenone resolved rapidly on discontinuation and in some instances resolved even with drug continuation. While yet unproven, cross reactivity to the liver injury that can occur with spironolactone should be assumed.\n\nDrug Class: Diuretics, Potassium-Sparing Diuretics\n\nOther Drugs in the Subclass: Amiloride, Spironolactone, Triamterene
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Eplerenone – Generic, Inspra®
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Diuretics
| null |
LoopDiuretics.nxml
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Loop Diuretics
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2021-10-13
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The loop diuretics are potent and widely used agents in the therapy of edematous states and congestive heart failure and less commonly for hypertension. Clinically apparent acute liver injury due to the loop diuretics is exceeding rare, if it occurs at all.
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The loop diuretics act by inhibition of the sodium-potassium-chloride symporter present in the thick ascending limb of the loop of Henle causing an inhibition of sodium reuptake. The increase in delivery of sodium to the distal convoluted loop overwhelms its capacity for sodium reabsorption and a brisk sodium diuresis ensues. The loop diuretics are grouped together because of shared mechanism of action, but they have distinct chemical structures. The loop diuretics are more potent than the typical thiazide diuretics and usually have a shorter duration of action. As a result, the loop diuretics are used more for the therapy of edema than long term therapy of hypertension. Common and shared side effects of the loop diuretics include dizziness, headache, gastrointestinal upset, hyponatremia, hypokalemia and dehydration. Uncommon but potentially severe adverse events include profound electrolyte and water loss, dehydration leading to hypotension and syncope, electrolyte depletion with hypokalemia, hypomagnesemia, and hyponatremia, increases in serum creatinine and uric acid with worsening of renal failure and precipitation of hepatic encephalopathy in patients with cirrhosis, hyperuricemia, gout, ototoxicity, thrombocytopenia and hypersensitivity reactions.\n\nFurosemide (fure oh' se mide) was the first loop diuretic to be approved in the United States (1966) and is still widely used with more than 37 million prescriptions filled yearly. Furosemide is available in tablets of 20, 40 and 80 mg in generic forms and under the brand name Lasix. Furosemide is also available as an oral solution and as a liquid solution for injection. The usual adult dose of furosemide is 20 to 320 mg daily, given in one to three divided doses.\n\nEthacrynic (eth a krin' ik) acid was the second loop diuretic to be approved for use in the United States (1967), but is now rarely used; it remains available in 25 mg tablets and a solution for intravenous use generically and under the brand name Edecrin. The usual oral adult dose is 25 to 100 mg in one to three divided doses daily.\n\nBumetanide (bue met' a nide) is a potent loop diuretic that was approved for use in the United States in 1983 and continues to be used for the treatment of edema. Bumetanide is available as tablets of 0.5, 1 and 2 mg in generic forms and under the trade name of Bumex as well as a solution for parenteral administration. The usual oral adult dose is 0.5 to 2 mg once daily.\n\nTorsemide (tor' se mide) was approved for use in edema in the United States in 1993 and is still in common use used for both edema and hypertension. Torsemide is available in tablets of 5, 10, 20 and 100 mg in generic forms and under the brand name of Demadex. Solutions are available for intravenous use as well. The usual oral adult dose is 5 to 20 mg once daily.
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Use of the loop diuretics has not been associated with an increased rate of serum aminotransferase elevations. There have been only rare, reported cases of clinically apparent liver injury associated with loop diuretics and most of these reports were not very convincing. Interestingly, furosemide causes a direct hepatotoxicity in mice and has been used as an animal model of drug induced liver injury. This injury does not appear to occur in humans. Instances of liver injury in patients on furosemide usually present with ischemic hepatitis (shock liver) caused by heart failure with diuretic induced dehydration and hypotension. Thus, idiosyncratic, clinically apparent liver injury from the loop diuretics must be exceeding rare, if it occurs at all.\n\nLikelihood score, all loop diuretics: E (unlikely causes of clinically apparent liver injury).
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The cause of the rare occurrence of clinically apparent liver injury associated with the loop diuretics is not known. These agents are metabolized minimally by the liver and generally have rapid renal excretion.
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Cases of clinically apparent liver injury due to the loop diuretics have been too few to characterize their severity and course. There have been no published instances of acute liver failure or chronic liver injury attributed to any of the loop diuretics. Cross reactivity among the four agents is unlikely because of the variability of their chemical structure.\n\nDrug Class: Diuretics
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Bumetanide – Generic, Bumex®
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Diuretics
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[
{
"cas_registry_number": "28395-03-1",
"molecular_formula": "C17-H20-N2-O5-S",
"name": "Bumetanide"
},
{
"cas_registry_number": "58-54-8",
"molecular_formula": "C13-H12-Cl2-O4",
"name": "Ethacrynic Acid"
},
{
"cas_registry_number": "54-31-9",
"molecular_formula": "C12-H11-Cl-N2-O5-S",
"name": "Furosemide"
},
{
"cas_registry_number": "56211-40-6",
"molecular_formula": "C16-H20-N4-O3-S",
"name": "Torsemide"
}
] |
Apalutamide.nxml
|
Apalutamide
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2023-03-15
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Apalutamide is a third generation, oral nonsteroidal antiandrogen used to treat nonmetastatic castration-resistant prostate cancer. Apalutamide is associated with a low rate of serum enzyme elevation during therapy but has not been linked to cases of clinically apparent liver injury with jaundice.
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Apalutamide (a pa lut' a mide) is a small molecule androgen receptor antagonist which binds to the intracellular receptor and prevents its translocation to the nucleus and subsequent DNA binding, thereby blocking its activity. Therapy with apalutamide lowers residual testosterone levels after surgical castration in men with prostate cancer and has been shown to prolong metastasis free survival in men with castration-resistant prostate cancer with rising levels of prostate-associated antigen (PSA) without measurable metastatic disease. Apalutamide was approved for use in the United States in 2018 and current indications include metastatic, castration-sensitive prostate cancer and non-metastatic castration-resistant prostate cancer. Apalutamide is available as tablets of 60 and 240 mg under brand name Erleada. The recommended initial dose is 240 mg daily with subsequent dose reduction for intolerance. It should be administered with a gonadotropin-releasing hormone (GnRH) analog or after bilateral orchiectomy to insure optimal androgen suppression. Common side effects include symptoms of androgen deficiency including fatigue, diarrhea, nausea, anorexia, weight loss, constipation, joint and muscle pain, hot flushes, headaches, dizziness, and edema. Rare, but potentially serious side effects associated with long term therapy include seizures, osteoporosis, falls, bone fractures, severe cutaneous adverse events, embryo-fetal toxicity, and cardiovascular events.
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In prelicensure controlled trials of apalutamide, serum aminotransferase elevations were uncommon and generally transient and mild, not requiring dose modification. Clinically apparent liver injury with jaundice attributable to apalutamide was not reported in the preregistration trials and is not mentioned as an adverse event in the product label. Since the approval and general clinical use of apalutamide, there have been no publications or descriptions of the clinical features of hepatotoxicity with jaundice associated with its use. The first and second generation androgen receptor blockers, flutamide, nilutamide, and bicalutamide, have all been linked to instances of hepatitis-like liver injury with jaundice that can be severe and even fatal. However, such cases have not been described with apalutamide and other third generation androgen receptor antagonists. Thus, clinically apparent liver injury due to apalutamide must be rare, if it occurs at all.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).
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The possible cause of liver injury due to apalutamide therapy is unknown. While first and second generation antiandrogens have been implicated in causing liver injury, the more potent third general factors have not. Apalutamide is extensively metabolized in the liver predominantly by CYP 2C8 and 3A and is an inducer of CYP 3A4. While coadministration of apalutamide with substrates of CYP 3A4 and with modulators of CYP 2C8 and 3A4 may result in drug-drug interactions, the effects are relatively modest.
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The liver injury linked to apalutamide therapy has been generally mild, consisting of transient and asymptomatic elevations in serum aminotransferase levels and rarely requiring dose modification or discontinuation. Apalutamide has not been linked to cases of acute liver failure, chronic hepatitis or vanishing bile duct syndrome. There is no information on cross sensitivity to hepatic injury between apalutamide and other antiandrogens, such as flutamide, bicalutamide, or abiraterone.\n\nDrug Class: Antineoplastic Agents, Antiandrogens
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Apalutamide – Erleada®
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Antineoplastic Agents
| null |
Temozolomide.nxml
|
Temozolomide
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2020-09-02
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Temozolomide is an orally administered alkylating agent used largely in the therapy of malignant brain tumors including glioblastoma and astrocytoma. Temozolomide has been associated with a low rate of serum enzyme elevations during treatment and with rare instances of clinically apparent cholestatic liver injury.
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Temozolomide (tem" oh zol' oh mide) is an imidazotetrazine derivative similar to dacarbazine (DTIC), which acts as an alkylating agent disrupting DNA replication, causing modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis and causing programmed cell death (apoptosis) in rapidly dividing cells. Temozolomide rapidly crosses the blood-brain barrier and has been evaluated largely in the therapy of malignant brain tumors. Temozolomide has been shown to induce tumor regression and remissions in patients with malignant astrocytoma and glioblastoma multiforme. It may also have activity in melanoma. Temozolomide was approved for use in the United States in 1999 and is now commonly used in treating patients with malignant brain tumors. Temozolomide is available in capsules of 5, 20, 100, 140, 180 and 250 mg and as a solution for injection generically and under the brand name of Temodar. The recommended dose regimen is calculated based on phase (initial cycles, maintenance), body weight, bone marrow toxicity and tolerance. It is typically given in a dose of 150 mg/m2 once a day during concurrent radiation therapy for 42 days followed by 75 mg/m2 on days 1 to 5 of each 28 day cycle. Temozolomide is considered somewhat less toxic and better tolerated than many other alkylating agents, but does have the common side effects of fatigue, nausea and vomiting, gastrointestinal upset, alopecia and bone marrow suppression. Less common but potentially severe adverse events included severe myelosuppression, myelodysplastic syndromes, pneumocystis pneumonia, hepatotoxicity and embryo-fetal toxicity.
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Serum aminotransferase elevations occur during temozolomide therapy in up to 12% of patients, but these elevations are usually mild and self-limited, not requiring dose adjustment or drug discontinuation. An instance of serum aminotransferase elevation with jaundice was reported in the registration trials of temozolomide and subsequent to its approval. More strikingly, multiple single case reports and several case series of temozolomide hepatotoxicity have been reported in the literature. The onset of injury was typically within 2 to 8 weeks of starting temozolomide but several patients had received multiple courses before the onset of liver injury. The pattern of serum enzyme elevations was usually mixed initially, but the disease tended to be cholestatic. In several instances, jaundice was deep and prolonged. Features of hypersensitivity (rash, fever, eosinophilia) and autoantibody formation were not present. Liver histology demonstrated cholestasis and bile duct injury and a striking decrease in bile ducts (bile duct loss or paucity). Jaundice and pruritus tended to be prolonged and some patients developed vanishing bile duct syndrome, while others recovered clinically but had persistent serum alkaline phosphatase elevations during follow up and to the time of death from the brain tumor. Rechallenge was not done, but several patients subsequently received other antineoplastic agents, some of which were alkylating agents without recurrence of liver injury.\n\nIn addition, temozolomide has been associated with several cases of reactivation of chronic hepatitis B in patients who were hepatitis B surface antigen (HBsAg) positive at the start of chemotherapy. Clinical symptoms and signs of a flare of hepatitis B arose 6 to 12 weeks after starting temozolomide frequently in a cyclic pattern. Most patients had not received corticosteroids or other immunosuppressive agents that are more traditionally associated with reactivation. The episodes are marked by rises in HBV DNA levels and mild jaundice and responded to prompt antiviral therapy for hepatitis B which allowed for restarting of temozolomide in some cases. Fatal cases of reactivation have not been reported, but in general hepatitis B reactivation with jaundice has a mortality rate in excess of 10%.\n\nLikelihood score: B (highly likely but uncommon cause of clinically apparent liver injury and reactivation of hepatitis B).
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Temozolomide is hydrolyzed to the active intermediate at physiological pH and does not require hepatic metabolism or affect the cytochrome P450 (CYP) system to a major degree, perhaps accounting for its relative lack of direct hepatotoxicity. The cases of acute cholestatic liver injury have resembled idiosyncratic drug induced liver injury.
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The severity of liver injury caused by temozolomide ranges from minor transient elevations in serum enzymes to severe cholestatic hepatitis that can be prolonged. Temozolomide has not been reported to cause acute liver failure but has been linked to instances of chronic liver injury and paucity of bile ducts on liver biopsy suggestive of mild vanishing bile duct syndrome. Because temozolomide is used as therapy of highly malignant brain tumors, long term follow up of liver injury from its use is rarely available. Most patients recover clinically, but may persist in having mild and asymptomatic alkaline phosphatase elevations. There is no evidence for cross sensitivity to hepatic injury between temozolomide and other alkylating agents. Because temozolomide has been linked to instances of reactivation of hepatitis B, it is appropriate to screen all patients scheduled to receive temozolomide for HBsAg and anti-HBc. Patients with serologic evidence of ongoing or previous hepatitis B should be monitored for evidence of reactivation (rise in HBV DNA). If evidence of reactivation arises, prompt therapy with an antiviral with potent activity against HBV is appropriate (such as entecavir or tenofovir). An alternative approach is to use the antiviral agent prophylactically in such patients. The antiviral therapy (either as prophylaxis or treatment) should be continued as long as the chemotherapy is planned and for 3 to 6 months thereafter.\n\nDrug Class: Antineoplastic Agents, Alkylating Agents
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Temozolomide – Generic, Temodar®
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Antineoplastic Agents, Alkylating Agents
| null |
Teplizumab.nxml
|
Teplizumab
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2023-01-15
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Teplizumab is a humanized monoclonal antibody to CD3 which is used to delay the onset of clinically significant type 1 diabetes (stage 3 diabetes) in a patient at high risk as shown by the presence of anti-pancreatic islet cell autoantibodies and dysglycemia (stage2 diabetes). Teplizumab is given intravenously once daily for 14 days, is generally well tolerated, and is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent liver injury with jaundice.
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Teplizumab (tep liz’ ue mab) is a humanized monoclonal IgG1 antibody directed against CD3, which results in inhibition of cytotoxic T cell activation and proliferation. Because type 1 diabetes is thought to be caused by cytotoxic T cell destruction of pancreatic islet beta cells that produce insulin, teplizumab was evaluated as a means of therapy and prevention of type 1 diabetes. While a limited course of teplizumab appeared to have little effect on established type 1 diabetes, it did appear to delay the onset of clinically apparent type 1 diabetes. In preregistration trials, stage 2 diabetes was defined by the presence of at least two anti-pancreatic islet cell autoantibodies and dysglycemia without frank hyperglycemia (stage 3 diabetes). Patients with stage 2 diabetes were generally identified among relatives of patients with type 1 diabetes by screening for anti-pancreatic islet cell autoantibodies. Natural history studies demonstrated that almost all subjects with stage 2 diabetes develop stage 3 diabetes, generally within 1 to 5 years. In a single, randomized controlled trial of teplizumab given as daily intravenous infusions daily for 14 days, therapy was associated with a subsequent median delay in onset of stage 3 diabetes of 24 months. On the basis of this trial, teplizumab was approved in 2022 the United States for use in preventing stage 3 diabetes in adults and children (8 years of age or older) with stage 2 diabetes. Teplizumab is available in single use vials of 2 mg per 2 mL (1 mg/mL). The recommended regimen is a daily infusion in escalating doses for the first 5 days from 65 to 1,030 µg/m2, which is then continued for another 9 days. Premedication is recommended at least during the first 5 days using an oral analgesic (acetaminophen or a nonsteroid antiinflammatory agent), antihistamine, and antiemetic. Monitoring of symptoms, blood counts and liver enzymes is also recommended during the 14 days. Common side effects during and for the several weeks after treatment include mild local injection reactions, nasopharyngitis, fatigue, headache, nausea, diarrhea, arthralgia and skin rash. Uncommon, potentially severe adverse reactions include cytokine release syndrome, severe hypersensitivity reactions, lymphopenia, and reactivation of latent viral infections or tuberculosis.
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Mild-to-moderate serum aminotransferase elevations arise in up to 25% of patients treated with teplizumab, usually during the 14 days of therapy and often associated with evidence of mild-to-moderate cytokine release syndrome. The ALT and AST elevations are usually mild, transient and asymptomatic, rising to above 3 times the upper limit of normal (ULN) in 5% of patients and rarely necessitating drug discontinuation. Serum bilirubin levels also rise, particularly in patients with cytokine release syndrome, but clinically apparent liver injury with jaundice has not been reported, and liver test abnormalities resolve in almost all patients within days or a few weeks of ending the 14 day course. There has been limited clinical experience with use of teplizumab and scant information on the safety and efficacy of repeated courses of treatment. Development of antibodies to teplizumab is not uncommon (up to 50%), but the clinical significance of drug antibodies has not been defined.\n\nLikelihood score: E (unlikely cause of clinically apparent acute liver injury).
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The possible mechanisms of liver injury due to teplizumab are unclear, but probably relate to cytokine release induced by the binding of the monoclonal antibody to activated T cells that then release cytokines into the circulation that can cause transient liver injury. There is no evidence that the cytokine release induced by teplizumab can result in prolonged or chronic liver injury.
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Drug Class: Monoclonal Antibodies, Antidiabetic Agents
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Teplizumab – Tzield®
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Antidiabetic Agents
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Acetaminophen.nxml
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Acetaminophen
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2016-01-28
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Acetaminophen is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. Harmless at low doses, acetaminophen has direct hepatotoxic potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. Even in therapeutic doses, acetaminophen can cause transient serum aminotransferase elevations.
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Acetaminophen (a seet" a min' oh fen), which is known as paracetamol in Europe, is an aminophenol that is believed to act centrally as an analgesic and antipyretic agent. While technically a nonsteroidal antiinflammatory drug (NSAID), acetaminophen unlike typical NSAIDs (ibuprofen, naproxen, indomethacin) has only minor effects on tissue cyclooxygenase activity (Cox-1 and Cox-2) and appears to produce analgesia by increasing pain thresholds, perhaps through inhibition of the nitric oxide pathway which is activated by many pain neurotransmitter receptors. Acetaminophen has lower antiinflammatory activity than aspirin or typical NSAIDs. Acetaminophen is typically recommended for management of minor aches and pains from the common cold, viral and bacterial infections, sinusitis, headache, toothache, back ache, muscle strain, tendonitis, osteoarthritis, trauma or menstrual cramps. Acetaminophen has been available as an over-the-counter preparation in the United States since 1960. In 2011, an intravenous formulation of acetaminophen was approved in the United States for adults and children above the age of 2 years. The recommended oral dose is 660 to 1000 mg every 4 to 6 hours, but should not to exceed 3 grams per day. Multiple generic formulations of acetaminophen are available (e.g., Tylenol, Anacin Aspirin Free, Feverall, Neopap, Panadol and Tempra) in capsules or tablets of 330 or 500 mg each. Liquid formulations for children are available in concentrations that vary from 15 to 100 mg/mL; the dosage in children should be carefully chosen and kept to less than 75 mg/kg/day. In addition, acetaminophen is a frequent component in many over-the-counter and prescription combinations with decongestants and/or antihistamines for cold and allergy symptoms, or as a sleeping aid and with other analgesics (such as oxycodone, hydrocodone, dilaudid and codeine) for moderate-to-severe forms of pain. Common products in the United States include: Tylenol-PM, Nyquil, Darvocet, Vicodin, and many others. Acetaminophen is one of the most commonly used medications in the United States and more than 25 billion doses are sold yearly.
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Chronic therapy with acetaminophen in doses of 4 grams daily has been found to lead to transient elevations in serum aminotransferase levels in a proportion of subjects, generally starting after 3 to 7 days, and with peak values rising above 3-fold elevated in 39% of persons. These elevations are generally asymptomatic and resolve rapidly with stopping therapy or reducing the dosage, and in some instances resolve even with continuation at full dose (Case 1).\n\nWhile acetaminophen has few side effects when used in therapeutic doses, recent reports suggest that its standard use can result in severe hypersensitivity reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Both of these syndromes can be life-threatening and both may be accompanied by evidence of liver injury. However, the hepatic involvement is usually mild and marked only by asymptomatic mild-to-moderate elevations in serum aminotransferase levels.\n\nThe best known form of hepatoxicity from acetaminophen is an acute, serious hepatocellular injury as a result of intentional or unintentional overdose. The injury is due to a direct, toxic effect of the high doses of acetaminophen. Acetaminophen hepatotoxicity most commonly arises after a suicide attempt using more than 7.5 grams (generally more than 15 grams) as a single overdose (Case 2). Hepatic injury generally starts 24 to 72 hours after the ingestion with marked elevations in serum ALT and AST (often to above 2000 U/L), followed at 48 to 96 hours by clinical symptoms: jaundice, confusion, hepatic failure and in some instances death. Evidence of renal insufficiency is also common. Serum aminotransferase levels fall promptly and recovery is rapid if the injury is not too severe. Similar injury can occur with high therapeutic or supratherapeutic doses of acetaminophen given over several days for treatment of pain and not as a purposeful suicidal overdose (Case 3). This form of acetaminophen hepatotoxicity is referred to as accidental or unintentional overdose, and usually occurs in patients who have been fasting, or are critically ill with a concurrent illness, alcoholism or malnutrition, or have preexisting chronic liver disease. Some cases of unintentional overdose occur in patients taking acetaminophen in combinations with controlled substances (oxycodone, codeine), who take more than recommended amounts over several days in attempts to control pain or withdrawal symptoms. Instances of unintentional overdose in children are often due to errors in calculating the correct dosage or use of adult sized tablets instead of child or infant formulations. Because acetaminophen is present in many products, both by prescription and over-the-counter, another problem occurs when a patient ingests full or high doses of several products unaware that several contain acetaminophen.\n\nLikelihood score: A[HD] (well established cause of liver injury, but severe cases occur only with high doses).
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The mechanism of acetaminophen hepatotoxicity has been extensively analyzed in humans and in animal models. Acetaminophen is largely converted to nontoxic glucuronate or sulfate conjugates and secreted in the urine. A minor amount of acetaminophen is metabolized via the cytochrome P450 system to intermediates that can be toxic, particularly N-acetyl-p-benzoquinoneimine. Ordinarily, this intermediate is rapidly conjugated to reduced glutathione, detoxified and secreted. If levels of glutathione are low or the pathway is overwhelmed by high doses of acetaminophen, the reactive intermediate accumulates and binds to intracellular macromolecules that can lead to cell injury, usually through apoptotic pathways. Factors that increase the metabolism of acetaminophen through the P450 system (certain drugs, chronic alcohol use) or that decrease the availability of glutathione (fasting, malnutrition, alcoholism) can predispose to acetaminophen toxicity. Factors that affect downstream toxicity of acetaminophen metabolic intermediates may also affect toxicity. These factors are important in designing therapies for acetaminophen hepatotoxicity.
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The minor aminotransferase elevations that occur during chronic therapy with acetaminophen are rarely symptomatic, generally go undetected, resolve rapidly with discontinuation of acetaminophen and sometimes even with continuation at the same dose. Such transient aminotransferase elevations do not appear to have lasting effects on the liver but can cause diagnostic confusion and lead to expensive or invasive interventions. Acetaminophen overdose, in contrast, can cause a serious acute liver injury and hepatic failure that can result in death or need for emergency liver transplantation. Currently, acetaminophen is the major cause of acute liver failure in the United States, Europe and Australia. The liver injury from acetaminophen can be prevented or ameliorated by repletion of glutathione levels which can be accomplished with n-acetylcysteine (NAC), which is available in oral and intravenous forms and should be administered immediately upon diagnosis of acetaminophen overdose. A nomogram (Rumack-Matthew Nomogram) to calculate the likelihood of liver injury from acetaminophen is available that plots acetaminophen plasma concentrations against the number of hours post-ingestion that the sample was taken. Patients with plasma levels above the “treatment line” should receive either oral or intravenous NAC. Details of administration and assistance can be obtained from the U.S. National Poison Center: 1-800-222-1222. Patients who recover spontaneously from acetaminophen hepatotoxicity generally return to normal health without evidence of chronic liver injury. The nomogram is less accurate in assessing risk with chronic or unintentional overdose. Recently, tests for acetaminophen adducts have been developed that accurately reflect hepatic damage from acetaminophen overdose and are detectable after plasma acetaminophen levels fall into undetectable range. Thus, the presence of acetaminophen adducts supports the diagnosis and their absence is a reliable in excluding acetaminophen as a cause of acute liver injury (if ALT levels are still elevated).\n\nDrug Class: Nonsteroidal Antiinflammatory Drugs
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Acetaminophen – Generic, Various Trade Names
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Nonsteroidal Antiinflammatory Drugs
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Lonafarnib.nxml
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Lonafarnib
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2021-01-07
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Lonafarnib is an oral, small molecule inhibitor of farnesyltransferase that is used to treat Hutchison-Gilford progeria syndrome and is under investigation as therapy of chronic hepatitis D. Lonafarnib is associated with transient and usually mild elevations in serum aminotransferase levels during therapy, but has not been linked to cases of clinically apparent acute liver injury.
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Lonafarnib (loe” na far’ nib) is an orally available, specific inhibitor of farnesyltransferase and is approved for the treatment of Hutchinson-Gilford progeria syndrome (HGPS), a rare autosomal dominant form of accelerated aging (arising in 1 in 4 million live births). Persons with HGPS develop cardiovascular disease at a young age and typically die of myocardial infarction, heart failure or stroke before the age of 20. Other manifestations of HGPS include sclerotic skin, joint contracture, bone abnormalities, alopecia, and growth impairment. Lonafarnib acts by prevention of farnesylation of proteins, a post-translational modification which alters membrane attachment. In HGPS a point mutation in the LMNA gene results in an abnormal lamin A protein called “progerin”. Lamin A is a normal component of the nuclear envelope providing structural organization to the nucleus and supporting normal chromatic function, DNA replication, RNA transcription, cell cycling and apoptosis. The abnormal progerin protein, however, lacks the ability to remove the post-translational isoprenyl that allows for membrane attachment. As a result, the abnormal lamin A remains and accumulates, acting as a dominant negative in causing abnormal nuclear membranes. The clinical manifestations of HGPS appear to be due to the abnormalities of nuclear membranes. In animal models and in subsequent human clinical trials, lonafarnib therapy was associated with a decrease in progerin farnesylation as well as a decrease in its accumulation, in clinical abnormalities and cardiovascular complications, resulting in prolonged survival. Lonafarnib was approved for use in HGPS in the United States in 2020. Lonafarnib has also been evaluated in several forms of cancer associated with abnormal RAS (whose activation is dependent on farnesyltransferase) and for chronic hepatitis D virus infection (the HDV replicative cycle requires the same enzyme). Current indications for lonafarnib are limited to patients with HGPS (or other processing-deficient progeroid laminopathies) who are 12 months of age or above with body surface area of at least 0.39/m2. Lonafarnib is available in capsules of 50 and 75 mg under the brand name Zokinvy. The recommended initial dose is 115 mg/m2 twice daily increasing after 4 months to 150 mg/m2 twice daily. Side effects are common, particularly with higher doses and include diarrhea, nausea, vomiting, abdominal pain, musculoskeletal pain, fatigue, electrolyte abnormalities (hypokalemia, hyponatremia, hypocalcemia), cough, hypertension, myelosuppression and infections. Severe adverse events include dehydration, electrolyte imbalance, nephrotoxicity, retinal abnormalities, impaired fertility, and embryo-fetal toxicity. Monitoring of electrolytes, complete blood counts and liver enzymes is recommended.
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In the small prelicensure clinical trials conducted in children with progeria, serum aminotransferase elevations occurred in 35% of lonafarnib treated subjects but were usually mild and self-limited, rising to above 3 times the upper limit of normal (ULN) in only 5%. There were no liver related serious adverse events and no patient had a concurrent elevation in serum aminotransferase and bilirubin levels. Since approval of lonafarnib, there have been no published reports of drug induced liver injury associated with its use, although clinical experience with the drug, particularly with long term therapy, has been limited.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
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The causes of serum enzyme elevations during lonafarnib therapy are not known. Lonafarnib is metabolized in the liver largely through the cytochrome P450 pathway and specifically by CYP 3A4, and liver injury may be related to production of a toxic or immunogenic intermediate. Because it is a substrate for CYP 3A4, lonafarnib is susceptible to drug-drug interactions with agents that inhibit or induce this specific hepatic microsomal activity.
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Monitoring of laboratory tests including routine liver tests is recommended for patients treated with lonafarnib. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There are no data to suggest a cross reactivity in risk for hepatic injury between lonafarnib and other small molecule enzyme inhibitors.\n\nDrug Class: Genetic Disease Agents, Protein Kinase Inhibitors
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Lonafarnib – Zokinvy®
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Genetic Disease Agents, Small Molecule Enzyme Inhibitors
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Phenotypes_acutehepa.nxml
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Acute Hepatitis
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2019-05-04
| null | null | null | null | null | null | null | null |
Umbralisib.nxml
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Umbralisib
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2023-10-10
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Umbralisib is an oral kinase inhibitor that is was given accelerated approved for use in adults with relapsed or refractory marginal zone and follicular lymphoma in 2021, but the approval was withdrawn a year later because of data from a trial showing excess mortality with its use. Umbralisib was associated with a modest rate of serum enzyme elevations during therapy but was not reported to cause clinically apparent acute liver with symptoms or jaundice.
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Umbralisib (um" bra lis' ib) is an orally available, small molecule inhibitor of multiple kinases that play a role in B cell malignant cellular pathways and that was used in the therapy of refractory cases of marginal zone and follicular lymphoma. The kinases inhibited by umbralisib include phosphatidylinositol 3-kinase delta (PI3Kδ), which is an essential component in the B cell signaling pathways that drive migration of B cells to lymph nodes and bone marrow. This pathway is upregulated in many B cell malignancies and has been shown to be critical for proliferation and survival of leukemia and lymphomatous malignant B lymphocytes. Inhibition of this pathway inhibits B cell chemotaxis and adherence and reduces cell viability. Umbralisib also has activity against casein kinase epsilon which plays a role in protein synthesis and RNA translation and is altered in some malignancies. Other activities of umbralisib include inhibition of cell adhesion molecules and other kinases including BCR-ABL1. Studies in animal models and in early phase clinical trials showed that umbralisib had activity against several hematologic malignancies. Umbralisib was given tentative approval for use in the United States as therapy for refractory or relapsed marginal zone and follicular lymphoma after failure of one or more systemic therapies in February 2021. A little over a year later, FDA approval was withdrawn because of concerns about excess mortality in patients receiving Umbralisib in follow up clinical trials. The deaths on treatment were not liver related but the nature and relatedness of the mortality to umbralisib therapy was not well defined. Umbralisib was previously available in tablets of 200 mg under the brand name Ukoniq. The recommended dose was 800 mg once daily until disease progression or unacceptable toxicity. Side effects of umbralisib were common but usually mild-to-moderate in severity, and included fatigue, nausea, diarrhea, headache, musculoskeletal pain, stomatitis, fever, pain, rash, and infections. Common laboratory abnormalities included cytopenias, liver enzyme elevations, hyper- or hypo-glycemia, and hyponatremia. Severe potential adverse events included neutropenia, severe infections, severe diarrhea, allergic and hypersensitivity reactions, and embryo-fetal toxicity. Because of excess mortality among umbralisib- in comparison to placebo-treated patients, FDA approval was withdrawn in June 2022 and the product was withdrawn by the sponsor.
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In clinical trials of umbralisib in adults with lymphoma, the rates of serum enzyme elevations during therapy ranged from 15% to 35% and were above 5 times the ULN in 5% to 8% and occasionally above 20 times ULN (<1%). The aminotransferase elevations arose within 4 to 12 weeks of starting therapy in most instances and usually resolved without dose modification or temporary discontinuation. Nevertheless, there were no instances of serum enzyme elevations accompanied by jaundice and no liver related deaths.\n\nBecause umbralisib affects B cell function, it may also be capable of inducing reactivation of hepatitis B, although in published trials of the agent, instances of HBV reactivation were not reported.\n\nLikelihood score: E* (unproven, but suspected rare cause of clinically apparent liver injury).
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The reason why umbralisib causes serum enzyme elevations is not known, but may be a direct toxicity to hepatocytes caused by inhibition of PI3K activity or the result of change in B cell activity and caused by induction of autoimmunity. Umbralisib is metabolized primarily by aldehyde oxidase which is present in many tissues, but highest concentrations are in the liver. The cytochrome P450 system plays a minor role in the metabolism (CYP 3A4) of umbralisib, but concentrations may be affected by drugs that induce or inhibit CYP 3A activity.
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Serum enzyme elevations were not uncommon during chemotherapy with umbralisib and were often dose limiting. The product label recommended that umbralisib not be used with other agents with hepatotoxic potential. Furthermore, regular monitoring of liver tests every 2 to 4 weeks was recommended during the first six months of umbralisib therapy and every 1 to 3 months thereafter, with more frequent monitoring if serum aminotransferase values rise. It was recommended that umbralisib be held if ALT or AST values rise above 5 times ULN, and treatment resumed only if and when values fall into the normal range and then with a reduced dose and careful monitoring. Elevations of aminotransferase values of more than 20 times the ULN, or appearance of jaundice or symptoms of liver injury were considered to require permanent discontinuation. There was no known cross sensitivity to hepatic injury between umbralisib and other protein kinase inhibitors.\n\nDrug Class: Antineoplastic Agents, Protein Kinase Inhibitors\n\nOther PI3 Kinase Inhibitor Drugs: Alpelisib, Copanlisib, Duvelisib, Idelalisib
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Umbralisib – Ukoniq® [On June 1, 2022, FDA approval was withdrawn due to safety concerns.]
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Antineoplastic Agents
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Troglitazone.nxml
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Troglitazone
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2018-06-06
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Troglitazone was the first thiazolidinedione approved for use in the United States and was licensed for use in type 2 diabetes in 1997, but withdrawn 3 years later because of the frequency of liver injury including acute liver failure associated with its use.
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Troglitazone (troe gli' ta zone) is an insulin sensitizing agent thought to act by engagement of PPAR-γ receptors which induce multiple genes involved in glucose and fatty acid metabolism. In clinical trials, troglitazone was found to lower blood glucose and HbA1c levels and had additive effects with the sulfonylureas and metformin. Troglitazone was approved for use in the United States in 1997 to be used alone or in combination with other antidiabetic medications. However, reports of severe liver injury and death from acute liver failure began to arise soon after its general availability, and it was withdrawn from use in 2000. Troglitazone was sold under the brand name Rezulin and was available in 400 mg tablets. The recommended dosage was 400 to 800 mg once daily. Troglitazone was used as monotherapy as well as in combination with metformin, sulfonylureas or insulin.
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Large prospective studies showed that significant elevations in serum aminotransferase levels (equal to or greater than 3 times the upper limit of the normal range [ULN]) occurred in 1.9% of patients with diabetes treated with troglitazone for 24 to 48 weeks, compared to only 0.6% in placebo recipients. These enzyme elevations were usually asymptomatic and often resolved despite continuation of therapy. Nevertheless, elevations >10 times ULN occurred in 0.5% of patients (but in no placebo recipient) and a proportion of these developed symptoms of liver injury and jaundice. Soon after the approval of troglitazone as therapy for type 2 diabetes in the United States, cases of severe acute liver injury began to be reported, and dramatic case reports as well as small case series documented that clinically significant injury was occurring in 1:1000 to 1:10,000 recipients. The latency to onset of injury was typically 1 to 6 months and the onset was marked by fatigue, weakness, dark urine and jaundice, and an acute hepatitis-like elevation in serum enzymes (hepatocellular pattern). Allergic phenomena (rash, fever, eosinophilia) were uncommon and serum autoantibodies were not usually present. Liver biopsies showed acute inflammatory changes and variable degrees of necrosis, ranging from rare spotty necrosis to bridging hepatic necrosis and submassive or massive necrosis. At least two dozen cases of acute liver failure and death or need for liver transplantation were reported to the FDA before troglitazone was withdrawn from use in 2000.\n\nLikelihood score: A (well recognized cause of clinically apparent liver injury).
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The mechanism of liver injury due to troglitazone is unknown. Signs and symptoms of allergic and immune reactivity are rare and a metabolic defect in its metabolism is suspected to be the cause. Troglitazone is a potent inducer of CYP 3A4 and has a distinctive alpha tocopherol (vitamin E-like) side chain which can be metabolized to a highly active quinolone-like metabolite, which may account for its occasional aberrant metabolism and hepatotoxicity.
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The liver injury from troglitazone can be severe and even fatal. In several cases there was incomplete recovery at the time of the last follow up evaluation, suggesting that the injury can become chronic in some instances. Prednisone has been reported to have a beneficial effect, but only in anecdotal reports. While several patients with mild troglitazone liver injury were later treated with other thiazolidinediones without recurrence of injury, other patients have developed worsening liver injury; switching therapy to other thiazolidinediones is inadvisable and, if done, should be with careful monitoring of serum aminotransferase levels.\n\nReferences to safety and hepatotoxicity of troglitazone are given together with references to the related agents in the Overview section on the Thiazolidinediones (updated June 2018).\n\nDrug Class: Antidiabetic Agents\n\nOther Drugs in the Subclass, Thiazolidinediones: Pioglitazone, Rosiglitazone
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Troglitazone – Rezulin® (Withdrawn from U.S. Market)
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Hypoglycemic Agents
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Acarbose.nxml
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Acarbose
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2021-01-10
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Acarbose is an alpha glucosidase inhibitor which decreases intestinal absorption of carbohydrates and is used as an adjunctive therapy in the management of type 2 diabetes. Acarbose has been linked to rare instances of clinically apparent acute liver injury.
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Acarbose (ay' kar bose) is an inhibitor of intestinal alpha glucosidase, an enzyme responsible for digestion and absorption of starch, disaccharides and dextrin. Acarbose is a complex oligosaccharide produced in bacteria that has activity against glucoamylase, sucrase, maltase and isomaltase, intestinal brush border glucosidases. The inhibition of the glucosidase activity blocks the breakdown of starch and disaccharides to absorbable monosaccharides, leading to delay in glucose absorption and a degree of carbohydrate malabsorption which results in a blunting of the postprandial rise in blood glucose. Acarbose was approved for use in the United States in 1995 and was the first alpha glucosidase inhibitor introduced into clinical practice. A similar alpha glucosidase inhibitor, miglitol, was approved the following year. The current indications for acarbose are for management of glycemic control in type 2 diabetes used in combination with diet and exercise, with or without other oral hypoglycemic agents or insulin. Acarbose is available generically and under the brand name Precose in tablets of 25, 50 and 100 mg. The typical initial dose in adults is 25 mg with each meal (with the first bite), followed by a gradual increase to a maximum of 100 mg three times daily. Acarbose causes malabsorption and gastrointestinal side effects of flatulence, diarrhea and abdominal boating are not uncommon. More severe but rare adverse events include skin rash and pneumatosis cystoides intestinalis.
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In several large clinical trials, serum enzyme elevations above 3 times the upper limit of normal were more common with acarbose therapy (2% to 5%) than with placebo, but all elevations were asymptomatic and resolved rapidly with stopping therapy. These studies reported no instances of clinically apparent liver injury. Subsequent to approval and with wide clinical use, however, at least a dozen instances of clinically apparent liver injury have been linked to acarbose use. The liver injury typically arises 2 to 8 months after starting therapy and is associated with a hepatocellular pattern of serum enzyme elevations with marked increases in serum ALT levels, suggestive of acute viral hepatitis. Immunoallergic features and autoantibody formation are not typical. While most cases are mild, some are associated with marked jaundice and cases with a fatal outcome have been reported to the sponsor. No cases of chronic liver injury or vanishing bile duct syndrome have been linked to acarbose use, and most large series of cases of drug induced liver injury and acute liver failure have not identified cases due to acarbose. Rechallenge has been carried out in several instances and resulted in recurrence with a shortening of the time to onset.\n\nLikelihood score: B (rare but likely cause of clinically apparent liver injury).
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The cause of liver injury during acarbose therapy is not known. Acarbose is an oligosaccharide of microbial origin and is minimally absorbed (0.5% to 1.7%), so that systemic toxicity and liver injury were not expected and remain unexplained. Liver injury from acarbose is clearly idiosyncratic and may relate to an immunological reaction to the bacterially derived oligosaccharide molecule or to alterations in the microbiome and absorption of bacterial products.
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The liver injury caused by acarbose has generally been mild and self-limited with the injury resolving rapidly once acarbose is discontinued. Cross sensitivity with other hypoglycemic agents has not been described. Furthermore, liver injury has not been described in patients taking the other currently available alpha glucosidase inhibitor, miglitol. Recurrence of injury with reintroduction of acarbose has been reported and should be avoided.\n\nDrug Class: Antidiabetic Agents\n\nOther Drugs in the Subclass Alpha Glucosidase Inhibitors: Miglitol
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Acarbose – Generic, Precose®
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Antidiabetic Agents
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Phenobarbital.nxml
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Phenobarbital
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2020-07-30
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Phenobarbital is a barbiturate that is widely used as a sedative and an antiseizure medication. Phenobarbital has been linked to rare instances of idiosyncratic liver injury that can be severe and even fatal.
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Phenobarbital (fee" noe bar' bi tal) is a barbiturate and is believed to act as a nonselective depressant. Phenobarbital also has anticonvulsant activity and is thought to act by suppressing spread of seizure activity by enhancing the effect of gamma aminobutyric acid (GABA), raising the seizure threshold. Phenobarbital was introduced into clinical medicine in 1911 but was never subjected to critical controlled studies to demonstrate safety and efficacy. For these reasons, phenobarbital is now considered of unproven benefit in controlling seizures. Nevertheless, it is commonly used for prevention and management of partial and generalized seizures, usually as an adjunctive agent in combination with other anticonvulsants. Phenobarbital is also used for sedation and insomnia although its use for these conditions is now uncommon. Phenobarbital is also used in fixed combinations with other antispasmodics or anticholinergic agents and used for gastrointestinal complaints, including irritable bowel syndrome. The typical starting dose in treating seizures in adults is 60 to 100 mg in three divided doses daily. Oral formulations of tablets or capsules of 15, 16, 30, 60, 90 and 100 mg are available in multiple generic forms. Parenteral formations and oral elixirs for pediatric use are also available. Phenobarbital has declined in general use in recent years with availability of more efficacious and better tolerated agents. Its major advantage is low cost, but it is more sedating than other anticonvulsants. Frequent side effects include drowsiness, sedation, hypotension, and skin rash. Uncommon but potentially severe adverse events included severe sedation, dependence, hypersensitivity reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis.
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Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term phenobarbital therapy. Clinically apparent hepatotoxicity from phenobarbital is rare but can be abrupt in onset, severe and even fatal. Phenobarbital hepatotoxicity typically occurs in the setting of anticonvulsant hypersensitivity syndrome with onset of fever, rash, facial edema, lymphadenopathy, elevations in white count and eosinophilia occurring 1 week to several months after starting therapy. Liver involvement is common, but is usually mild and anicteric and overshadowed by other features of hypersensitivity (rash, fever). In some cases, hepatic involvement is more prominent with marked elevations in serum enzyme levels, jaundice and even signs of hepatic failure. The typical pattern of serum enzyme elevations is mixed, but can be hepatocellular or cholestatic. Liver biopsy shows mixed hepatitis-cholestatic injury with prominence of eosinophils and occasionally granulomata. Re-exposure usually results in recurrence and should be avoided.\n\nLikelihood score: B (likely rare cause of clinically apparent liver injury).
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The mechanism of phenobarbital hepatotoxicity is thought to be hypersensitivity or an immunological response to a metabolically generated drug-protein complex.
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Phenobarbital hepatotoxicity is usually rapidly reversible with improvements beginning within 5 to 7 days of stopping the drug and being complete within 1 to 2 months. In cases of severe injury, progression to acute liver failure and death can occur. Corticosteroids have been used but with uncertain effectiveness. Prolonged cholestasis can occur, but chronic injury and vanishing bile duct syndrome have not been reported from phenobarbital therapy. Cross reactivity with other aromatic anticonvulsants (phenytoin, carbamazepine, primidone, and lamotrigine) is common but not invariable. Patients with hypersensitivity to phenobarbital should be monitored carefully if they are to start other aromatic anticonvulsants.\n\nDrug Class: Anticonvulsants, Sedatives and Hypnotics
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Phenobarbital – Generic, Luminal® Sodium
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Anticonvulsants
| null |
Quinupristin-Dalfopr.nxml
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Quinupristin-Dalfopristin
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2018-05-21
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Quinupristin and dalfopristin are intravenously administered, streptogramin antibiotics used in fixed combination to treat severe bacterial infections due to susceptible organisms including methicillin resistant Staphylococcus aureus (MRSA). The fixed combination of quinupristin and dalfopristin is associated with a low rate of serum enzyme elevations during therapy but has not been convincingly linked to instances of clinically apparent liver injury.
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Quinupristin (kwin" ue pris' tin) and dalfopristin (dal” foe pris’ tin) are streptogramin antibiotics that were initially isolated from Streptomyces pristinaspiralis. Quinupristin, a derivative of pristamycin IA, and dalfopristin, a derivative of pristamycin IIA, are synergistic in activity and are used in a fixed dose combination in a ratio of 30:70 by weight. This combination binds and inhibits the activity of the 50S subunit of bacterial ribosomes, which yields potent bactericidal activity against many gram positive bacteria including methicillin resistant forms of Staphylococcus aureus (MRSA). Quinupristin and dalfopristin also have activity against some gram negative bacteria including Enterococcus species. The combination of quinupristin and dalfopristin under the brand same of Synercid was approved for use in the United States in 1999. Current indications include complicated skin and skin structure infections caused by susceptible strains of Staphylococcus aureus or Streptococcus pyogenes and severe infections due to susceptible vancomycin-resistant Enterococcus faecium. The combination of quinupristin and dalfopristin is available in solution in 10 mL vials of 500 mg (150 mg of quinupristin and 350 mg of dalfopristin) and the typical dose regimen is 7.5 mg/kg intravenously every 8 to 12 hours for 5 to 14 days. Side effects may include nausea, diarrhea, headache, skin rash, myalgia, arthralgia and injection site reactions (burning, irritation, pain). Rare, but potentially severe side effects include anaphylaxis and angioneurotic edema.
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Elevations in serum aminotransferase levels occur in a proportion of patients receiving quinupristin and dalfopristin, but rates are minimally higher than with placebo or comparator drugs. The elevations are generally mild-to-moderate, asymptomatic and self-limited, frequently resolving without discontinuation or even interruption of therapy. Elevations above 5 times ULN occur in less than 1% of patients. Quinupristin-dalfopristin can also cause elevations in direct as well as total bilirubin, but these elevations are mild and not accompanied by elevations in serum enzymes or other evidence of liver injury. In the many clinical trials of quinupristin and dalfopristin there were no instances of clinically apparent liver injury that could be attributed convincingly to their use. Patients who receive quinupristin and dalfopristin are often severely ill, septic and receiving multiple medications or parenteral nutrition, so that jaundice arising during therapy is often multifactorial and difficult to assign to a specific cause. Nevertheless, since the approval and more wide spread use of this antibiotic combination, there have been no published reports of hepatitis or jaundice linked specifically to it use. Thus, clinically apparent liver injury from quinupristin and dalfopristin may occur, but is quite rare.\n\nLikelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).
|
The cause of the mild-to-moderate serum aminotransferase elevations that occur during quinupristin and dalfopristin therapy is unknown. Both are extensively metabolized in the liver, largely via the cytochrome P450 system (CYP 3A4) and the combination is susceptible to drug-drug interactions with agents that are substrates for 3A4.
| null |
Quinupristin-Dalfopristin – Synercid®
|
Antiinfective Agents
|
[
{
"cas_registry_number": "120138-50-3",
"molecular_formula": "C53-H67-N9-O10-S",
"name": "Quinupristin"
},
{
"cas_registry_number": "112362-50-2",
"molecular_formula": "C34-H50-N4-O9-S",
"name": "Dalfopristin"
}
] |
Brexanolone.nxml
|
Brexanolone
|
2019-04-12
|
Brexanolone is a unique, intravenously administered, neuroactive steroidal antidepressant used in the therapy of moderate-to-severe postpartum depression. In prelicensure clinical trials, brexanolone therapy was not associated with an increased rate of serum aminotransferase elevations, and it has not been linked to instances of clinically apparent acute liver injury.
|
Brexanolone (brex an' oh lone) is allopregnanolone an active metabolite of progesterone which is found in high concentrations during pregnancy and falls precipitously at the time of delivery, shortly before the usual time of onset of postpartum depression. When given intravenously in doses that achieve plasma levels typical of pregnancy, brexanolone was found to be associated with marked improvement in depression symptoms, an effect that was sustained when the infusion was stopped. In vitro assays have shown that brexanolone also modulates synaptic and extra-synaptic GABA receptors, another possible mechanism of antidepressant activity. In two randomized controlled trials, a 60 hour intravenous infusion of brexanolone was found to be more effective than placebo in improving depression symptom scales and, in some instances, reversed the functional impairment that often accompanies severe postpartum depression. Brexanolone was approved in the United States in 2019 for use in treatment of moderate or severe postpartum depression. Brexanolone is available in solution in single use vials of 100 mg in 20 mL (5 mg/mL) under the brand name Zulresso. The recommended regimen starts with a dose of 30 mcg/kg/hour, which is gradually increased to a maintenance dose of 90 mcg/kg/hour which is decreased back 30 mcg/kg/hour before stopping, the total duration being 60 hours. Common, nonserious side effects include infusion site discomfort, sedation, headache, dizziness, dry mouth and flushing. Rare, potentially severe adverse events include loss of consciousness and suicidal thoughts or behaviors. The treatment requires continuous monitoring and is typically given in hospital which is often problematic for a new mother.
|
In premarketing studies, liver test abnormalities were uncommon in patients receiving brexanolone (<1%) and no more frequent than in placebo recipients. No instances of acute, clinically apparent liver injury attributed to brexanolone have been reported. However, general clinical experience with brexanolone has been limited.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).
|
The mechanism by which brexanolone might cause liver injury is not known. Brexanolone is metabolized largely via non-cytochrome P450 pathways, predominantly by keto-reduction, glucuronidation and sulfation. It has few significant drug-drug interactions. Concurrent use of other antidepressants may lead to excess sedation.\n\nDrug Class: Antidepressant Agents
| null |
Brexanolone – Zulresso®
|
Antidepressant Agents
| null |
PKEnhancers.nxml
|
Pharmacokinetic Enhancers
|
2017-08-17
| null | null | null | null | null | null | null | null |
Elvitegravir_Cobicis.nxml
|
Elvitegravir
|
2018-01-30
|
Elvitegravir is a human immunodeficiency virus (HIV) integrase inhibitor which is used largely in a four drug combination with cobicistat, emtricitabine and tenofovir as therapy of HIV infection. Therapy with this elvitegravir based regimen is often associated with transient serum aminotransferase elevations during therapy, but has not been implicated in cases of clinically apparent acute liver injury.
|
Elvitegravir (el" vi teg' ra vir) is a 4-quinolone-3-glyoxylic acid and antiretroviral agent that acts by inhibition of viral DNA strand transfer by the HIV integrase, a necessary step in HIV replication. Elvitegravir has been shown to lower serum levels of HIV RNA and to raise CD4 counts. In multiple prospective clinical trials, the combination of elvitegravir with tenofovir and emtricitabine has been found to be as effective as other standard antiretroviral combinations. Elvitegravir is given with cobicistat, a pharmacokinetic enhancer that inhibits CYP 3A4 activity, causing increased levels and more prolonged activity of drugs like elvitegravir that are metabolized by the hepatic cytochrome P450 isomer CYP 3A4. Elvitegravir was approved as a part of a four drug combination including cobicistat, emtricitabine and tenofovir disoproxil fumarate as therapy of HIV infection in 2012 under the brand name Stribild. A similar four drug combination that includes tenofovir alafenamide instead of tenofovir disoproxil fumarate was approved for use in HIV infection in 2016 under the brand name Genvoya. These combinations are available as tablets of 150 mg of elvitegravir with 150 mg of cobicistat, 200 mg of emtricitabine and either 300 mg of tenofovir disoproxil fumarate (Stribild) or 10 mg of tenofovir alafenamide (Genvoya). The recommended dose is one tablet daily, these combination being two of several "single tablet regimens" (STRs) for therapy of HIV infection. Elvitegravir was the second HIV integrase to be approved in the United States and shares structural similarity and resistance patterns with the initial agent, raltegravir. Elvitegravir is also available as a single agent for use with other antiretroviral agents in 85 and 150 mg tablets under the brand name Vitekta. Common side effects of the four drug combination include fatigue, diarrhea, nausea, dizziness, headache, depression, abnormal dreams and skin rashes. Cobicistat has inhibitory activity against several drug metabolizing enzymes besides CYP 3A4, including CYP 2D6 and the P-glycoprotein transporter, making it likely to cause drug-drug interactions and important to avoid when using other agents that are metabolized by the P450 system. Cobicistat also inhibits creatinine secretion, which artificially raises serum creatinine levels without affecting the glomerular filtration rate. With long term use, tenofovir disoproxil fumarate can be associated with decline in kidney function, phosphate wasting and decline in bone mineral density. These adverse effects appear to be less with tenofovir alafenamide which is more potent and is given in a lower dose that the disoproxil fumurate form of tenofovir.
|
In premarketing clinical trials, serum ALT elevations greater than 5 times the upper limit of normal occurred in 15% of patients treated with elvitegravir combined with cobicistat, emtricitabine and tenofovir. This rate was somewhat lower than what occurred in comparator arms. Most serum enzyme elevations with elvitegravir based regimens were transient and asymptomatic, and occurred in patients with known underlying chronic liver disease such as hepatitis B or C or alcoholic liver disease. In at least one study, 1% of patients on the elvitegravir based four drug regimen developed "acute hepatitis", but the relatedness of the liver injury to elvitegravir was unclear and clinical details were not provided. No specific reports of clinically apparent liver injury attributed to elvitegravir have appeared in the published literature. The product label for elivitegravir mentions two other forms of acute liver injury that have been linked to potent antiretroviral regimens: the immune reconstitution syndrome when these regimens are started and reactivation of hepatitis B when regimens with anti-HBV acitivity (as with tenofovir) are discontinued. Neither of these effects are specific to elvitegravir or other integrase inhibitors.\n\nLikelhood score: E* (unproven but suspected cause of clinically apparent liver injury).
|
The possible mechanism of liver injury due to elvitegravir is unknown. Elvitegravir is extensively metabolized in the liver via the cytochrome P450 system (predominantly CYP 3A4), and production of a toxic or immunogenic intermediate may trigger liver injury.
| null |
Elvitegravir – Vitekta®
|
Antiviral Agents
|
[
{
"cas_registry_number": "697761-98-1",
"molecular_formula": "C23-H23-Cl-F-N-O5",
"name": "Elvitegravir"
},
{
"cas_registry_number": "1004316-88-4",
"molecular_formula": "C40-H53-N7-O5-S2",
"name": "Cobicistat"
}
] |
Eszopiclone.nxml
|
Eszopiclone
|
2018-02-20
|
Eszopiclone is a benzodiazepine receptor agonist that is used for the treatment of insomnia. Eszopiclone has not been implicated in causing serum enzyme elevations or clinically apparent liver injury.
|
Eszopiclone (es zoe' pi klone) is a non-benzodiazepine, benzodiazepine receptor agonist of the cyclopyrrolone class that acts by binding to the benzodiazepine (BZ) site on the GABA receptor complex, causing neural inhibition and helping to induce sleep. Eszopiclone has selectivity for certain BZ receptor subtypes, and does not have the neuromuscular relaxation or anticonvulsant effects of the standard benzodiazepines. Eszopiclone has a relatively short half life and rapid onset of action. In multiple placebo controlled trials, eszopiclone was shown to decrease the latency to onset of sleep and improve perceived sleep quality, with few next day residual effects and minimal evidence of rebound insomnia after withdrawal. Eszopiclone is the S-isomer of zopiclone that has been available in other countries for more than 20 years. Eszopiclone was approved for use in the United States in 2004 for the treatment of insomnia and remains in common use. Eszopiclone is available in 1, 2 and 3 mg tablets generically and under the brand name Lunesta. The recommended dose is 1 to 3 mg taken orally immediately before bedtime. Like the other benzodiazepine receptor agonists, eszopiclone is classified as a Schedule IV controlled substance (low potential for abuse and limited physical or psychological dependence). Side effects are uncommon, usually mild and may include unpleasant taste (bitter), headache, nausea, dizziness, dry mouth and drowsiness.
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In multiple premarketing randomized controlled trials, eszopiclone was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy, and no instance of clinically apparent liver injury was reported. Since its approval and widescale use, eszopiclone has not been implicated in causing clinically apparent liver disease, although hepatitis and liver injury are listed as a rare adverse reactions in the product label. Eszopiclone is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4 and 2E1). Nevertheless, drug-drug interactions appear to be uncommon. Thus, eszopiclone induced liver injury must be rare, if it occurs at all.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nDrug Class: Sedatives and Hypnotics\n\nOther Drugs in the Subclass, Benzodiazepine Receptor Agonists: Zaleplon, Zolpidem
| null | null |
Eszopiclone – Generic, Lunesta®
|
Sedatives and Hypnotics
| null |
Ponesimod.nxml
|
Ponesimod
|
2021-07-15
|
Ponesimod is an orally available immunomodulatory drug used to treat relapsing forms of multiple sclerosis. Ponesimod is associated with transient serum enzyme elevations during therapy but has not been linked to instances of clinically apparent liver injury with jaundice, although experience with its use has been limited.
|
Ponesimod (poe nes’ i mod) is an immunomodulatory agent used in the treatment of multiple sclerosis that is believed to act by modulating sphingosine-1-phosphate (S1P) receptors. Ponesimod is an analogue of sphingosine and related in structure to fingolimod, the first S1P receptor modulator approved for use in multiple sclerosis. While fingolimod demonstrates nonspecific S1P receptor binding (subtypes 1, 3, 4 and 5), ponesimod has a more limited specificity and primarily blocks S1P receptor-1 activity. The S1P receptor modulators, once phosphorylated intracellularly, render T and B cells insensitive to signals necessary for egress from lymphoid tissue. In animal models of multiple sclerosis, ponesimod resulted in reduced recirculation of autoaggressive lymphocytes to the central nervous system. Subsequently, in several randomized controlled trials, ponesimod was shown to reduce relapse rates and improve neuro-radiologic outcomes in adult patients with relapsing multiple sclerosis. Ponesimod was approved for use in the United States in 2021 as therapy of relapsing multiple sclerosis in adults. It is available in tablets of 2 to 10 mg for dose initiation and 20 mg for maintenance therapy under the brand name Ponvory. As with other S1P receptor modulators, a period of dose escalation (14 days) is recommended for initiation of therapy with ponesimod. Ponesimod has also been shown to have beneficial effects in plaque psoriasis, but has yet to be approved for that indication. Common side effects of ponesimod (as with most S1P receptor modulators) are lymphopenia, headache, dizziness, diarrhea, cough, rhinorrhea, peripheral edema and back and abdominal pain. Rare, but potentially severe adverse events include severe viral, bacterial or fungal infections, atrial arrhythmias and bradycardia, macular edema, decrease in pulmonary function, progressive multifocal leukoencephalopathy (PML), and embryonal-fetal toxicity. Patients on long term ponesimod should be monitored for infectious complications and for cardiac, pulmonary and ophthalmologic status.
|
In preregistration trials of ponesimod, serum ALT elevations were common (in up to 23% of recipients) but were typically mild and asymptomatic, returning to baseline values even with continuation of therapy or within a few months of stopping. In one prospective, carefully monitored trial, serum aminotransferase elevations above 3 times upper limit of normal (ULN) were reported in 17% of ponesimod recipients and above 5 times ULN in 4.6%. In these prelicensure clinical trials, there were no cases of acute hepatitis or clinically apparent liver injury with jaundice, but elevations in liver tests led to early discontinuation in at least 2% of subjects. While ponesimod is associated with lymphopenia and long-term therapy is associated with risk for reactivation of herpes simplex and zoster infections, it has not been linked to cases of reactivation of hepatitis B although one such case has been reported with fingolimod. Thus, mild-to-moderate and transient serum enzyme elevations during therapy are common, but clinically apparent liver injury with jaundice due to ponesimod has not been reported, although the clinical experience with its use has been limited.\n\nLikelihood score: E* (suspected but unproven cause of clinically apparent liver injury).
|
The mechanism by which ponesimod might cause liver injury is not known. It is extensively metabolized by liver via multiple enzymes in the cytochrome P450 system, predominantly CYP 3A4, and drug-drug interactions with agents that induce or inhibit these enzymes are likely to occur. Serum enzyme elevations have been frequent with all of the oral S1P receptor modulators, particularly with fingolimod.
|
While chronic therapy with ponesimod can be associated with mild-to-moderate serum aminotransferase elevations, it has not been linked to any cases of clinically apparent liver injury. Because of the frequency of enzyme elevations detected during therapy, the product label for ponesimod recommends obtaining baseline liver tests before initiation of treatment. However, no specific recommendations for monitoring liver tests during treatment have been made. Any ALT or AST elevation associated with symptoms or jaundice should lead to prompt discontinuation of ponesimod. Patients with persistent elevations above 3 times ULN should be assessed for other causes of liver injury and discontinue ponesimod if not other cause is found. There is no known cross sensitivity of the hepatic injury from ponesimod with other agents used to treat multiple sclerosis. Because of the similarity in chemical structure and mechanism of action, there may be cross sensitivity to side effects with fingolimod, siponimod and ozanimod.\n\nDrug Class: Multiple Sclerosis Agents\n\nOther Drugs in the Subclass, S1P Receptor Modulators: Fingolimod, Ozanimod, Siponimod
|
Ponesimod – Ponvory®
|
Multiple Sclerosis Agents
| null |
Hydroxyzine.nxml
|
Hydroxyzine
|
2017-01-16
|
Hydroxyzine is a first generation antihistamine that is used largely for symptoms of itching, nausea, anxiety and tension. Hydroxyzine has not been linked to instances of clinically apparent acute liver injury.
|
Hydroxyzine (hye drox' i zeen) is a first generation antihistamine that is used mostly to treat itching and nausea. Because of its sedating effects, hydroxyzine is also used for anxiety, tension and as a mild sleeping aid. Hydroxyzine belongs to the piperazine class of antihistamines (with cyclizine and meclizine) which are more commonly used for itching, nausea and anxiety than for their effects on symptoms of allergic rhinitis or coryza. Hydroxyzine was approved for use in the United States in 1957 and continues to be widely used. It is available as tablets or capsules of 10, 25, 50 and 100 mg in multiple generic forms and under the trade names Atarax and Vistaril. Hydroxyzine is also available as an oral suspension or syrup and as a liquid for injection. Most formulations are available without prescription. The recommended adult oral dose ranges from 25 to 100 mg three to four times daily. Doses used for itching are generally lower than those for anxiety and tension. Common side effects include sedation, impairment of motor function, confusion, dizziness, blurred vision, dry mouth and throat, palpitations, tachycardia, abdominal distress, constipation and headache. Antihistamines can worsen urinary retention and glaucoma.
|
Despite widespread use, hydroxyzine has not been linked to liver test abnormalities or to clinically apparent liver injury. Indeed, hydroxyzine is commonly used for the pruritus associated with liver disease. The reason for its safety may relate to low daily dose and limited duration of use.\n\nLikelihood score: E (unlikely to be a cause of clinically apparent liver injury).\n\nReferences on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.\n\nDrug Class: Antihistamines
| null | null |
Hydroxyzine – Generic, Atarax®, Vistaril®
|
Antihistamines
| null |
Bacopa.nxml
|
Bacopa monnieri
|
2024-04-24
|
Bacopa is an herbal extract made from the leaves of Bacopa monnieri, a herbaceous plant native to the Indian subcontinent which has been used in Ayurvedic medicine for centuries to treat anxiety, insomnia, and epilepsy and to improve memory and cognitive function. Bacopa has not been linked to liver enzyme elevations during therapy nor to instances of clinically apparent acute liver injury.
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Bacopa is an herbal extract made from the fresh or dried leaves of Bacopa monnieri, a creeping, herbaceous plant native to the Indian subcontinent that has been used for centuries in Ayurvedic medicine to treat anxiety, depression, memory loss, and epilepsy. Currently it is widely used to boost memory and improve cognitive function and mental focus. Also known as water hyssop, bacopa monnieri leaves and roots have more than 100 components including flavonoids, flavones, saponins, triterpenoids, glycosides, sterols, and lipids. The active ingredients are thought to be saponin glycosides referred to as bacosides. In vitro and in vivo studies suggest that bacosides have anxiolytic, antiinflammatory, antioxidant, antiulcer, and neuroprotective properties leading to purported effects in many diseases and disease conditions including dementia, hyperactivity, memory loss, and depression. However, bacopa has not been shown to be effective for any disease or medical symptom in adequately controlled, prospective trials in humans, and bacopa is not approved in the United States as therapy of any medical condition. Nevertheless, Bacopa monnieri is available in multiple over-the-counter herbal products. The typical dose is 300 to 600 mg of the extract daily, the equivalent of 5 to 10 grams of the dried herb. Bacopa has only minor and usually short-lived side effects which may include abdominal pain, nausea, diarrhea, flatulence, dry mouth, headache, dizziness, insomnia, and rash. The overall rate of adverse events in bacopa-treated subjects has usually been similar to that in placebo controls. In small clinical trials, bacopa has had no serious or severe adverse effects.
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Bacopa extract has not been linked to serum enzyme elevations during therapy, although there have been few prospective studies in humans that have reported on laboratory test results during treatment. Importantly, despite widespread use, bacopa has not been implicated in cases of clinically apparent liver disease.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).
| null | null |
Bacopa – Generic
|
Herbal and Dietary Supplements
| null |
Causality.nxml
|
Causality
|
2019-11-20
| null | null | null | null | null | null | null | null |
Riociguat.nxml
|
Riociguat
|
2018-06-04
|
Riociguat is a stimulator of guanylate cyclase which causes relaxation of vascular smooth muscle and is used to treat severe pulmonary arterial hypertension. Riociguat has not been linked to significant serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury.
|
Riociguat (rye" oh sig' ue at) is small molecular weight stimulator of soluble guanylate cyclase, an enzyme responsible for synthesis of cyclic guanine monophosphate (cyclic GMP), an important mediator of endothelial cell relaxation. By stimulating cyclic GMP, riociguat leads to relaxation of vascular smooth muscle cells, particularly in the pulmonary vasculature. In humans, riociguat induces pulmonary arterial vasodilation and reduces pulmonary artery pressure. In several clinical trials, prolonged therapy with riociguat has been shown to improve exercise capacity and pulmonary function in patients with severe idiopathic as well as chronic thromboembolic pulmonary arterial hypertension (PAH). Riociguat was approved for use in chronic idiopathic and thromboembolic PAH in 2013 and it is currently available in tablets of 0.5, 1.0, 1.5, 2.0 and 2.5 mg under the brand name Adempas. The recommended starting dose is 1 mg three times daily which can be increased in 0.5 mg amounts every two weeks based upon tolerance to a maximum of 2.5 mg thrice daily. Side effects are generally dose related and can include hypotension, syncope, dizziness, headache, diarrhea, gastrointestinal upset, nausea, vomiting and constipation, symptoms that are frequent with most vasodilator therapies. Rare, but potentially severe adverse reactions include pulmonary hemorrhage and fetal toxicity. Women of childbearing potential can receive riociguat only as a part of a risk evaluation and mitigation strategy (REMS) program that requires regular monitoring.
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In preregistration studies, riociguat was not associated with serum enzyme elevations or with episodes of clinically apparent liver injury. Since approval of riociguat, there have been no published reports of hepatotoxicity, and the product label does not mention liver injury as an adverse event.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).
|
The mechanism by which riociguat might cause serum aminotransferase elevations or liver injury is not known. It is metabolized by the hepatic cytochrome P450 system (predomination 3A4 and is susceptible to drug-drug interactions. The absence of significant hepatotoxicity from riociguat may related to the relatively low daily doses used (3.0 to 7.5 mg).
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The serum enzyme elevations associated with riociguat use have been rare, mild-to-moderate and self-limited in course, usually resolving despite drug continuation. Clinically apparent liver injury from riociguat has not been described. There is no information on cross sensitivity to hepatic injury among the various agents used to treat pulmonary artery hypertension.\n\nDrug Class: Pulmonary Arterial Hypertension Agents\n\nOther Drugs in the Subclass, Guanylate Cyclase Inhibitors: Vericiguat\n\nOther Drugs in the Class: Ambrisentan, Bosentan, Macitentan, Selexipag; Prostacyclin Analogs, Epoprostenol, Iloprost, Treprostinil
|
Riociguat – Adempas®
|
Pulmonary Arterial Hypertension Agents
| null |
Risankizumab.nxml
|
Risankizumab
|
2021-06-09
|
Risankizumab is a humanized monoclonal antibody to IL-23 which is used to treat moderate-to-severe plaque psoriasis. Risankizumab is generally well tolerated and is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent liver injury.
|
Risankizumab (ris” an kiz’ ue mab) is a humanized monoclonal IgG1 antibody directed against the p19 subunit of IL-23, which results in inhibition of IL-23 signaling and decrease in synthesis of proinflammatory cytokines such as IL-17. Risankizumab has been evaluated as therapy of several immune and inflammatory conditions, most extensively in plaque psoriasis. In several large, preregistration randomized controlled trials, 48 weeks of risankizumab therapy resulted in a significant improvement in psoriatic skin lesions in more than 70% of patients. Clinical responses were generally maintained with long term therapy. Risankizumab was approved in the United States in 2019 as therapy for moderate-to-severe plaque psoriasis in adult candidates for systemic therapy. It is also being evaluated in patients with psoriatic arthritis, inflammatory bowel disease and atopic dermatitis. Risankizumab is available in single dose pre-filled syringes of 75 mg in 0.83 mL under the brand name Skyrizi. The recommended dose is 150 mg (two syringes) administered subcutaneously at weeks 0 and 4 followed by every 12 weeks thereafter. Common side effects include mild local injection reactions, nasopharyngitis, fatigue, headache, arthralgia and skin rashes. Uncommon, potentially severe adverse reactions include severe infections, reactivation of tuberculosis and skin cancer.
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Mild-to-moderate serum aminotransferase elevations arise in up to 10% of patients treated with risankizumab, but the abnormalities are generally transient and asymptomatic, rarely necessitating drug discontinuation. In large, preregistration trials there were no instances clinically apparent liver injury or severe hepatic adverse events attributed to risankizumab. Since its approval and more general use, there have been no reports of clinically significant liver injury attributed to risankizumab.\n\nLikelihood score: E (unlikely cause of clinically apparent acute liver injury).
|
The possible mechanisms of liver injury due to risankizumab are unclear. Monoclonal antibodies and immunoglobulins are generally taken up and metabolized intracellularly to short peptides and amino acids. There is no evidence to suggest that inhibition of IL23 signaling would trigger liver injury or autoimmune liver conditions.\n\nDrug Class: Monoclonal Antibodies, Psoriasis Agents
| null |
Risankizumab – Skyrizi®
|
Psoriasis Agents
| null |
Resveratrol.nxml
|
Resveratrol
|
2024-11-30
|
Resveratrol is a plant polyphenol found in high concentrations in red grapes that has been proposed as a treatment for hyperlipidemia and to prevent fatty liver, diabetes, atherosclerosis and aging. Resveratrol use has been associated with rare instances of serum enzyme elevations during therapy but has not been convincingly linked to episodes of clinically apparent liver injury.
|
Resveratrol is a natural plant polyphenol (3,5,4’-trihydroxystilbene) that is found in highest concentrations in the skin of red grapes and other fruits (mulberries, blueberries, blackberries). In cell culture, resveratrol has antiinflammatory, cytoprotective, and antineoplastic properties which can be reproduced in several animal models. In model systems such as yeast (S. cerevisiae), worms (C. elegans), and fruit flies (Drosophila), chronic administration of resveratrol extends lifespan in a manner similar to caloric restriction. These results were somewhat controversial, but subsequent studies in several mammalian species supported the finding to some extent. Thus, resveratrol extended lifespan in mice fed a high fat diet (but not in normal mice), seemingly by counteracting the detrimental effects of the diet, and improving insulin sensitivity and mitochondrial function. The bases for the beneficial effects of resveratrol are unclear. Resveratrol has direct antioxidant effects, but also stimulates expression of antioxidant enzymes and the activity of sirtuin 1 (SIRT1) and adenosine monophosphate activated protein kinase (AMP-K), both of which have major effects on glucose and fat metabolism and may play a role in aging. Resveratrol is available without prescription as a nutritional supplement in multiple preparations and doses. In human trials, doses of resveratrol have ranged from 20 mg to 5 gm daily, but a typical over-the-counter recommended dose is 500 mg twice daily. Importantly, the purity of commercial products is rarely well defined, its oral bioavailability is poor and the component responsible for its activity is not known. Thus, resveratrol exists in both trans and cis configuration and the major form found in plasma is a sulfated or glucuronidal conjugate rather than free resveratrol. At present, there is no conclusive evidence that resveratrol has beneficial effects in humans. On the other hand, it has few if any side effects. Side effects may include minor gastrointestinal upset, nausea, headache and fatigue and possible supplement-drug interactions with estrogens and anticoagulants.
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There have been multiple trials of resveratrol in human subjects, but the dose regimen and duration of therapy has varied greatly and many trials lacked information on adverse events, ALT elevations, and hepatotoxicity. Nevertheless, in most studies there was no mention of serum ALT elevations or only rare and mild-to-moderate increases that were asymptomatic and resolved rapidly upon stopping therapy. However, in studies using high doses of resveratrol (1.5 to 3.0 grams daily), average serum ALT and AST levels rose slightly during therapy and promptly fell into the normal range with stopping. There were, however, no instances of serum ALT elevations with jaundice or symptoms. Furthermore, despite widespread clinical use, there have been no published reports of clinically apparent liver injury attributed to resveratrol. In large case series and nationwide registries on herbal induced liver injury, resveratrol is not listed as a cause. Thus, hepatotoxicity due to resveratrol must be rare, if it occurs at all.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).\n\nDrug Class: Herbal and Dietary Supplements
| null | null |
Resveratrol – Generic
|
Herbal and Dietary Supplements
| null |
Omega3FattyAcids.nxml
|
Omega-3 Fatty Acids
|
2017-04-08
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Omega-3 fatty acids are essential polyunsaturated fatty acids that have diverse functions in normal metabolism and health and are used as nutritional supplements for general health and for disease prevention and as prescription drugs for treatment of hypertriglyceridemia. The omega-3 fatty acids are generally safe and well tolerated and have not been implicated in causing serum enzyme elevations or clinically apparent liver injury.
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The omega-3 fatty acids are essential fatty acids that serve several important functions in normal metabolism and health. Omega-3 refers to their common structural feature of an unsaturated double bond at the third carbon bond from the “omega” end of the long chain fatty acid (n-3). There are three essential omega-3 fatty acids: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is an 18-carbon fatty acid with 3 double bonds (18:3n-3) and is found in plant oils such as walnut, flaxseed and canola oil. EPA, a 21-carbon molecule with 5 double bonds (21:5n-3), and DHA, a 22-carbon molecule with 6 double bonds (22:6n-3), are found in marine oils such as fish oils, squid oils and krill oil. Being essential, these fatty acids are not (or poorly) synthesized by humans and the necessary amounts must be provided in the diet. The amounts of omega-3 fatty acids in a typical Western diet can be marginal or inadequate, particularly EPA and DHA in persons with limited fish intake. For these reasons, the omega-3 fatty acids are some of the most commonly used nutrition supplements. They have been proposed to be not only necessary for good health, but also to be effective in prevention of many chronic conditions, including different forms of cancer, coronary artery disease, cerebrovascular disease, developmental disabilities, depression, bipolar illness, cognitive decline, Alzheimer disease, macular degeneration, rheumatoid arthritis, eczema and allergic conditions. However, efficacy of omega-3 fatty acid supplementation in any of these conditions has not been proven and results of prospective controlled trials have been largely negative or at most conflicting. Nevertheless, omega-3 fatty acids are popular nutritional supplements and hundreds of products are available under many commercial names such as “GNC Krill Oil”, “Nordic Natural DHA”, “Carlson Fish Oil Q”, “iHealth Overga-3”, “Jarrow Formulas Flaxseed Oil”, “ProThera Eicosamax Fish”, and “Swanson EFAs”, among others. These products are usually in the form of capsules and vary widely in concentration of the individual omega-3 fatty acids, but are generally in the range of 250 mg to 1,000 mg of total omega-3 fatty acids and recommended as being taken once daily. Side effects of omega-3 fatty acid and fish oil supplements in these doses are minimal, but may include mild gastrointestinal discomfort, nausea, diarrhea and headache. More clinically significant side effects include platelet dysfunction and an increased risk of bleeding, particularly in patients on anticoagulant and antithrombotic therapy.
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In the many, large, randomized controlled trials of the omega-3 fatty acids, side effects have been minimal. Use of omega-3 fatty acids even in high doses has not been linked convincingly to serum enzyme elevations or to instances of clinically apparent liver injury. At high doses used to treat hypertriglyceridemia, minor ALT elevations were identified in up to 12% of patients, but similar rates occurred in placebo treated subjects and the abnormalities were transient, mild and not associated with symptoms or jaundice. Indeed, there have been several clinical trials of various formulations of the omega-3 fatty acids in patients with nonalcoholic fatty liver and preexisting elevations in serum aminotransferase levels. While not demonstrating a convincing beneficial effect in fatty liver disease, the omega-3 fatty acids also did not demonstrate any evidence of hepatic injury or worsening of the preexisting serum enzyme elevations.\n\nLikelihood score: E (unlikely cause of clinically apparent liver injury).
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Omega-3 fatty acids are metabolized in the liver by beta-oxidation and broken down locally, usually into short chain fatty acids. They have little effect on hepatic cytochrome P450 or drug transporter activity. Their effects on triglyceride metabolism are more likely to be beneficial than harmful to hepatocytes.
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Omega-3 Fatty Acids – Generic®
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Herbal and Botanical Supplements
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[
{
"cas_registry_number": "463-40-1",
"molecular_formula": "C18-H30-O2",
"name": "ALA"
},
{
"cas_registry_number": "1553-41-9",
"molecular_formula": "C20-H30-O2",
"name": "EPA"
},
{
"cas_registry_number": "25167-62-8",
"molecular_formula": "C22-H32-O2",
"name": "DHA"
}
] |
Eculizumab.nxml
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Eculizumab
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2017-03-25
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Eculizumab is a humanized monoclonal antibody to complement factor 5 which acts to block complement activation and is used to treat paroxysmal nocturnal hemoglobinuria and hemolytic uremic syndrome. Eculizumab has been linked to several instances of serum enzyme elevations after repeated infusions and to rare instances of clinically apparent acute liver injury.
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Eculizumab (e" kue liz' ue mab) is a recombinant, humanized IgG monoclonal antibody to complement factor 5, which inhibits its enzymatic cleavage and activation. Activated complement is an important mediator of immune damage including hemolysis of red blood cells and plays an essential role in the hemolysis and tissue damage that accompanies paroxysmal nocturnal hemoglobinuria (PNH) and hemolytic uremic syndrome (HUS). In clinical trials in PNH, eculizumab was found to reduce hemolysis and the need for blood transfusions with subsequent improvement in symptoms and quality of life. Eculizumab was approved for use in PNH in the United States in 2007. The indications were later broadened to include atypical hemolytic uremic syndrome with complement-mediated thrombotic events in 2011. Eculizumab is available as a solution in single dose vials of 300 mg in 30 mL (10 mg/mL) under the commercial name Soliris. The recommended dose varies by body weight and indication, but it is typically given by intravenous infusion (over 35 minutes) weekly for 5 weeks and every two weeks thereafter. Side effects are not common, but can include headache, diarrhea, nausea, fatigue and upper respiratory tract infections. Rare, but potentially severe adverse reactions include serious infections, including meningococcal infections, for which reason eculizumab is available only as a part of a risk evaluation and mitigation strategy (REMS) that requires physician training in its use and enrollment of the patient in a surveillance program.
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In clinical trials of eculizumab in patients with PNH and atypical HUS, serum enzyme levels were rarely mentioned and laboratory test results were described as being stable or unremarkable. In preregistration studies of eculizumab there were no reports of clinically apparent liver injury with jaundice. Indeed, in many studies, a steady improvement in ALT and AST values during treatment was described, perhaps reflecting the decrease in intravascular hemolysis that occurred. After approval and more widespread use of eculizumab, however, a case series of eculizumab therapy in 11 children with atypical HUS, reported that 5 children developed marked serum enzyme elevations during therapy that was accompanied by jaundice in three cases and led to discontinuation of treatment in one patient after development of symptoms and jaundice (Case 1). The onset of injury was within the first 4 doses of eculizumab and tended to recur with subsequent doses, but to a lesser extent. Indeed, 4 children were able to continue eculizumab therapy without recurrence. The pattern of serum enzyme elevations was mixed. There was no mention of immunoallergic symptoms or autoantibody formation. Similar cases have not been reported in other case series or clinical trials. Thus, liver injury may occur with eculizumab therapy but it is typically mild, asymptomatic and self-limited in course, not requiring dose modification or discontinuation. There have been no reports of acute liver failure, chronic hepatitis or vanishing bile duct syndrome associated with eculizumab therapy.\n\nLikelihood score: D (possible cause of clinically apparent liver injury).
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The mechanism by which eculizumab might cause liver injury is unknown. Eculizumab is a monoclonal antibody and, like other proteins, is metabolized into amino acids and is unlikely to have intrinsic toxicity. Because it blocks the activation of complement, it might predispose to conditions that depend on complement activation for resolution (such as meningococcemia), but it is not clear whether this applies to any liver diseases.
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Eculizumab therapy has been linked to rare instances of mild, transient serum enzyme elevations during therapy, typically arising 1 to 3 weeks after an initial or early infusion of the monoclonal antibody. Instances of jaundice and symptoms from liver injury with eculizumab therapy are rare and not well described, but there have been no reports of acute liver failure, chronic hepatitis, cirrhosis or vanishing bile duct syndrome associated with it use. In patients who develop persistent elevations of serum ALT or alkaline phosphatase or who develop jaundice and symptoms, therapy should be interrupted.\n\nDrug Class: Hematologic Agents, Monoclonal Antibodies
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Eculizumab – Soliris®
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Hematologic Agents
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