Case Report 13-0149(0401) Crepin, Godet, Carrier et al. Galley Page 1 LNJ/DB/MWS 2 tables case report xxxxx
UNPROOFED GALLEY c a s e r e p o r t
Probable drug-induced liver injury associated with aliskiren: Case report and review of adverse event reports from pharmacovigilance databases Sabrina Crepin, Bertrand Godet, Paul Carrier, Claire Villeneuve, Louis Merle, and Marie-Laure Laroche Purpose. A case of probable drug-induced liver injury (DILI) attributed to use of the antihypertensive agent aliskiren is reported. Summary. A 61-year-old woman undergoing routine liver function monitoring in conjunction with long-term antiepileptic therapy was noted to have an asymptomatic acute hepatic cytolysis one month after the initiation of concomitant aliskiren therapy (150 mg/day). Liver enzyme testing showed dramatically elevated aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, with substantial rises also noted in g-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels. The calculated ALT:ALP value indicated hepatocellular injury. On discontinuation of aliskiren use, rapid biological improvement occurred, including normalization of serum AST and a sharp decline in serum ALT within one week and the return of GGT and ALP levels to baseline a few weeks later; the patient’s AST and ALT concentrations remained normal during 18 months of subsequent monitoring. Using the algorithm of Naranjo et al. and a DILIspecific causality assessment instrument, it
Sabrina Crepin, Pharm.D., M.P.H., is Hospital Pharmacist, Department of Pharmacology—Toxicology, Pharmacovigilance; Bertrand Godet, M.D., is [QUERY: Pls. give job title], Department of Neurology; Paul Carrier, M.D., is [QUERY: Pls. give job title], Department of Hepatogastroenterology; Claire Villeneuve, M.S.I., is [QUERY: Pls. give job title], Department of Pharmacology—Toxicology, Pharmacovigilance; Louis Merle, Ph.D., M.D., is [QUERY: Pls. give job title], Department of Pharmacology—Toxicology, Pharmacovigilance; and Marie-Laure Laroche, Ph.D., M.D., is [QUERY: Pls. give job title], Department of Pharmacology—Toxicology, Pharma-
covigilance, Limoges University Hospital, Limoges, France. Address correspondence to Dr. Crepin ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/xxxx-xxxx$06.00. DOI 10.2146/ajhp130149
Am J Health-Syst Pharm—Vol 71 Mth x, 2014
1
Case Report 13-0149(0401) Crepin, Godet, Carrier et al. Galley Page 2 LNJ/DB/MWS 2 tables case report xxxxx was determined that aliskiren use was the probable cause of the patient’s liver injury. While this is believed to be the first report of aliskiren-associated DILI in the professional literature, a review of information from several European and North American pharmacovigilance databases (through October 2012) identified 117 reports of suspected alilskiren hepatotoxicity, including 6 reports of liver failure and 12 deaths. Conclusion. Asymptomatic acute hepatic cytolysis was observed in a 61-year-old woman approximately one month after initiation of aliskerin for treatment of hypertension. Rapid improvement in AST and ALT concentrations was observed shortly after the drug was discontinued. Am J Health-Syst Pharm. 2014; 71:xxxx-xx
D
rug-induced liver injury (DILI) is an adverse effect usually resulting in acute liver injury, which could extend from an asymptomatic elevation of liver enzyme activity to an acute liver failure resulting in death or the need for liver transplantation. DILI is a frequent cause of liver injury. The worldwide annual incidence rate of DILI is estimated at 1 in 10,000–100,000 persons per year of exposure,1 and DILI accounts for an estimated 3–10% of all adverse drug effects reported to health authorities in selected countries (Denmark, New Zealand, and England).2-5 Over 1,000 medications and herbal products have been implicated in the occurrence of DILI.6,7 The predominant clinical presentation of DILI is acute hepatitis or cholestasis, although almost any clinical pathological pattern of acute or chronic liver disease can occur. DILI accounts for approximately half of cases of acute liver failure.8 DILI is usually dose dependent, reproducible in animal models, and manifests after a short latency (ranging from hours to a few days). The drugs involved are usually identified in preclinical studies (acetaminophen is a classic example); therefore, DILI may be predictable. However, in most cases, liver injury is unpredictable or idiosyncratic, occurs with variable latency (one week to one year) and 2
Am J Health-Syst Pharm—Vol 71 Mth x, 2014
Case Report 13-0149(0401) Crepin, Godet, Carrier et al. Galley Page 3 LNJ/DB/MWS 2 tables case report xxxxx
low incidence, and may not be dose related. Accurate reporting of DILI is important for early detection and awareness of drug-induced hepatotoxicity. We report here what appears to be the first published case of probable DILI associated with the use of aliskiren and review similar reports in the pharmacovigilance databases of our country (France) and several others. Case presentation A 61-year-old Caucasian woman (weight, 54 kg) who had been treated for several years with insulin for type 2 diabetes, cholecalciferol for osteomalacia, and carbamazepine (1200 mg/day), clobazam (15 mg/day), pregabalin (400 mg/day) and primidone (750 mg/day) for focal epilepsy before the initiation of aliskiren (Rasilez , Novartis Europharm Limited) 150 mg daily for hypertension. In conjunction with the patient’s ongoing antiepileptic treatment, monitoring of hepatic function was conducted regularly. The most recent monitoring results, obtained three to four months before the patient’s first use of aliskiren, showed that serum concentrations of aspartate transaminase (AST) and alanine transaminase (ALT) were within normal limits, while the g-glutamyltransferase (GGT) and alkaline phosphatase (ALP) concentrations had increased (the serum GGT was 1.5 times upper limit of normal [ULN], and the serum ALP was 1.2 times the ULN). The slight increases of GGT and ALP levels were documented before the introduction of aliskiren and had remained stable over time. One month after the initiation of asliskiren therapy, acute hepatic cytolysis without clinical symptoms was discovered during routine laboratory tests. The patient reported no change in her overall health or functional status. No intercurrent recent health event was noted during patient consultation. Liver funcAm J Health-Syst Pharm—Vol 71 Mth x, 2014
3
Case Report 13-0149(0401) Crepin, Godet, Carrier et al. Galley Page 4 LNJ/DB/MWS 2 tables case report xxxxx
tion tests revealed the following: a serum AST of 1631 IU/L (27 times the ULN), a serum ALT of 987 IU/L (25 times the ULN), a serum ALP of 466 IU/L (4 times the ULN), and a serum GGT of 820 IU/L (15 times the ULN). The ratio of ALT to ALP (in terms of multiples of the respective ULN values) was greater than 5, defining a hepatocellular injury. The patient’s prothrombin ratio was 68% (normal range, ≥80%), and her bilirubin concentration (5 mg/L) was within the normal range (
UNPROOFED GALLEY c a s e r e p o r t
Probable drug-induced liver injury associated with aliskiren: Case report and review of adverse event reports from pharmacovigilance databases Sabrina Crepin, Bertrand Godet, Paul Carrier, Claire Villeneuve, Louis Merle, and Marie-Laure Laroche Purpose. A case of probable drug-induced liver injury (DILI) attributed to use of the antihypertensive agent aliskiren is reported. Summary. A 61-year-old woman undergoing routine liver function monitoring in conjunction with long-term antiepileptic therapy was noted to have an asymptomatic acute hepatic cytolysis one month after the initiation of concomitant aliskiren therapy (150 mg/day). Liver enzyme testing showed dramatically elevated aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, with substantial rises also noted in g-glutamyl transferase (GGT) and alkaline phosphatase (ALP) levels. The calculated ALT:ALP value indicated hepatocellular injury. On discontinuation of aliskiren use, rapid biological improvement occurred, including normalization of serum AST and a sharp decline in serum ALT within one week and the return of GGT and ALP levels to baseline a few weeks later; the patient’s AST and ALT concentrations remained normal during 18 months of subsequent monitoring. Using the algorithm of Naranjo et al. and a DILIspecific causality assessment instrument, it
Sabrina Crepin, Pharm.D., M.P.H., is Hospital Pharmacist, Department of Pharmacology—Toxicology, Pharmacovigilance; Bertrand Godet, M.D., is [QUERY: Pls. give job title], Department of Neurology; Paul Carrier, M.D., is [QUERY: Pls. give job title], Department of Hepatogastroenterology; Claire Villeneuve, M.S.I., is [QUERY: Pls. give job title], Department of Pharmacology—Toxicology, Pharmacovigilance; Louis Merle, Ph.D., M.D., is [QUERY: Pls. give job title], Department of Pharmacology—Toxicology, Pharmacovigilance; and Marie-Laure Laroche, Ph.D., M.D., is [QUERY: Pls. give job title], Department of Pharmacology—Toxicology, Pharma-
covigilance, Limoges University Hospital, Limoges, France. Address correspondence to Dr. Crepin ([email protected]). The authors have declared no potential conflicts of interest. Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/xxxx-xxxx$06.00. DOI 10.2146/ajhp130149
Am J Health-Syst Pharm—Vol 71 Mth x, 2014
1
Case Report 13-0149(0401) Crepin, Godet, Carrier et al. Galley Page 2 LNJ/DB/MWS 2 tables case report xxxxx was determined that aliskiren use was the probable cause of the patient’s liver injury. While this is believed to be the first report of aliskiren-associated DILI in the professional literature, a review of information from several European and North American pharmacovigilance databases (through October 2012) identified 117 reports of suspected alilskiren hepatotoxicity, including 6 reports of liver failure and 12 deaths. Conclusion. Asymptomatic acute hepatic cytolysis was observed in a 61-year-old woman approximately one month after initiation of aliskerin for treatment of hypertension. Rapid improvement in AST and ALT concentrations was observed shortly after the drug was discontinued. Am J Health-Syst Pharm. 2014; 71:xxxx-xx
D
rug-induced liver injury (DILI) is an adverse effect usually resulting in acute liver injury, which could extend from an asymptomatic elevation of liver enzyme activity to an acute liver failure resulting in death or the need for liver transplantation. DILI is a frequent cause of liver injury. The worldwide annual incidence rate of DILI is estimated at 1 in 10,000–100,000 persons per year of exposure,1 and DILI accounts for an estimated 3–10% of all adverse drug effects reported to health authorities in selected countries (Denmark, New Zealand, and England).2-5 Over 1,000 medications and herbal products have been implicated in the occurrence of DILI.6,7 The predominant clinical presentation of DILI is acute hepatitis or cholestasis, although almost any clinical pathological pattern of acute or chronic liver disease can occur. DILI accounts for approximately half of cases of acute liver failure.8 DILI is usually dose dependent, reproducible in animal models, and manifests after a short latency (ranging from hours to a few days). The drugs involved are usually identified in preclinical studies (acetaminophen is a classic example); therefore, DILI may be predictable. However, in most cases, liver injury is unpredictable or idiosyncratic, occurs with variable latency (one week to one year) and 2
Am J Health-Syst Pharm—Vol 71 Mth x, 2014
Case Report 13-0149(0401) Crepin, Godet, Carrier et al. Galley Page 3 LNJ/DB/MWS 2 tables case report xxxxx
low incidence, and may not be dose related. Accurate reporting of DILI is important for early detection and awareness of drug-induced hepatotoxicity. We report here what appears to be the first published case of probable DILI associated with the use of aliskiren and review similar reports in the pharmacovigilance databases of our country (France) and several others. Case presentation A 61-year-old Caucasian woman (weight, 54 kg) who had been treated for several years with insulin for type 2 diabetes, cholecalciferol for osteomalacia, and carbamazepine (1200 mg/day), clobazam (15 mg/day), pregabalin (400 mg/day) and primidone (750 mg/day) for focal epilepsy before the initiation of aliskiren (Rasilez , Novartis Europharm Limited) 150 mg daily for hypertension. In conjunction with the patient’s ongoing antiepileptic treatment, monitoring of hepatic function was conducted regularly. The most recent monitoring results, obtained three to four months before the patient’s first use of aliskiren, showed that serum concentrations of aspartate transaminase (AST) and alanine transaminase (ALT) were within normal limits, while the g-glutamyltransferase (GGT) and alkaline phosphatase (ALP) concentrations had increased (the serum GGT was 1.5 times upper limit of normal [ULN], and the serum ALP was 1.2 times the ULN). The slight increases of GGT and ALP levels were documented before the introduction of aliskiren and had remained stable over time. One month after the initiation of asliskiren therapy, acute hepatic cytolysis without clinical symptoms was discovered during routine laboratory tests. The patient reported no change in her overall health or functional status. No intercurrent recent health event was noted during patient consultation. Liver funcAm J Health-Syst Pharm—Vol 71 Mth x, 2014
3
Case Report 13-0149(0401) Crepin, Godet, Carrier et al. Galley Page 4 LNJ/DB/MWS 2 tables case report xxxxx
tion tests revealed the following: a serum AST of 1631 IU/L (27 times the ULN), a serum ALT of 987 IU/L (25 times the ULN), a serum ALP of 466 IU/L (4 times the ULN), and a serum GGT of 820 IU/L (15 times the ULN). The ratio of ALT to ALP (in terms of multiples of the respective ULN values) was greater than 5, defining a hepatocellular injury. The patient’s prothrombin ratio was 68% (normal range, ≥80%), and her bilirubin concentration (5 mg/L) was within the normal range (
