Rhabdomyolysis with Concurrent Atorvastatin and Diltiazem

Abstract

To report a case of rhabdomyolysis and acute hepatitis associated with the coadministration of atorvastatin and diltiazem.
A 60-year-old African American man with a significant past medical history presented to the emergency department with acute renal failure secondary to rhabdomyolysis. In addition, liver enzymes were elevated to greater than 3 times normal. The only change in medication was the initiation of diltiazem 3 weeks earlier for atrial fibrillation to a complicated medication regimen that included atorvastatin.
Rhabdomyolysis has been reported in patients receiving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors when coadministered with agents that may inhibit their metabolism. Atorvastatin is the most potent of this class of agents currently available and is commonly used in the treatment of hyperlipidemia. Rhabdomyolysis resulting from the drug interaction between diltiazem and other HMG-CoA reductase inhibitors has been described in the literature. However, no report has specifically associated this adverse event with atorvastatin and diltiazem. We describe a patient with a complex medication regimen who was admitted for rhabdomyolysis and accompanying acute renal failure, along with acute hepatitis, thought to be secondary to a drug interaction between atorvastatin and diltiazem.
While optimizing the patient's lipid profile should be the primary factor in choosing one statin over another, the potential for drug interactions requires close attention. All patients beginning HMG-CoA reductase inhibitor therapy should be counseled regarding the signs and symptoms of muscle injury; particular attention should be paid to those patients who are taking medications that may interact.

Full text

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CASE REPORTS
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A
torvastatin is a hydroxymethylglutaryl coenzyme A
(HMG-CoA) reductase inhibitor commonly used for
the treatment of hypercholesterolemia. This class of agents,
commonly referred to as “statins,” has an excellent safety
profile and carries a low risk of adverse drug reactions.
However, the voluntary withdrawal of cerivastatin from the
market has resulted in increasing concern and has empha-
sized the risk of rhabdomyolysis with statin therapy. Ac-
cording to the Food and Drug Administration, 31 deaths
due to severe rhabdomyolysis associated with cerivastatin
have been reported.
1
In 12 of these cases, cerivastatin was
used in conjunction with gemfibrozil.
Lovastatin, simvastatin, cerivastatin, and atorvastatin are
metabolized primarily via the CYP3A4 isoenzyme. Precipi-
tation of rhabdomyolysis has been associated with the coad-
ministration of agents competing for the same metabolic
pathway, such as erythromycin, diltiazem, mibefradil, cy-
closporine, and itraconazole.
2,3
In addition, statins may inter-
act with the fibrate derivatives gemfibrozil and fenofibrate to
cause rhabdomyolysis, although the exact mechanism is
poorly understood.
4,5
To our knowledge, rhabdomyolysis
from drug interactions with atorvastatin have been previous-
ly reported in the literature in association with cyclosporine,
6
gemfibrozil,
7
delavirdine,
8
and fusidic acid.
9
We report a pa-
tient with rhabdomyolysis whose condition we believe was
associated with the concomitant use of atorvastatin and dilti-
azem.
Case Report
A 60-year old African American man presented to the emergency de-
partment with a chief symptom of abdominal pain (peri-umbilical) and
reported a “racing heart” associated with shortness of breath over the
Rhabdomyolysis with Concurrent Atorvastatin and Diltiazem
John J Lewin III, Jean M Nappi, and Marian H Taylor
OBJECTIVE: To report a case of rhabdomyolysis and acute hepatitis associated with the coadministration of atorvastatin and
diltiazem.
CASE SUMMARY: A 60-year-old African American man with a significant past medical history presented to the emergency
department with acute renal failure secondary to rhabdomyolysis. In addition, liver enzymes were elevated to greater than 3 times
normal. The only change in medication was the initiation of diltiazem 3 weeks earlier for atrial fibrillation to a complicated medication
regimen that included atorvastatin.
DISCUSSION: Rhabdomyolysis has been reported in patients receiving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase
inhibitors when coadministered with agents that may inhibit their metabolism. Atorvastatin is the most potent of this class of agents
currently available and is commonly used in the treatment of hyperlipidemia. Rhabdomyolysis resulting from the drug interaction
between diltiazem and other HMG-CoA reductase inhibitors has been described in the literature. However, no report has specifically
associated this adverse event with atorvastatin and diltiazem. We describe a patient with a complex medication regimen who was
admitted for rhabdomyolysis and accompanying acute renal failure, along with acute hepatitis, thought to be secondary to a drug
interaction between atorvastatin and diltiazem.
CONCLUSIONS: While optimizing the patient’s lipid profile should be the primary factor in choosing one statin over another, the
potential for drug interactions requires close attention. All patients beginning HMG-CoA reductase inhibitor therapy should be
counseled regarding the signs and symptoms of muscle injury; particular attention should be paid to those patients who are taking
medications that may interact.
KEY WORDS: acute hepatitis, atorvastatin, diltiazem, rhabdomyolysis.
Ann Pharmacother 2002;36:1546-9.
Author information provided at the end of the text.
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previous 24 hours. He had also noticed increasing fatigue and decreasing
urine output over the previous 2–3 days. His medical history was signifi-
cant for 3-vessel coronary artery disease, moderate tricuspid valve regur-
gitation, mild to moderate aortic valve regurgitation, severe mitral valve
regurgitation, congestive heart failure, atrial fibrillation, hypertension,
hyperlipidemia, and type 2 diabetes. Past social history was negative
with the exception of tobacco use 20 years ago. The patient’s medication
regimen on admission consisted of atorvastatin 20 mg/d, diltiazem XL
180 mg twice daily, metoprolol 100 mg twice daily, digoxin 0.125 mg/d,
benazepril 40 mg/d, furosemide 40 mg twice daily, warfarin 7.5 mg/d,
aspirin 325 mg/d, insulin 70/30 twice daily, and sublingual nitroglycerin
as needed. The patient had been taking all medications except diltiazem
for >1 year. The diltiazem had been initiated 3 weeks before this admis-
sion while the patient was hospitalized for treatment of his atrial fibrilla-
tion. The patient did not report use of any over-the-counter or prescrip-
tion agents other than those listed. During this previous admission, he
had refused triple valve replacement and coronary artery bypass grafting
as well as percutaneous coronary intervention and stent placement. In the
3 weeks prior to his presentation, the patient received a total of 16 days
of diltiazem therapy and reported adherence to all of his medication regi-
mens.
Physical examination on admission was significant for BP 91/43 mm
Hg, heart rate 66 beats/min, and no signs of traumatic injury. Pertinent
laboratory findings were as follows: creatine kinase (CK) 1898 units/L
with MB fraction 1.3%, troponin-I <1.0 ng/mL, serum myoglobin 674.7
mg/mL, urine myoglobin negative, sodium 131 mEql/L, potassium 6.3
mEq/L, phosphorus 8.2 mg/dL, blood urea nitrogen (BUN) 48 mg/dL,
serum creatinine (SCr) 3.4 mg/dL, prothrombin time (PT) 46.5 sec, in-
ternational normalized ratio (INR) 19.7, total bilirubin 0.7 mg/dL, direct
bilirubin 0.4 mg/dL, aspartate transaminase (AST) 1236 units/L, alanine
transaminase (ALT) 1610 units/L, alkaline phosphatase (ALP) 287
units/mL, and digoxin 1.3 ng/mL.
A diagnosis of acute hepatitis and rhabdomyolysis with accompany-
ing acute renal failure (ARF) was made, and the patient was subsequent-
ly admitted to the coronary care unit. All medications were discontinued,
with the exception of aspirin, digoxin, and furosemide. The patient was
hydrated with bicarbonate-containing fluids, and the coagulopathy was
treated with phytonadione and fresh frozen plasma. The complete heart
block resolved with correction of metabolic abnormalities. The rest of
the patient’s hospital course was largely uneventful, with the ARF re-
solving rapidly, resulting in transfer to the floor on hospital day 2 and
subsequent discharge on hospital day 6.
Over the course of hospitalization, the patient’s renal function re-
turned to baseline (SCr 1.1 mg/dL). His CK reached a maximum of
2092 units/L on hospital day 1 and decreased to 623 units/L on discharge
(Table 1). He did not report muscle fatigue or weakness at any point dur-
ing his hospitalization. Liver function test results reached a maximum on
hospital day 2 (AST 3070 units/L, ALT 2708 units/L, ALP 227 units/L)
and decreased through discharge (AST 150 units/L, ALT 882 units/L,
ALP 194 units/L), eventually returning to normal by 3 months (Table 2).
Prior to discharge, diltiazem was reinstated, as other measures to control
his heart rate had proven ineffective. The patient was given a follow-up
appointment to reevaluate treatment of his hypercholesterolemia as an
outpatient.
Discussion
RHABDOMYOLYSIS
Rhabdomyolysis is a potentially lethal consequence of
widespread muscle necrosis resulting from trauma, infec-
tion, toxins, and medications; it has been described in de-
tail elsewhere.
3
The mechanism by which statins cause
skeletal muscle damage has not been fully elucidated.
However, it has been proposed
10,11
that the depletion of
ubiquinone (coenzyme Q10), a necessary cofactor in the
mitochondrial electron transport system, is the major
mechanism causing this adverse effect. The synthesis of
ubiquinone is dependent on mevalonate as a precursor, the
production of which is reduced by statins. While the inci-
dence of rhabdomyolysis from statins is rare, the risk is in-
creased when they are used in combination with agents
that share similar metabolic pathways.
12
Two previously
reported pharmacokinetic studies have shown that atorva-
statin plasma concentrations are increased when coadmin-
istered with erythromycin
13
and itraconazole,
14
both potent
inhibitors of the CYP3A4 isoenzyme. Diltiazem is a nondi-
hydropyridine calcium-channel antagonist that is a substrate
and inhibitor of the CYP3A4 isoenzyme.
15
A pharmacoki-
netic analysis
16
has demonstrated increased plasma con-
centrations of lovastatin, which shares a similar metabolic
pathway to that of atorvastatin, when coadministered with
diltiazem.
In our patient, the initiation of diltiazem and subsequent
onset of the adverse event reveals a strong temporal relation-
ship and is considered probable according to the Naranjo
probability scale.
17
While the atorvastatin serum concentra-
tion was not measured, we believe that the most likely
cause of rhabdomyolysis and ARF in this patient was the
initiation of diltiazem leading to competitive inhibition of
atorvastatin metabolism and subsequent elevation of ator-
vastatin serum concentration. While hepatic enzyme inhi-
bition typically occurs within 24 hours of initiation of the
precipitant drug, our patient’s adverse event occurred 3
weeks after onset. This may be a result of the longer half-
life of atorvastatin (14 h) and the time required for accumu-
lation of a significant amount of drug within the myocytes.
We suggest that the elevation of atorvastatin concentrations
resulted in skeletal muscle damage and rhabdomyolysis, as
evidenced by the elevation of CK, serum myoglobin, serum
potassium, and subsequent deposition of myoglobin in the
kidneys, causing ARF. While our patient’s urine dipstick
for myoglobin was negative, a urinary myoglobin concen-
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Table 1. Time Course for Changes in Serum
Creatine Kinase
Date Creatine Kinase (units/L)
2/14/01 (diltiazem initiated) 783
3/7/01 (diltiazem discontinued) 2092
3/9/01 1408
7/12/01 519
Table 2. Time Course for Changes in Serum Transaminases
Date ALT (units/L) AST (units/L)
10/30/00 23 21
2/14/01 (diltiazem initiated)
3/7/01 (diltiazem discontinued) 1610 1236
3/8/01 2708 3070
3/9/01 1636 614
3/11/01 882 150
7/12/01 40 43
ALT = alanine transaminase; AST = aspartate transaminase.

tration is not the most sensitive marker for rhabdomyoly-
sis. Although our patient did not admit to muscle pain or
weakness, up to 50% of patients with rhabdomyolysis may
not admit to the presence of muscle pain.
18
HEPATOTOXICITY
Increasing concentrations of liver enzymes and, rarely,
acute hepatitis have been associated with the use of statins.
All statins currently carry the recommendation to monitor
liver enzymes. However, the statins’ potential for directly
causing hepatotoxicity may not be a class effect and has
been debated.
19
As with the elevation of CK, the elevation of transami-
nases also depicts a strong temporal relationship to the ini-
tiation of diltiazem therapy and is associated with a Naran-
jo probability rating
17
of probable. We suspect that the
acute rise in transaminases and subsequent decline to base-
line depicted in Table 2 may be a result of numerous fac-
tors. It is unclear, and perhaps unlikely, that increased ator-
vastatin concentrations and direct hepatotoxicity are solely
responsible for this acute elevation in transaminases. It is
likely that the development of ARF in addition to the pa-
tient’s valvular disease and congestive heart failure result-
ed in some degree of ischemia and/or passive congestion
of the liver. The marked elevation in PT and INR (46.5 sec
and 19.7, respectively) resulting from hepatic congestion
and presumable reduction in warfarin elimination support
this assumption.
Summary
When initiating therapy with statins, clinicians should
consider the potential impact that drug interactions may
have on the long-term safety of these agents. The potential
for drug interactions must be weighed against the relative
potencies of these agents and the likelihood of achieving
the patient’s goal lipid profile. Atorvastatin, lovastatin,
simvastatin, and cerivastatin are primarily metabolized via
Phase I metabolism by the CYP3A4 isoenzyme, predis-
posing these agents to drug interactions with medications
metabolized in the same fashion. In contrast, fluvastatin is
primarily metabolized by the CYP2C9 isoenzyme, and
pravastatin does not undergo substantial metabolism via
the cytochrome P450 system. Pravastatin and fluvastatin
may be preferable for patients taking agents metabolized
via the CYP3A4 system, provided they are capable of
achieving the goals of therapy.
While optimizing the patient’s lipid profile should be
the primary concern in choosing one statin over another,
the potential for drug interactions requires close attention.
All patients beginning statin therapy should be counseled
regarding the signs and symptoms of muscle injury; partic-
ular attention should be paid to those patients who are tak-
ing medications that may interact.
John J Lewin III PharmD, at time of writing, Resident, Critical
Care Pharmacy Practice, College of Pharmacy, Medical University of
South Carolina, Charleston, SC; now, Clinical Specialist, Critical
Care, University of Maryland Hospital, and Clinical Assistant Pro-
fessor, University of Maryland College of Pharmacy, Baltimore, MD
Jean M Nappi PharmD BCPS FCCP, Vice-Chair and Professor
of Pharmacy, College of Pharmacy, Medical University of South Car-
olina
Marian H Taylor MD, Cardiology Fellow, Department of Medicine,
Medical University of South Carolina
Reprints: John J Lewin III PharmD, University of Maryland Hospi-
tal, Department of Pharmacy Services, 22 South Greene St., Room
N1W89, Baltimore, MD 21201, FAX 410/328-8984, E-mail
jlewin@umm.edu
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EXTRACTO
OBJETIVO: Informar un caso de rabdomiólisis y hepatitis aguda asociada
a la administración concurrente de atorvastatina y diltiazem
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Case Reports
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RESUMEN: Un hombre de 60 años de edad con un amplio historial
médico se presenta a la sala de urgencias en fallo renal agudo secundario
a rabdomiólisis. Además, las enzimas hepáticas estaban elevadas tres
veces sobre lo normal. El único cambio en medicación fue añadirle
diltiazem a un regimen complejo de medicación que incluía
atorvastatina tres semanas antes para fibrilación auricular.
DISCUCION: Rabdomiólisis se ha reportado en pacientes que reciben
inhibidores de la reductasa de 3-hidroxi-3-metil glutaril coenzima A
(HMG-CoA, por sus siglas en inglés) cuando estos se administran
concurrentemente con agentes que inhiben su metabolismo.
Atorvastatina es el más potente de esta clase de agentes que se encuentra
disponible en la actualidad y se usa comúnmente en el tratamiento de
hiperlipidemia. Como resultado de la interacción entre diltiazem y otros
inhibidores de HMG-CoA, se ha descrito en la literatura que ocurre
rabdomiólisis. Sin embargo no hay reportes que asocien este evento
adverso con atorvastatina y diltiazem. En este reporte se descrbe a un
paciente complicado que se admite por rabdomiólisis y fallo renal agudo
además de hepatitis aguda que se piensa es secundaria a la interacción
de atorvastatina y diltiazem.
CONCLUSIONES: A pesar de que el factor primario para la selección de
una estatina sobre las otras debe ser la optimacióm del perfil de lípidos
de un paciente, el potencial para interacción de medicamentos requiere
de mucha atención. Todos los pacientes que comienzan una terapia con
inhibidores de la reductasa de HMG CoA deben recibir orientación
sobre los signos y síntomas de daño muscular, en particular los que están
tomando medicamentos que pueden interaccionar.
Sonia I Lugo
RÉSUMÉ
OBJECTIF: Signaler un cas de rhabdomyolyse et d’hépatite aiguë associé
à l’utilisation concomitante d’atorvastatine et de diltiazem.
PRÉSENTATION SOMMAIRE DU CAS: Un homme âgé de 60 ans avec un
lourd passé médical se présente à la salle d’urgence en insuffisance
rénale aiguë secondaire à une rhabdomyolyse. De plus, ses enzymes
hépatiques sont élevés à plus de trois fois la limite supérieure normale.
Le seul changement à sa médication remonte à il y a trois semaines
lorsque, pour traiter une fibrillation auriculaire, du diltiazem a été ajouté
à son régime médicamenteux complexe comprenant de l’atorvastatine .
DISCUSSION: La rhabdomyolyse a déjà été signalée chez des patients
recevant des inhibiteurs de la 3-hydroxy-3-méthylglutaryl- coenzyme A
(HMG-CoA) réductase alors qu’ils étaient administrés concomitamment
avec des agents pouvant inhiber leur métabolisme. L’atorvastatine est le
plus puissant des agents de cette classe et est fréquemment employé
dans le traitement de l’hyperlipidémie. Des cas de rhabdomyolyse
résultant de l’interaction entre le diltiazem et les autres inhibiteurs de
l’HMG-CoA réductase ont déjà été signalés dans la documentation
scientifique. Cependant, cet effet indésirable n’a pas encore été signalé
spécifiquement avec l ‘atorvastatine et le diltiazem. Les auteurs
décrivent le cas d’un patient admis pour une insuffisance rénale aiguë
secondaire à une rhabdomyolyse et associée à une hépatite aiguë qu’ils
pensent secondaire à une interaction médicamenteuse entre
l’atorvastatine et le diltiazem.
CONCLUSIONS: Alors que l’amélioration du profil lipidique du patient
devrait être le facteur principal à considérer lors de la sélection d’une
statine par rapport à une autre, la possibilité d’une interaction
médicamenteuse doit aussi retenir notre attention. On devrait informer
tous les patients qui débutent une thérapie avec un inhibiteur de l’HMG-
CO-A réductase de surveiller les signes et symptômes qui pourraient
être reliés à une atteinte musculaire, encore plus si ces patients reçoivent
une médication qui peut causer une interaction médicamenteuse.
Marie Larouche