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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Isotretinoin

Last Update: November 10, 2020.

OVERVIEW

Introduction

Isotretinoin is a retinoid and vitamin A derivative used in the treatment of severe acne and some forms of skin, head and neck cancer. Isotretinoin, like many retinoids, can lead to increase in serum aminotransferase levels, but, unlike acitretin and etretinate, isotretinoin has not been clearly implicated in cases of clinically apparent acute liver injury with jaundice.

Background

Isotretinoin (eye" soe tret' i noyn), also known as 13-cis-retinoic acid, is an aromatic retinoid similar to vitamin A which is effective in treating refractory nodular acne and other disorders of keratinization. Unlike vitamin A, isotretinoin is not stored in the liver and is not associated with many of the toxic effects of high dose vitamin A therapy. Its mechanism of action in acne is believed to be mediated by activation of retinoic acid and retinoid X receptors, which regulate gene expression important in normalizing cell growth and differentiation. Isotretinoin is considered a second generation retinoid and its relative lack of receptor specificity accounts for its adverse side effects. All oral retinoids are potent teratogens and must be avoided or used with extreme caution in women of childbearing potential. Isotretinoin was approved for use in acne in the United States in 1982 and it is currently used, but only under strict requirements for monitoring and birth control. Indications are limited to severe nodular acne in a patient who has failed to respond to conventional therapy including systemic antibiotics. Isotretinoin is available in generic forms and under several brand names (Absorica, Amnesteem, Claravis, Myorisan, Sotret, Zenatane and previously Accutane) in capsules of 10, 20, 30 and 40 mg, the usual dose in adults being 0.5 to 2.0 mg/kg per day given in two divided doses for 15 to 20 weeks. Higher doses have been used in treatment of head and neck cancers. Side effects are common and include dry skin, nose bleeds, conjunctivitis and hair loss. Use of isotretinoin has also been linked to worsening of hyperlipidemia, hyperostosis, vision and hearing loss, pancreatitis, pseudotumor cerebri, birth defects, depression and suicide.

Hepatotoxicity

Liver test abnormalities occur in up to 15% of patients on isotretinoin, although marked elevations above three times the upper limit of normal or requiring drug discontinuation are rare (<1%). The liver test abnormalities are typically asymptomatic and transient and can resolve even with continuing therapy. Clinically apparent liver injury due to isotretinoin is exceedingly rare. The acute liver injury with signs of hypersensitivity that occurs with etretinate and acitretin has not been described with isotretinoin therapy. Vitamin A-like effects on the liver with accumulation of lipids in nonparenchymal stellate cells has been described in rare patients on isotretinoin therapy, but the role of supplementary use of vitamin A in these cases was not ruled out. Thus, the majority of reported cases of liver injury attributed to isotretinoin have been anicteric with no or minimal symptoms. However, the lack of reports of more severe hepatitis with jaundice may be due to the close monitoring and early discontinuation of isotretinoin which is required in the use of this agent for acne.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which isotretinoin causes serum aminotransferase elevations is not known, but it may represent a direct toxic effect, in that it appears to be more frequent with higher dose therapy.

Outcome and Management

Monitoring of liver tests is recommended for patients receiving isotretinoin at regular intervals. The serum aminotransferase elevations that occur during treatment are usually self-limited and do not always require dose modification or discontinuation of therapy. However, de novo elevations in serum aminotransferase levels of more than 5 times the upper limit of normal should prompt at least temporary discontinuation, particularly if confirmed on a second sample or if accompanied by symptoms or jaundice. Patients with acitretin or etretinate associated acute liver injury have been found to tolerate isotretinoin without recurrence of liver injury, although isotretinoin is not approved and may not be as effective as acitretin in treating psoriasis.

Drug Class: Dermatologic Agents; Vitamins

Other Drugs in the Subclass:

CASE REPORT

Case 1. Acute anicteric hepatitis with autoimmune features due to isotretinoin.(1)

A 16 year old adolescent female was found to have serum aminotransferase elevations 11 weeks after starting isotretinoin for severe acne. She had no history of liver disease, drug allergies, risk factors for viral hepatitis or alcohol use. Her past medical history included Hashimoto thyroiditis and hypothyroidism for which she took levothyroxine (50 mg daily). She was taking no other medications including over-the-counter products and herbal supplements. She had no symptoms of liver disease and the elevations were identified during routine monitoring of the isotretinoin therapy. Physical examination showed no evidence of hepatomegaly, abdominal tenderness or jaundice. Laboratory tests showed a serum ALT of 853 [22.4 times ULN], AST 501 U/L [12.5 times ULN], alkaline phosphatase 48 U/L [normal <340], and bilirubin 0.3 mg/dL [direct 0.10]. The R ratio was 22. The following week the ALT had risen to 1199 U/L and AST to 756 U/L, and isotretinoin was stopped (Table). Serum bilirubin remained normal, albumin was 4.3 g/dL, globulins 2.9 g/dL and INR 1.1. Tests for hepatitis A, B, C and E were negative. While serum SMA was negative, ANA was positive in a titer of 1:160 and IgG was mildly elevated [1659 mg/dL, normal 700-1550 mg/dL]. Abdominal ultrasonography showed no evidence of biliary obstruction and no organomegaly or hepatic masses. A liver biopsy showed focal hepatocyte degeneration and parenchymal lymphocytic infiltration as well as mild portal inflammation and mild interface hepatitis. Because of the possibility of autoimmune hepatitis, she was started on prednisone (40 mg daily) to which azathioprine was added 2 weeks later. The serum aminotransferase levels rapidly improved and were normal 6 weeks after starting therapy. The prednisone was gradually reduced in dosage and eventually discontinued. The liver tests remained normal thereafter; isotretinoin was not restarted.

Key Points

Medication:Isotretinoin (20 mg twice daily)
Pattern:Hepatocellular (peak R=32)
Severity:1+ (anicteric)
Latency:11 weeks
Recovery:8 weeks
Other medications:Levothyroxine

Laboratory Values

Time After
Starting
Time After
Stopping
ALT
(U/L)
Alk P
(U/L)
Bilirubin
(mg/dL)
Comments
Pre026430.4Isotretinoin started
11 weeks0853480.3Asymptomatic
12 weeks011991140.4Isotretinoin stopped
14 weeks2 weeks3271050.3Prednisone 40 mg/d
15 weeks3 weeks123780.3Azathioprine added
17 weeks5 weeks68520.3Prednisone dose reduced
19 weeks7 weeks41290.3
5 months2 months40230.4Prednisone 5 mg/d
6 months3 months24190.3
1.5 years1 year23410.7No Pred or Azathioprine
2 years2 years16400.4
3 years3 years25310.4
Normal Values<38<340<1.2

Comment

An acute anicteric hepatitis arose during isotretinoin therapy in an adolescent girl with acne and a history of autoimmune thyroid disease. The hepatitis was asymptomatic, but ALT levels rose to 32 times ULN and the drug was stopped. Testing revealed a high titer of ANA and mild immunoglobulin elevations prompting a liver biopsy that was read as compatible with autoimmune hepatitis. She was treated with prednisone and azathioprine and liver tests fell to normal within 6 to 8 weeks. The dose of prednisone was gradually decreased and both prednisone and azathioprine were subsequently discontinued. She was followed carefully thereafter, and liver tests remained normal. This case nicely demonstrates the marked serum aminotransferase elevations that can occur during isotretinoin therapy. Unique in this case was the accompanying autoimmune features which led to use of immunosuppression. Importantly, prednisone and azathioprine were subsequently reduced in dose and then discontinued. Liver tests remained normal indicating that the injury was probably drug induced liver injury with autoimmune features rather than spontaneous autoimmune hepatitis. [Addition details and test results kindly provided by Dr. Patricia Guzman.]

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Isotretinoin – Generic, Absorica®, Claravis®, Zenatane®

DRUG CLASS

Dermatologic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Isotretinoin4759-48-2C20-H28-O2Image Isotretinoin-Image001.jpg

CITED REFERENCES

1.
Guzman Rojas P, Gallegos Lopez R, Ciliotta Chehade A, Scavino Y, Morales A, Tagle M. Rev Gastroenterol Peru. 2016;36:86–9. [Autoimmune hepatitis induced by isotretionine] Spanish. [PubMed: 27131947]

ANNOTATED BIBLIOGRAPHY

References updated: 10 November 2020

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    (Textbook of pharmacology and therapeutics).
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    (150 patients with nodulocystic acne were treated with one of 3 doses of isotretinoin [0.1, 0.5 or 1.0 mg/kg/day] for 20 weeks; side effects were common [dry skin, nosebleeds, hair loss, headache], mean ALT and AST values increased slightly in the highest dose group, and AST increases occurred in 15-18% of patients, but did not lead to dose modification or clinical symptoms).
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    (Discussion of two synthetic analogues of vitamin A introduced into dermatology: isotretinoin [used in acne] and etretinate [used in psoriasis]; these retinoids are less toxic than vitamin A and not stored in the liver, although they are metabolized there; minor liver test abnormalities may arise during therapy, but rarely required dose modification).
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    (64 year old woman was found to have abnormal liver tests 5 months after starting etretinate [bilirubin 0.7 mg/dL, ALT 950 U/L, Alk P 402 U/L], liver biopsy showing hepatitis without steatosis, resolving with stopping and prednisone therapy, recurring upon rechallenge, but not when isotretinoin was started which was less effective for the psoriasis).
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    (Retinoids are modifications of vitamin A molecule and are not stored in the liver; hepatotoxicity of retinoids is different from that of vitamin A, usually arising within first 1-2 months and having features of hypersensitivity).
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    (Review of toxicity of retinoids including description of liver biopsy results described by Glazer [1982]).
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    (Review of liver injury due to hypervitaminosis A and retinoids identified 18 reports of vitamin A hepatotoxicity in the English literature, patient ages 6 to 63 years, presenting with rash, fatigue, hepatomegaly and hepatic synthetic dysfunction, biopsy showing fat in stellate cells and fibrosis; little evidence that isotretinoin causes liver injury other than mild rapidly reversible ALT elevations; etretinate causes ALT elevations in ~20% of patients and case reports of clinically apparent injury have been published, but vary in clinical patterns).
  • Marhold I, Duschet P, Schwarz T, Gschnait F. Hautarzt. 1991;42:580–3. [Successful use of isotretinoin in type Zumbusch generalized pustular psoriasis following recovered etretinate-induced hepatitis] German. [PubMed: 1938411]
    (29 year old woman with psoriasis responded to etretinate but developed rising Alk P levels [172 to 1736 U/L] without jaundice and only mild ALT increases [38 to 178 U/L] 24 days after starting therapy, which improved on stopping and she later tolerated isotretinoin without recurrence [Alk P 118 U/L, ALT 14 U/L]).
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    (18 year old male body builder developed elevated ALT levels [134 U/L] without jaundice during 6 month course of isotretinoin for acne; liver biopsy showed marked steatosis, but ALT levels remained high 20 months after stopping drug).
  • McElwee NE, Schumacher MC, Johnson SC, Weir TW, Greene SL, Scotvold MJ, Hunter JR, et al. An observational study of isotretinoin recipients treated for acne in a health maintenance organization. Arch Dermatol. 1991;127:341–6. [PubMed: 1825596]
    (Retrospective analysis of 466 patients treated with isotretinoin in a health care maintenance organization found 6 [1.8%] with moderate AST elevations [90-350 U/L], but levels often normalized despite drug continuation; isotretinoin stopped in 3 patients for liver tests abnormalities).
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    (Patients have been treated with retinoids for up to 15 years, generally without toxicity; retinoids do not accumulate in the liver and do not cause accumulation of fat droplets in stellate cells as occurs with hypervitaminosis A; two types of hepatotoxicity, one idiosyncratic acute hepatitis typically occurring with aromatic retinoids and one a long term low grade injury that can lead to cirrhosis, perhaps aggravated by alcohol that the author claims can occur with all retinoids).
  • Barth JH, Macdonald-Hull SP, Mark J, Jones RG, Cunliffe WJ. Isotretinoin therapy for acne vulgaris: a re-evaluation of the need for measurements of plasma lipids and liver function tests. Br J Dermatol. 1993;129:704–7. [PubMed: 8286255]
    (Retrospective analysis of 209 patients treated with isotretinoin found "no significant change in any of the tests of liver function", which led the authors to argue against the recommendation for routine monitoring of liver tests during therapy).
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    (Summary of warnings placed on isotretinoin regarding suicide and potential of liver test abnormalities; 15% of patients on therapy had some degree of liver test abnormality arising on therapy, mostly asymptomatic and resolving without altering dose).
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    (Review and hypothesis regarding interactions of vitamin A, retinoids and hepatitis B virus infection).
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    (Prospective analysis of safety in two trials of isotretinoin in 369 patients with acne found no overall change in mean ALT levels "to a significant extent" and no episodes of hepatitis and jaundice; no mention of drug discontinuation for ALT elevations).
  • Alcalay J, Landau M, Zucker A. Analysis of laboratory data in acne patients treated with isotretinoin: is there really a need to perform routine laboratory tests? J Dermatolog Treat. 2001;12:9–12. [PubMed: 12171680]
    (Retrospective analysis of computerized medical files from 1292 patients treated with isotretinoin for 5 to 9 months, found no patient who required discontinuation because of liver tests; elevations occurred in a "minority of patients", with peak ALT levels of 40-240 U/L).
  • Charakida A, Mouser PE, Chu AC. Safety and side effects of the acne drug, oral isotretinoin. Expert Opin Drug Saf. 2004;3:119–29. [PubMed: 15006718]
    (Review of myriad of toxicities of isotretinoin from clinical trials: approximately 15% of patients have mild-to-moderate liver test abnormalities, although frank hepatotoxicity is "a fairly rare event").
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    (Among 638 patients with moderate acne treated with isotretinoin, improvement in >90%; 5% had ALT elevations [all less than 2 times ULN]; no mention of jaundice, symptomatic hepatitis or dose modification because of liver test abnormalities).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, one was attributed to acitretin: Case 1 for acitretin).
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    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, isotretinoin was the most frequently mentioned agent [420 cases: 6.4%], but no information on the characteristics of the cases is provided).
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    (Among 313 cases of drug induced liver injury seen between 1997 and 2008 at a large hospital in Bangalore, India, no cases were attributed to vitamin A or retinoids).
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  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, three of which were attributed to isotretinoin [ranking 6th in frequency] all of which were anicteric and only one symptomatic).
  • Blasiak RC, Stamey CR, Burkhart CN, Lugo-Somolinos A, Morrell DS. High-dose isotretinoin treatment and the rate of retrial, relapse, and adverse effects in patients with acne vulgaris. JAMA Dermatol. 2013;149:1392–8. [PubMed: 24173086]
    (Among 116 patients with severe acne treated with isotretinoin, ALT levels above 105 U/L arose in only 1 patient).
  • Kızılyel O, Metin MS, Elmas ÖF, Çayır Y, Aktaş A. Effects of oral isotretinoin on lipids and liver enzymes in acne patients. Cutis. 2014;94:234–8. [PubMed: 25474452]
    (In a retrospective analysis of 320 patients with acne treated with isotretinoin for up to 6 months, average ALT levels increased, but the change was not statistically significant).
  • Fernández-Crehuet P, Fernández-Crehuet JL, Allam MF, Fernández-Crehuet Navajas R. Hepatotoxicity of isotretinoin in patients with acne and Gilbert's syndrome: a comparative study. BMJ Open. 2014;4:e004441. [PMC free article: PMC3963066] [PubMed: 24650805]
    (Among 37 patients with acne treated with isotretinoin for up to 20 weeks, serum bilirubin and ALT levels did not worsen, bilirubin levels actually falling in 11 patients with Gilbert's syndrome).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, two of which were attributed to retinoids, unclear which ones).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 3 cases were attributed to acitretin, but none to other retinoids or vitamin A).
  • Homma Y, Otani N, Ishimatsu S. A case report of acute vitamin A intoxication due to ocean perch liver ingestion. J Emerg Med. 2015;49:15–7. [PubMed: 25850632]
    (27 year old man developed flushing, headache, nausea and joint pains one day after eating 800 g of ocean perch liver, with normal liver enzymes, but high retinol levels and subsequent facial desquamation).
  • Mengual-Moreno E, Lizarzábal-García M, Ruiz-Soler M, Silva-Suarez N, Andrade-Bellido R, Lucena-González M, Bessone F, et al. Invest Clin. 2015;56:3–12. [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela] Spanish. [PubMed: 25920181]
    (During a one year period, 13 cases of drug induced liver injury were seen at a single hospital in Venezuela, the implicated agents being acetaminophen [3], ibuprofen [3], isoniazid [2], Herbalife products [2: one fatal], and 1 each of isotretinoin, amoxicillin/clavulanate and methotrexate).
  • Ahmad HM. Analysis of clinical efficacy, side effects, and laboratory changes among patients with acne vulgaris receiving single versus twice daily dose of oral isotretinoin. Dermatol Ther. 2015;28:151–7. [PubMed: 25754162]
    (Among 58 patients with acne treated with isotretinoin for an average of 22 weeks, ALT levels increased by 21% with once daily and 3% with twice daily administration of the same average dose, but all elevations were transient and less than 100 U/L).
  • Bugdayci G, Polat M, Oguzman H, Cinpolat HY. Interpretation of biochemical tests using the reference change value in monitoring adverse effects of oral isotretinoin in 102 ethnic Turkish patients. Lab Med. 2016;47:213–9. [PMC free article: PMC4985773] [PubMed: 27346869]
    (Among 102 Turkish patients with acne, ages 15 to 37 years, treated with oral isotretinoin for 24 weeks, mean ALT and AST values did not change, but instances of "Reference Change Values" were more frequent than in controls).
  • Guzman Rojas P, Gallegos Lopez R, Ciliotta Chehade A, Scavino Y, Morales A, Tagle M. Rev Gastroenterol Peru. 2016;36:86–9. [Autoimmune hepatitis induced by isotretionine] Spanish. [PubMed: 27131947]
    (16 year old girl with acne developed serum enzyme elevations 3 months after starting isotretinoin [ALT 1196 U/L, Alk P 114, ANA 1:180] and improved with stopping isotretinoin and starting corticosteroid therapy).
  • DeKlotz CMC, Roby KD, Friedlander SF. Dietary supplements, isotretinoin, and liver toxicity in adolescents: a retrospective case series. Pediatrics. 2017;140:e20152940. pii. [PubMed: 28864554]
    (Eight adolescents with acne in an isotretinoin monitoring program were found to have mild elevations in serum aminotransferase levels [ALT 34-59 U/L, AST 41-187 U/L, bilirubin normal and Alk P not provided], but all were also taking herbal and dietary supplements, including green tea, energy shakes and amino acids and creatine, and the elevations appeared to be more related to these products than the isotretinoin therapy).
  • Fox R, Stace N, Wood K, French C. Liver toxicity from vitamin A. JGH Open 2019; 4: 287-8.
    (27 year old female with acne who had received several six-month courses of isotretinoin in the past developed fatigue 18 months after starting vitamin A [bilirubin 0.9 mg/dL, ALT 15 U/L, Alk P 208 U/L], biopsy showing microvesicular fat and prominent stellate cells, with slow improvement after stopping).
  • Nazarian RS, Zheng E, Halverstam C, Cohen SR, Wolkoff AW. Prolonged serum alanine aminotransferase elevation associated with isotretinoin administration. Case Reports Hepatol. 2019;2019:9270827. [PMC free article: PMC6662412] [PubMed: 31380129]
    (16 year old teenage boy developed ALT elevations within 2 months of starting isotretinoin which continued to rise for the month after stopping [peak bilirubin 0.5 mg/dL, ALT 288 U/L, Alk P 153 U/L, INR 1.2], which improved on starting cholestyramine and eventually fell to baseline two months later; he later tolerated restarting isotretinoin without recurrence of liver injury).
  • Barbieri JS, Frieden IJ, Nagler AR. Isotretinoin, patient safety, and patient-centered care-time to reform iPLEDGE. JAMA Dermatol. 2020;156:21–2. [PubMed: 31664426]
    (Viewpoint on the FDA program restricting use of isotretinoin and requiring rigorous monitoring for birth control mentions that pregnancy prevention programs are often ineffective but can be financially burdensome and interfere with appropriate therapy of severe acne; no discussion of ALT elevations or hepatotoxicity).
  • Bagatin E, Costa CS. The use of isotretinoin for acne - an update on optimal dosing, surveillance, and adverse effects. Expert Rev Clin Pharmacol. 2020;13:885–97. [PubMed: 32744074]
    (Review of the literature on the efficacy and safety of isotretinoin concludes that it is highly effective in patients with severe acne and that its serious side effects can be effectively managed; ALT elevations generally arise during the first few months of therapy and often resolve even without discontinuation or dose modification).

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