Acute Hepatic Injury Associated with Varenicline in a Patient
with Underlying Liver Disease
Andrew J Franck and Lisa R Sliter
arenicline is a drug with a unique
V mechanism of action that is consid-
ered, along with nicotine replacement
therapies and sustained-release bupropi-
on, to be a first-line agent for smoking
cessation.1 Varenicline is a partial agonist
for α4β2 nicotinic acetylcholine recep-
tors. Varenicline is thought to provide
smoking cessation effects by acting as
agonist at these receptors while simulta-
neously antagonizing the binding of
nicotine to the same receptors.2
Acute hepatic injury is defined as
damage to hepatocytes occurring over a
short period of time and can present as
jaundice or nonspecific acute illness with
elevated aspartate aminotransferase (AST)
and/or alanine aminotransferase (ALT)
levels. Common causes of acute hepatic
injury include viral hepatitis, alcoholic
hepatitis, ischemic injury, or toxic injury.
Less common causes of hepatic injury in-
clude Wilson’s disease and autoimmune
hepatitis.3 Drug-induced liver injury is the
most common reason for drug withdrawal
from the market.4 To our knowledge, there
have been no previous case reports of hep-
atotoxicity associated with varenicline.
Case Report
A 53-year-old white male (height 165 cm; weight 65
kg) was admitted to the palliative care unit for symptom
management while awaiting liver transplantation. The pa-
tient’s past medical history included alcoholic liver dis-
Author information provided at the end of the text.
theannals.com
OBJECTIVE: To report a case of acute hepatic injury associated with varenicline.
CASE SUMMARY: A 53-year-old white male with underlying alcoholic liver disease
and history of hepatitis C virus infection experienced elevated aminotransferase
and alkaline phosphatase levels consistent with acute hepatic injury after initiation
of varenicline for smoking cessation. The hepatic injury manifested 4 weeks after
initiation of varenicline therapy at 0.5 mg once daily for 3 days, 0.5 mg twice daily
for 4 days, and then 1 mg twice daily. Following discontinuation of varenicline, the
patient’s aminotransferase levels continued to rise for 2 days before steadily
decreasing and returning to baseline levels in approximately 4 months. Alkaline
phosphatase continued to rise for 8 days after discontinuation of varenicline
before returning to baseline within 1 month. Rechallenge was not attempted.
DISCUSSION: Varenicline is a novel, first-line agent for smoking cessation. The
presentation of this patient is most consistent with an acute hepatic injury related
to drug toxicity. The pattern of the patient’s elevated hepatic enzyme levels is not
consistent with his underlying alcoholic liver disease or hepatitis C. Using the
Naranjo probability scale, as well as the Counsel for International Organizations
of Medical Science/Roussel Uclaf Causality Assessment Method algorithm for
drug-induced liver toxicity, we determined that varenicline was the probable
cause of the acute hepatic injury. Varenicline was a possible cause of the acute
hepatic injury using the algorithm for drug-induced liver toxicity developed by
Maria and Victorino. To our knowledge, this is the first report of acute hepatic
injury associated with varenicline.
CONCLUSIONS: While the benefits of smoking cessation are likely greater than the
risk of hepatic injury, clinicians should be cognizant of this reaction associated
with varenicline.
KEY WORDS: acute hepatic injury, hepatitis, hepatotoxicity, varenicline.
Ann Pharmacother 2009;43:1539-43.
Published Online, 28 Jul 2009, theannals.com, DOI 10.1345/aph.1M131
ease, portal hypertension, hepatorenal syndrome, esopha-
geal varices, thrombocytopenia, ascites, anasarcus, hypoal-
buminemia, encephalopathy, chronic kidney disease, and
macrocytic anemia. The patient also had a history of hep-
atitis C virus (HCV) infection. On admission, he had posi-
tive serum antibodies for HCV, but HCV RNA was unde-
tectable. The patient had undergone repeated paracenteses
and a transjugular intrahepatic portosystemic shunt proce-
The Annals of Pharmacotherapy n 2009 September, Volume 43 n 1539
AJ Franck and LR Sliter
dure. He was a retired welder with a social history that was
significant for an 80 pack-year smoking history and alco-
hol abuse for 30 years, which included drinking approxi-
mately 12 beers/day plus an additional unknown amount
of grain alcohol. Family history included a living mother
and siblings with alcohol abuse disorder, as well as a father
who died of prostate cancer.
Upon admission, the patient was started or continued on
the following scheduled medications: furosemide 80 mg
orally twice daily, lactulose syrup 20 g (30 mL) orally
twice daily, spironolactone 150 mg orally once daily, Cal-
moseptine (active ingredients: zinc oxide and menthol)
ointment twice daily, vitamin A and D ointment once dai-
ly, trazodone 150 mg orally once daily at bedtime, lo-
razepam 1 mg orally once daily at bedtime, paroxetine 10
mg orally once daily, magnesium oxide 400 mg orally
twice daily, and ciprofloxacin 750 mg orally once weekly.
The patient also received the following as-needed medica-
tions: hydromorphone 0.5–1.0 mg intravenously as needed
for pain taken on average once weekly, hydroxyzine 25–50
mg orally as needed for itching, taken on average 3– 4
times each week, lorazepam 0.5–1.0 mg subcutaneously or
orally as needed for anxiety/nausea/sleep taken on average
2–3 times each week, oxycodone immediate-release 5 mg
orally as needed for pain taken on average once or twice
daily, and simethicone 80 mg orally as needed for gas/indi-
gestion taken on average 3– 4 times each week. The pa-
tient had received a measles-mumps-rubella vaccination at
an unknown time in the past, as well as influenza and
pneumococcal vaccinations within the past year, but no
other known immunizations. He was not taking over-the-
counter or herbal medicines. Since the patient was in the
facility, adherence to drug therapy was ensured. The pa-
tient did not have a history of known allergies or adverse
reactions to any drugs.
Approximately 3 months after admission,
the patient made the decision to quit smoking
and was referred to the smoking cessation pro-
gram. Varenicline was initiated at 0.5 mg once
daily for 3 days, then 0.5 mg twice daily for 4
days, then 1 mg twice daily for smoking cessa-
tion. The patient developed nausea within 1
week after starting varenicline treatment. Four
weeks after starting varenicline treatment, he
complained of increased pruritus, nausea, and
vomiting. Liver chemistry tests were per-
formed at that time, and the patient’s AST,
ALT, and alkaline phosphatase levels were
found to be 868 U/L, 657 U/L, and 183 U/L,
respectively. Physical examination showed no
jaundice, 2+ ascites, 2+ edema, and mild ab-
dominal pain, but was otherwise unremark-
able. The complete cell blood count showed Figure 1. Patient’s values for aspartate aminotransferase (AST), alanine amino-
eosinophils, monocytes, lymphocytes, hemo- transferase (ALT), and alkaline phosphatase (ALP).
1540 n The Annals of Pharmacotherapy n 2009 September, Volume 43
globin, and hematocrit to be 19.5%, 11.1%, 23.0%, 10.5
g/dL, and 29.0% respectively; the findings were otherwise
within normal limits. These values were similar to those at
baseline for the patient. Total bilirubin, total protein, albu-
min, and serum creatinine were 1.0 mg/dL, 6.3 g/dL, 2.0
g/dL, and 0.7 mg/dL, respectively. Abdominal ultrasound
revealed no new findings and ruled out biliary obstruction.
Serologic tests were negative for acute viral hepatitis. HCV
antibodies remained positive and HCV RNA remained neg-
ative after the event. HCV RNA was rechecked several
months after the event and remained negative. The patient
did not have a history of cytomegalovirus, Epstein-Barr
virus, or herpes virus. He also did not have a history of car-
diac diseases or any episodes of recent hypotension. The pa-
tient had not started or discontinued any scheduled medica-
tions during the same timeframe. Additionally, as-needed
medication use was consistent throughout the patient’s ad-
mission. He was maintained in the palliative care unit
throughout treatment and was kept on a consistent diet. He
did not have access to outside food, drugs, or alcohol. Due
to varenicline being the only new medication and therefore
the possible cause of the elevated liver enzyme levels, it was
discontinued. No other medications were discontinued.
Aminotransferase levels continued to rise for 2 days af-
ter discontinuation of varenicline before declining steadily
and returning to baseline in approximately 4 months. Al-
kaline phosphatase levels continued to rise for 8 days be-
fore returning to baseline within 1 month (Figure 1). Maxi-
mum AST, ALT, and alkaline phosphatase levels were 951
U/L, 746 U/L, and 228 U/L, respectively. The patient’s as-
needed medications were all continued after the hepatic in-
jury and use remained consistent before and after the
event. Varenicline was the only drug that was started and
discontinued during this timeframe. The patient was not
rechallenged with varenicline.
theannals.com

Discussion
Patients with underlying alcoholic liver disease or
chronic hepatitis C infection may have elevated amino-
transferase levels as a sign of their disease. However, the
elevation of aminotransferase levels in this case is not consis-
tent with a chronic liver disease.5-8 Aminotransferase en-
zymes are rarely elevated more than 10 times the upper limit
of normal except in cases of acute hepatic injury.3 On admis-
sion, the patient had positive HCV antibodies and negative
HCV RNA. This could indicate an acute hepatitis C infection
during a low level of viremia, but more commonly represents
a resolution of HCV infection. Based on the patient’s history
and lack of acute hepatitis symptoms, this would most likely
indicate resolution of HCV infection. HCV RNA is usually
detectable before HCV antibodies in acute infections and
retesting for HCV RNA after 4–6 months can confirm the
resolution of HCV infection. The patient’s HCV RNA re-
mained negative for several months after the event, which
rules out the possibility of acute hepatitis C.7
Based on the degree of aminotransferase elevation, the
patient experienced an acute hepatic injury. Aminotrans-
ferase levels are not strongly related to severity of acute
hepatic injury, but can be used to help determine the cause
of the injury.3,5 Potential causes of acute hepatic injury in-
clude viral hepatitis, alcoholic hepatitis, toxic injury, and
ischemic injury.3,6 As discussed above, an acute HCV in-
fection was ruled out by negative HCV RNA test results.
Other potential viral causes, such as hepatitis A virus, hep-
atitis B virus, cytomegalovirus, herpesvirus, and Epstein-
Barr virus, were ruled out through use of serologic testing
and patient history. Additionally, acute viral hepatitis typi-
cally presents with an AST:ALT ratio less than 1.3 This pa-
tient had an AST:ALT ratio greater than 1. Alcoholic hep-
atitis can be ruled out as a possible cause because it typi-
cally presents with an AST:ALT ratio greater than 2 and
rarely results in AST or ALT levels greater than 10 times
the upper limit of normal.3,8 This patient had an AST:ALT
ratio less than 2 and aminotransferase levels over 15 times
the upper limits of normal. Ischemic injury was ruled out
in this patient because he did not have a history of cardio-
vascular disease or any episodes of acute hypotension.
The presentation of this patient is consistent with acute
hepatic injury from drug toxicity. This includes AST and
ALT levels greater than 300 U/L, AST:ALT ratio greater
than 1, peak bilirubin less than 5 mg/dL, and alkaline
phosphatase less than 3 times the upper limit of normal.
Furthermore, drug-induced causes of acute hepatic injury
should particularly be considered when alkaline phos-
phatase is increased along with aminotransferase levels, as
it was in this patient’s case.3 Other potential drug causes
were excluded because the patient’s drug regimen re-
mained consistent before and after the event, with the ex-
ception of varenicline. Varenicline was the only drug with
a temporal relationship to the event.
theannals.com The Annals of Pharmacotherapy
Acute Hepatic Injury Associated with Varenicline
According to the Naranjo probability scale, this case
represents a probable adverse drug event related to vareni-
cline.9 Additionally, using the Counsel for International
Organizations of Medical Science/Roussel Uclaf Causality
Assessment Method for drug-induced liver toxicity, we de-
termined that varenicline was the probable cause of hepa-
totoxicity.10 The method for assessing drug-induced liver
toxicity developed by Maria and Victorino showed vareni-
cline to be a possible cause of hepatotoxicity.11 These prob-
ability scales take into account factors such as time rela-
tionship to event, other potential causes, and previous re-
ports of similar events. While rechallenging the patient
with varenicline could have provided a more definitive
conclusion, it was not done because both the patient and
treatment team deemed the drug to have an unacceptable
risk-benefit ratio.
Although patients with underlying liver disease are not
universally at higher risk for acute hepatic injury, it may be
the case for certain drugs.4,12,13 Types of drug-induced liver
injury include predictable reactions and idiosyncratic reac-
tions. Predictable drug-induced liver toxicity can be com-
pensated for by adjusting the dose of the medication based
on the patient’s hepatic function. Idiosyncratic reactions
are far more common and are unlikely to be affected by
underlying liver dysfunction.12
Varenicline does not have warnings for use in patients
with hepatic impairment. It is not extensively metabolized,
but is eliminated primarily (92%) by glomerular filtration and
excreted unchanged in the urine. Because of this, pharma-
cokinetics in patients with hepatic insufficiency should be un-
affected and no dosage adjustments are recommended.2
Due to the low incidence of drug-induced liver injury, it
is often not detected during clinical trials.14 In clinical trials
evaluating varenicline for smoking cessation, the drug was
found to be safe and effective. The most common adverse
reactions were nausea, sleep disturbances, constipation,
flatulence, and vomiting. However, one limitation of these
trials is exclusion of patients with serious medical condi-
tions such as liver disease and history of alcohol abuse.
Similarly, patients with psychiatric disorders, such as bipo-
lar disorder and major depressive disorder, were also ex-
cluded from the trials.15-19 Postmarketing surveillance has
shown that varenicline may induce neuropsychiatric symp-
toms including depression, agitation, and suicidal behav-
ior.2 In fact, the Food and Drug Administration released an
alert highlighting the changes made to package insert and
medication guide regarding these findings.20 A PubMed
search (1950 –July 2009) of case reports, using the term
varenicline, returned entries related to neuropsychiatric ef-
fects, acute renal failure, hypoglycemia, exanthema, and
ataxia, but none related to hepatotoxicity. This case has
been reported to MedWatch.
Practice guidelines for evaluation of patients for liver
transplantation recommend that patients undergo efforts to
n 2009 September, Volume 43 n 1541
AJ Franck and LR Sliter
abstain from smoking before transplantation.21 Sustained-
release bupropion, a first-line agent for smoking cessation,
should be used with extreme caution in patients with hep-
atic cirrhosis.22 Since varenicline is the only other non-
nicotine replacement first-line agent for smoking cessa-
tion,1 many patients with hepatic cirrhosis may be prefer-
entially treated with varenicline and therefore at risk of this
reaction.
Clinicians using varenicline should be cognizant of the
possibility of hepatotoxicity with this agent, perhaps more
so in patients with underlying liver disease, and may
choose to monitor aminotransferase levels in these pa-
tients. Further research is needed to confirm the findings of
this case and elucidate the mechanism of hepatotoxicity.
Therefore, any cases similar to this one should be reported.
Andrew J Franck PharmD, Pharmacy Resident, Department of
Pharmacy, North Florida/South Georgia Veterans Health System,
Gainesville, FL
Lisa R Sliter PharmD BCPS CDE, Clinical Pharmacist, Primary
Care, Department of Pharmacy, North Florida/South Georgia Vet-
erans Health System
Reprints: Dr. Franck, Department of Pharmacy, North Florida/South
Georgia Veterans Health System,1601 SW Archer Rd., Gainesville,
FL 32608, fax 386/758-6017, Andrew.Franck@va.gov
Financial disclosure: None reported
References
1. Hudmon KS, Corelli RL. ASHP therapeutic position statement on the
cessation of tobacco use. Am J Health Syst Pharm 2009;66:291-307.
2. Product information. Chantix (varenicline). New York: Pfizer Labs, May
2008.
3. Dufour DR, Lott JA, Nolte NS, Gretch DR, Koff RS, Seeff LB. National
Academy of Clinical Biochemistry. Diagnosis and monitoring of hepatic
injury. II. Recommendations for use of laboratory tests in screening,
diagnosis, and monitoring. Clin Chem 2000;46:2050-68.
4. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003;349:474-85.
5. Johnston DE. Special considerations in interpreting liver function tests.
Am Fam Physician 1999;59:2223-32.
6. Green RM, Flamm S. American Gastroenterological Association. Tech-
nical review on the evaluation of liver chemistry tests. Gastroenterology
2002;123:1367-84.
7. Ghany MG, Strader DB, Thomas DL, Seeff LB. American Association
for the Study of Liver Diseases. Diagnosis, treatment, and management
of hepatitis C: an update. Hepatology 2009;49:1335-74.
8. McCullough AJ, O’Conner JFB. Alcoholic liver disease: proposed rec-
ommendations for the American College of Gastroenterology. Am J
Gastroenterol 1998;93:2022-36.
9. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the prob-
ability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
10. Danan G, Benichou. Causality assessment of adverse reactions to
drugs—I. A novel method based on the conclusions of international con-
sensus meetings: application to drug-induced liver injuries. J Clin Epi-
demiol 1993;46:1323-30.
11. Maria VAJ, Victorino RMM. Development and validation of a clinical
scale for the diagnosis of drug-induced hepatitis. Hepatology 1997;26:
664-9.
12. Schenker S, Martin RR, Hoyumpa AM. Antecedent liver disease and
drug toxicity. J Hepatol 1999;31:1098-105.
13. Gupta NK, Lewis JH. Review article: the use of potentially hepatotoxic
medications in patients with liver disease. Aliment Pharmacol Ther
2008;28:1021-41.
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14. Holt MP, Ju C. Mechanisms of drug-induced liver injury. AAPS J 2006;
8:Article 6. www.aapsj.org (accessed 2009 Feb 5).
15. Gonzales D, Rennard SI, Nides M, et al. Varenicline, an α4β2 nicotinic
acetylcholine receptor partial agonist, vs sustained-release bupropion and
placebo for smoking cessation: a randomized controlled trial. JAMA
2006;296:47-55.
16. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an α4β2
nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-
release bupropion for smoking cessation: a randomized controlled trial.
JAMA 2006;296:56-63.
17. Tonstad S, Tonnesen P, Hajek P, Williams KE, Billing CB, Reeves KR.
Effect of maintenance therapy with varenicline on smoking cessation: a
randomized controlled trial. JAMA 2006;296:64-71.
18. Oncken C, Gonzales D, Nides M, et al. Efficacy and safety of the novel
selective nicotinic acetylcholine receptor partial agonist, varenicline, for
smoking cessation. Arch Intern Med 2006;166:1571-7.
19. Nides M, Oncken C, Gonzales D, et al. Smoking cessation with vareni-
cline, a selective α4β2 nicotinic receptor partial agonist. Arch Intern
Med 2006;166:1561-8.
20. United States Food and Drug Administration. Varenicline (marketed as
Chantix) information. www.fda.gov/ cder/drug/infopage/varenicline/de-
fault.htm (accessed 2009 Mar 3).
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angle Park, NC: GlaxoSmithKline, August 2007.
Lesión Hepática Aguda Asociada con Vareniclina en un Paciente
con Enfermedad Hepática Subyacente
AJ Franck y LR Sliter
Ann Pharmacother 2009;43:1539-43.
EXTRACTO
OBJETIVO: Notificar un caso de lesión hepática aguda asociada con
vareniclina.
RESUMEN DEL CASO: Un varón de 53 años de raza caucásica con enferme-
dad hepática subyacente de causa alcohólica e historial de infección por
el virus de la hepatitis C presentó una elevación de los niveles de amino-
transferasa y fosfatasa alcalina congruente con lesión hepática aguda tras
el inicio del tratamiento con vareniclina para dejar de fumar. Tras la
interrupción del tratamiento con vareniclina, los niveles de aminotrans-
ferasas del paciente siguieron en aumento durante 2 días y posteriormente
fueron descendiendo de forma constante hasta volver al nivel basal 4
meses después. El nivel de fosfatasa alcalina del paciente siguió aumen-
tando durante 8 días tras la interrupción del tratamiento con vareniclina
antes de volver al nivel basal 1 mes después.
DISCUSIÓN: Vareniclina es un agente novedoso de primera línea para dejar
de fumar. El caso de este paciente es congruente con una lesión hepática
aguda relacionada con la toxicidad del fármaco. El patrón de elevación
de enzimas hepáticas del paciente no es congruente con la enfermedad
hepática subyacente de causa alcohólica o con la hepatitis C. Según el
nomograma de reacciones adversas de Naranjo, así como el algoritmo
del Counsel for International Organizations of Medical Science/Roussel
Uclaf Causality Assessment Method (CIOMS/RUCAM) para la toxicidad
hepática inducida por fármacos, vareniclina fue la causa probable de la
lesión hepática aguda. Vareniclina fue una causa posible de la lesión hepá-
tica aguda según el algoritmo para la toxicidad hepática inducida por
fármacos desarrollado por María y Victorino. Hasta el momento, éste es el
primer caso conocido de lesión hepática aguda asociada con vareniclina.
CONCLUSIONES: Aunque los beneficios del cese del tabaco probablemente
sean mayores que el riesgo de este efecto adverso, los facultativos deben
estar al corriente de esta reacción asociada con vareniclina.
Traducido por Enrique Muñoz Soler
theannals.com

Une Atteinte Hépatique Aigue Associée à l’Utilisation de la
Varénicline
AJ Franck et LR Sliter
Ann Pharmacother 2009;43:1539- 43.
RÉSUMÉ
OBJECTIF: Décrire un cas de patient qui a développé une atteinte
hépatique aigue suite à l’administration de la varénicline.
RÉSUMÉ DU CAS: Un homme âgé de 53 ans avec de lourds antécédents
médicaux dont notamment, une maladie hépatique alcoolique et une
hépatite C, a été admis à l’unité de soins palliatifs en attente d’une trans-
plantation hépatique. Près de 3 mois après son admission, le patient
décide de cesser de fumer et est référé à un programme de désaccoutu-
mance au tabac. Le patient débute alors une thérapie orale de varénicline
dont la posologie quotidienne est augmentée jusqu’à 1 mg bid. Le patient
manifeste des nausées environ une semaine après avoir débuté la
varénicline et 4 semaines plus tard, se plaint de prurit, de nausées et de
vomissements. Des tests sanguins sont alors effectués et une élévation des
aminotransférases et de la phosphatase alcaline est documentée.
L’examen physique ne décèle aucun épisode de jaunisse, bien qu’un
œdème, une ascite et une douleur abdominale légère soient notés. Une
obstruction des voies biliaires est exclue suite à une échographie
abdominale. La varénicline est alors cessée. Malgré cet arrêt de traitement,
theannals.com The Annals of Pharmacotherapy
Acute Hepatic Injury Associated with Varenicline
les niveaux d’aminotransférases continuent à augmenter pour 2 jours
puis diminuent de façon régulière pour retourner à des valeurs normales
de référence à l’intérieur de 4 mois suivant l’arrêt. Les niveaux de
phosphatase alcaline continuent aussi à augmenter pendant 8 journées
après l’interruption de la varénicline avant de retourner dans l’écart
normal 1 mois plus tard.
DISCUSSION: La varénicline est un nouvel agent de première intention
comme aide de désaccoutumance au tabac. La présentation de ce patient
est un exemple classique d’une atteinte hépatique aigue d’origine médica-
menteuse. L’évolution des enzymes hépatiques n’est pas concordant
avec l’évolution usuelle d’une maladie hépatique alcoolique ou d’une
hépatite C. Selon l’algorithme de Naranjo et les échelles d’évaluation de
la causalité de l’Organisation mondiale de la Santé et de RUCAM pour
les toxicités d’origine hépatique, la varénicline a été la cause probable de
l’atteinte hépatique aigue chez ce patient. La varénicline a aussi été
classifiée comme la cause probable de cette toxicité hépatique selon
l’algorithme développé par Maria et Victorino. Selon les auteurs, il
s’agit du premier cas d’atteinte hépatique aigue associée à la varénicline.
CONCLUSIONS: Bien que les bénéfices d’une aide antitabagique soient
possiblement plus importants que le risque d’une atteinte hépatique
aigue, les cliniciens doivent demeurer vigilants quant à la survenue
possible de cet effet indésirable grave.
Traduit par Sylvie Robert
n 2009 September, Volume 43 n 1543