Rhabdomyolysis in Association with Simvastatin and Amiodarone

Abstract

To report a case of severe myopathy associated with concomitant simvastatin and amiodarone therapy.
A 63-year-old white man with underlying insulin-dependent diabetes, recent coronary artery bypass surgery, and postoperative hemiplegia was treated with aspirin, metoprolol, furosemide, nitroglycerin, and simvastatin. Due to recurrent atrial fibrillation, oral anticoagulation with phenprocoumon and antiarrhythmic treatment with amiodarone were initiated. Four weeks after starting simvastatin 40 mg/day and 2 weeks after initiating amiodarone 1 g/day for 10 days, then 200 mg/day, he developed diffuse muscle pain with generalized muscular weakness. Laboratory investigations revealed a significant increase of creatine kinase (CK) peaking at 40 392 U/L. Due to a suspected drug interaction of simvastatin with amiodarone, both drugs were stopped. CK normalized over the following 8 days, and the patient made an uneventful recovery. An objective causality assessment revealed that the myopathy was probably related to simvastatin.
Myopathy is a rare but potentially severe adverse reaction associated with statins. Besides high statin doses, concomitant use of fibrates, defined comorbidities, and concurrent use of inhibitors of cytochrome P450 are important additional risk factors. This is especially relevant if statins predominantly metabolized by CYP3A4 are combined with inhibitors of this isoenzyme. Amiodarone is a potent inhibitor of several different CYP isoenzymes, including CYP3A4.
Avoiding the concomitant use of drugs with the potential to inhibit CYP-dependent metabolism (eg, amiodarone) or elimination of statins may decrease the risk of statin-associated myopathy. Alternatively, if drug therapy with a potent CYP inhibitor is inevitable, choosing a statin without relevant CYP metabolism (eg, pravastatin) should be considered.

Full text

978
■
The Annals of Pharmacotherapy
■
2004 June, Volume 38
CASE REPORTS
www.theannals.com
S
tatins (hydroxymethylglutaryl coenzyme A reductase
inhibitors) can induce myopathies such as myalgia
with or without elevated creatine kinase (CK) levels, mus-
cle weakness or cramps, and rhabdomyolysis, which is the
most severe form.
1
The risk of myopathy and rhabdomyol-
ysis is increased by several factors (eg, high dose, impaired
hepatic or renal function, diabetes, hypothyroidism, ad-
vanced age, recent surgery).
1-3
Concomitant use of drugs
that inhibit cytochrome P450–related statin metabolism,
thereby increasing statin plasma concentrations, also plays
an important role. We present a case of severe myopathy in
a patient with concomitant use of amiodarone, a CYP3A4
inhibitor, and simvastatin, a CYP3A4 substrate. As of
March 24, 2004, to our knowledge, this association has
been documented in only one case series of statin-induced
myotoxicity.
4
We identify clinical and pharmacologic fac-
tors associated with this medical emergency and suggest
recommendations for prevention.
Case Report
A 63-year-old white man (57 kg, 150 cm, body mass index 25.3
kg/m
2
) with a history of insulin-dependent diabetes mellitus underwent
coronary artery bypass surgery for triple-vessel disease with stable angi-
na pectoris. Thyrotropin (thyroid-stimulating hormone, TSH) measured
on the occasion of bypass surgery was normal (1.71 mU/L). Postopera-
tively he developed left-sided hemiplegia of probable cardio-embolic
origin due to intermittent atrial fibrillation. He was given aspirin 100
mg/day, metoprolol 50 mg/day, furosemide 40 mg/day, insulin, transder-
mal nitroglycerin 5 mg/day, and simvastatin 40 mg/day.
Eight days after surgery, the patient was transferred to the rehabilita-
tion facility. On admission, he showed discrete left-sided hemiparesis
with an unstable gait and was therefore enrolled in a physical therapy
program. The medication regimen was unchanged. Three days after ad-
mission, atrial fibrillation recurred. Therefore, oral anticoagulation with
phenprocoumon and antiarrhythmic therapy with oral amiodarone 1
g/day for 10 days, then 200 mg/day, were initiated within the following 2
days. Twenty-four hours later, cardioversion to sinus rhythm occurred.
His international normalized ratio (INR) was 1.93 four days after starting
phenprocoumon.
Nineteen days after admission, the patient was unable to complete an
exercise electrocardiogram stress test due to rapid exhaustion. The INR
at that time was 3.01. Five days later, he complained of diffuse muscle
pain and was hardly able to leave the bed due to generalized muscular
weakness. Laboratory investigations revealed a CK level of 18 852 U/L,
Rhabdomyolysis in Association with Simvastatin and
Amiodarone
Laurent Roten, Ronald A Schoenenberger, Stephan Krähenbühl, and Raymond G Schlienger
OBJECTIVE: To report a case of severe myopathy associated with concomitant simvastatin and amiodarone therapy.
CASE SUMMARY: A 63-year-old white man with underlying insulin-dependent diabetes, recent coronary artery bypass surgery, and
postoperative hemiplegia was treated with aspirin, metoprolol, furosemide, nitroglycerin, and simvastatin. Due to recurrent atrial
fibrillation, oral anticoagulation with phenprocoumon and antiarrhythmic treatment with amiodarone were initiated. Four weeks after
starting simvastatin 40 mg/day and 2 weeks after initiating amiodarone 1 g/day for 10 days, then 200 mg/day, he developed diffuse
muscle pain with generalized muscular weakness. Laboratory investigations revealed a significant increase of creatine kinase (CK)
peaking at 40 392 U/L. Due to a suspected drug interaction of simvastatin with amiodarone, both drugs were stopped. CK normalized
over the following 8 days, and the patient made an uneventful recovery. An objective causality assessment revealed that the
myopathy was probably related to simvastatin.
DISCUSSION: Myopathy is a rare but potentially severe adverse reaction associated with statins. Besides high statin doses,
concomitant use of fibrates, defined comorbidities, and concurrent use of inhibitors of cytochrome P450 are important additional risk
factors. This is especially relevant if statins predominantly metabolized by CYP3A4 are combined with inhibitors of this isoenzyme.
Amiodarone is a potent inhibitor of several different CYP isoenzymes, including CYP3A4.
CONCLUSIONS: Avoiding the concomitant use of drugs with the potential to inhibit CYP-dependent metabolism (eg, amiodarone) or
elimination of statins may decrease the risk of statin-associated myopathy. Alternatively, if drug therapy with a potent CYP inhibitor is
inevitable, choosing a statin without relevant CYP metabolism (eg, pravastatin) should be considered.
KEY WORDS: amiodarone, myopathy, rhabdomyolysis, simvastatin.
Ann Pharmacother 2004;38:978-81.
Published Online, 6 Apr 2004, www.theannals.com, DOI 10.1345/aph.1D498
Author information provided at the end of the text.
by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from

aspartate aminotransferase 438 U/L, and lactate dehydrogenase 807 U/L.
Serum creatinine and potassium levels were normal. Drug-induced my-
opathy was suspected and simvastatin was stopped.
Forced alkaline diuresis was started. Renal function was preserved, with
serum creatinine concentrations ranging between 0.40 and 0.56 mg/dL, but
the patient had dark, “salmon-colored” urine. However, serum CK activity
continued to rise and peaked 3 days later at 40 392 U/L (Figure 1); urinary
myoglobin concentration was 163 µg/L (reference <500 µg/L) at that time.
Muscular pain worsened, necessitating opiate medication.
Due to profound muscular weakness, the patient remained bedridden.
An interaction of simvastatin with amiodarone and/or phenprocoumon
was suspected, and both drugs were stopped. Eight days later, the CK
had normalized and TSH was still normal at 1.58 mU/L. The patient was
discharged with the following medications: aspirin 100 mg/day, metopro-
lol 25 mg/day, furosemide 40 mg/day, pravastatin 20 mg/day, and insulin.
During the following 4 weeks in a rehabilitation program, the patient’s
muscular strength gradually returned. He made an uneventful recovery
and was discharged home with mild residual hemiparesis. The case was
reported to the Swiss Agency for Therapeutic Products (Swissmedic).
Discussion
Myopathy occurs in 0.1–0.2% of patients receiving
statins in clinical trials. Rhabdomyolysis, the most severe
form of myopathy, with CK elevation >10 times the upper
limit of normal, occurs when extensive muscle damage re-
sults in the release of cellular contents into systemic circu-
lation. Major complications include acute renal failure and
compartment syndromes.
3 5
Myopathy and rhabdomyolysis
have been reported with all statins,
6
and rhabdomyolysis-re-
lated deaths have been reported with all statins except fluva-
statin.
7
The risk of statin-induced myopathy is increased by
the use of high doses of statins, concurrent use of fibrates,
acute viral infections, major trauma, surgery, hypothy-
roidism, diabetes, concurrent use of hepatic cytochrome
P450 inhibitors, and other conditions.
1-4,8
The interaction potential with regard to cytochrome me-
tabolism differs between individual statins.
9
Atorvastatin,
lovastatin, and simvastatin are metabolized predominantly
by CYP3A4,
10,11
the most abundant isoenzyme and the one
metabolizing most drugs undergoing CYP-associated bio-
transformation. Accordingly, the risk for interactions is
highest for statins metabolized by CYP3A4, particularly if
no other isoenzymes are involved in the biotransformation
of these drugs.
9 12,13
A recent analysis of Food and Drug
Administration reports on statin-associated rhabdomyolysis
revealed that mibefradil, fibrates, cyclosporine, macrolides
(especially erythromycin and clarithromycin), warfarin,
digoxin, and azole antifungals were the drugs or drug classes
most often involved as potential interacting agents in patients
with statin-induced rhabdomyolysis.
6
Mibefradil, some
macrolides, and azole antifungals are well-known and strong
CYP3A4 inhibitors. Other potent inhibitors of CYP3A4 are
protease inhibitors such as indinavir, nelfinavir, ritonavir, or
saquinavir; the antidepressant nefazodone; the calcium-
channel blockers verapamil and diltiazem; or grapefruit
juice.
13
On the other hand, fluvastatin is metabolized primar-
ily by CYP2C9,
10,11
which is less abundant than CYP3A4
and therefore has a lower risk for drug interactions.
9
Rosu-
vastatin undergoes minimal hepatic metabolism, primarily
via CYP2C9 and 2C19; there is essentially no metabolism
via CYP3A4.
14
Pravastatin differs from the other statins by a
hydroxyl group, rendering this drug more hydrophilic and
allowing conjugation of the drug without previous phase I
biotransformation.
11
Accordingly, the risk for interactions
with pravastatin is estimated to be lower than for statins
undergoing CYP-dependent metabolism.
9
Amiodarone is a class III antiarrhythmic drug that is
mainly metabolized by CYP3A4 and may potently inhibit
several different isoenzymes including CYP1A2, 2C9,
2D6, and 3A4.
15,16
It is therefore possible that concomitant
use of amiodarone and simvastatin leads to a relevant de-
crease of CYP3A4-related metabolism of simvastatin,
thereby increasing the plasma concentration of simvastatin
and/or of the active metabolite simvastatin acid. Unfortu-
nately, we do not have any plasma concentrations of sim-
The Annals of Pharmacotherapy
■
2004 June, Volume 38
■
979
www.theannals.com
Figure 1. Increase of creatine kinase in a patient with myopathy during concomitant use of simvastatin and amiodarone. ECG = electrocardiogram; LD = lactate
dehydrogenase.

vastatin or simvastatin acid in our patient to better support
our assumption of a potential interaction with amiodarone
leading to excessive statin plasma concentrations. So far,
pharmacokinetic studies regarding a potential interaction
between amiodarone and statins or reports of rhabdomyol-
ysis due to a potential simvastatin–amiodarone interaction
have not been published or are scarce. We are aware of
only one case in a case series of 10 patients with statin-in-
duced myopathy in which a potential interaction of sim-
vastatin and amiodarone was suggested as the underlying
mechanism of simvastatin-associated myotoxicity.
4
In an
ongoing clinical trial, myopathy has been reported in 6%
of patients receiving high-dose simvastatin 80 mg/day
with amiodarone according to the product information.
17
However, in patients receiving a daily dose of simvastatin
20 mg, there was no increase in the frequency of myopathy
in those taking amiodarone concomitantly.
Amiodarone may lead to hypothyroidism, which itself
may be associated with generally moderate myopathy.
18
Biological signs of myolysis, essentially a moderate rise in
CK plasma levels, are often found, but rhabdomyolysis
seems to be exceptional.
19,20
Additionally, in the absence of
statin therapy, amiodarone was rarely associated with my-
opathies, mostly in association with hypothyroidism.
19-22
Thus, the possibility of amiodarone-induced hypothyroidism
with secondary myopathy or direct amiodarone-induced
myopathy might be considered a potential cause in our
case. However, TSH levels were normal in our patient be-
fore amiodarone therapy was initiated, as well as shortly
after it was stopped. We can therefore exclude hypothy-
roidism as a potential cause of myopathy, but amiodarone-
induced myopathy cannot be completely ruled out as an
etiologic factor.
It is unclear whether the use of phenprocoumon may
have had some additional impact on simvastatin metabo-
lism, since phenprocoumon is partially metabolized by
CYP3A4.
23
However, it seems unlikely that the other con-
comitant drugs were associated with the myopathy or were
potentially inhibiting simvastatin metabolism, since none
of these drugs is known to induce myopathy alone or to
relevantly inhibit CYP3A4 metabolism. Using the Naranjo
probability scale, we assessed the causal relationship be-
tween the myopathy and simvastatin therapy as probable,
24
even though in the Heart Protection study, with >20 000
patients randomly allocated to receive simvastatin 40 mg
daily or placebo, there was no significant difference in the
frequency of myopathy between simvastatin and placebo.
25
It is possible that the patient’s underlying diabetes and
the surgical procedure one month prior to the onset of the
reaction may have further increased the risk for myopathy
since it has been recognized that those factors predispose
patients to statin-associated myopathy.
1 4 8
However, as dis-
cussed above, it is highly possible that the reaction result-
ed from an interaction with amiodarone.
Although the risk of statin-induced myopathy seems to
be low, avoiding concomitant use of drugs with the poten-
tial to inhibit the metabolism or elimination of statins may
further decrease the risk of this potentially severe adverse
reaction. If use of a drug with the potential to relevantly in-
hibit CYP3A4 is necessary, a statin that is metabolized not
via CYP3A4, such as pravastatin, fluvastatin, or rosuva-
statin, might be considered to minimize the risk of poten-
tially severe interactions. Furthermore, the American Col-
lege of Cardiology/American Heart Association/National
Heart, Lung and Blood Institute Clinical Advisory on the
Use and Safety of Statins suggests that statins be temporari-
ly discontinued prior to major surgery.
2
Unexpected muscle
pain, tenderness, or weakness; fatigue; or the appearance of
dark-colored urine should be considered as warning signs
to patients when a statin is prescribed. If myopathy is sus-
pected, statin therapy should be promptly discontinued and
serum CK levels should be monitored. Early diagnosis and
treatment of symptomatic CK elevations, including cessa-
tion of drug therapies potentially related to myopathy, can
prevent the progression to rhabdomyolysis.
12
Summary
Our patient experienced rhabdomyolysis probably relat-
ed to simvastatin. His underlying diabetes and recent
surgery, as well as the concomitant use of amiodarone,
may have been predisposing factors to increase the risk of
myopathy. Amiodarone is a well-known inhibitor of sever-
al isoenzymes including CYP3A4, the one responsible for
the metabolism of simvastatin. Clinicians should be aware
that the concomitant use of CYP3A4 inhibitors with sim-
vastatin, atorvastatin, or lovastatin, which are mainly bio-
transformed by CYP3A4, increases the risk of myopathy.
Amiodarone may be another drug that necessitates special
caution if used with statins metabolized by CYP3A4.
Laurent Roten MD, Resident, Department of Internal Medicine,
Bürgerspital, Solothurn, Switzerland
Ronald A Schoenenberger MD MPH, Head, Department of In-
ternal Medicine, Bürgerspital, Solothurn
Stephan Krähenbühl MD PhD, Head, Division of Clinical Phar-
macology & Toxicology, Department of Internal Medicine, Universi-
ty Hospital, Basel, Switzerland
Raymond G Schlienger PhD MPH, Head, Drug Information Unit
and Regional Pharmacovigilance Centre, Division of Clinical Phar-
macology & Toxicology, Department of Internal Medicine, Universi-
ty Hospital, Basel; Senior Associate, Institute of Clinical Pharmacy,
Department of Pharmacy, University of Basel, Basel
Reprints: Raymond G Schlienger PhD MPH, Division of Clinical
Pharmacology & Toxicology, University Hospital, Hebelstrasse 10,
4031 Basel, Switzerland, fax 41 61 265 88 64, schliengerr@uhbs.ch
References
1. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy.
JAMA 2003;289:1681-90.
2. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI,
Lenfant C. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety
of Statins. Circulation 2002;106:1024-8.
3. Hamilton-Craig I. Statin-associated myopathy. Med J Aust 2001;175:
486-9.
4. McKelvie PA, Dennett X. Myopathy associated with HMG-CoA reduc-
tase inhibitors (statins): a series of 10 patients and review of the litera-
ture. J Clin Neuromuscular Dis 2002;3:143-8.
5. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reduc-
tase inhibitors. Ann Pharmacother 2001;35:1096-107. DOI 10.1345/
aph.10228
980
■
The Annals of Pharmacotherapy
■
2004 June, Volume 38
www.theannals.com
L Roten et al.

Rhabdomyolysis with Simvastatin and Amiodarone
The Annals of Pharmacotherapy
■
2004 June, Volume 38
■
981
www.theannals.com
6. Omar MA, Wilson JP. FDA adverse event reports on statin-associated
rhabdomyolysis. Ann Pharmacother 2002;36:288-95. DOI 10.1345/
aph.1A289
7. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomy-
olysis (letter). N Engl J Med 2002;346:539- 40.
8. Shek A, Ferrill MJ. Statin–fibrate combination therapy. Ann Pharma-
cother 2001;35:908-17. DOI 10.1345/aph.10315
9. Paoletti R, Corsini A, Bellosta S. Pharmacological interactions of statins.
Atheroscler Suppl 2002;3:35- 40.
10. Igel M, Sudhop T, von Bergmann K. Metabolism and drug interactions
of 3-hydroxy-3-methylglutaryl coenzyme A–reductase inhibitors (statins).
Eur J Clin Pharmacol 2001;57:357-64.
11. Williams D, Feely J. Pharmacokinetic–pharmacodynamic drug interac-
tions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002;41:
343-70.
12. Ballantyne CM, Corsini A, Davidson MH, Holdaas H, Jacobson TA,
Leitersdorf E, et al. Risk for myopathy with statin therapy in high-risk
patients. Arch Intern Med 2003;163:553-64.
13. Martin J, Krum H. Cytochrome P450 drug interactions within the HMG-
CoA reductase inhibitor class: are they clinically relevant? Drug Saf
2003;26:13-21.
14. McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A,
Schneck D, et al. Preclinical and clinical pharmacology of rosuvastatin, a
new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J
Cardiol 2001;87(suppl 5A):28B-32B.
15. Ohyama K, Nakajima M, Suzuki M, Shimada N, Yamazaki H, Yokoi T.
Inhibitory effects of amiodarone and its N-deethylated metabolite on hu-
man cytochrome P450 activities: prediction of in vivo drug interactions.
Br J Clin Pharmacol 2000;49:244-53.
16. Yamreudeewong W, DeBisschop M, Martin L, Lower D. Potentially sig-
nificant drug interactions of class III antiarrhythmic drugs. Drug Saf
2003;26:421-38.
17. Moore LL, Minne K, Moore MB. DRUG-REAX system. Healthcare se-
ries vol. 118 ed. Greenwood Village, CO: Micromedex, 2003.
18. Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of amio-
darone on the thyroid. Endocr Rev 2001;22:240-54.
19. Gepner P, Botto H, Piette AM, Graveleau P, Chapman A. [Hypothyroid
myopathy: apropos of a case with a great increase of creatine phosphoki-
nase, myoglobinemia, and transient kidney failure] French. Rev Med In-
terne 1990;11:165-7.
20. Mallaret M, Mezin P, Chartier A. [Rhabdomyolyis in hypothyroidism.
Favourable role of amiodarone] French. Presse Med 1993;22:272.
21. Bonnet C, Zabraniecki L, Bertin P, Viger B, Fauquez-Cotillon C, Couratier
P, et al. Amiodarone-induced neuromyopathy mimicking polymyositis
(letter). Rev Rhum Engl Ed 1995;62:468.
22. Clouston PD, Donnelly PE. Acute necrotising myopathy associated with
amiodarone therapy. Aust N Z J Med 1989;19:483-5.
23. Morant J, Ruppanner H. Arzneimittelkompendium der Schweiz 2003.
Basel: Documed AG, 2003.
24. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A
method for estimating the probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30:239- 45.
25. Heart Protection Study Collaborative Group. MRC/BHF Heart Protec-
tion Study of cholesterol lowering with simvastatin in 20,536 high-risk
individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-
22.
EXTRACTO
OBJETIVO: Reportar un caso de miopatía severa asociada con el uso
concomitante de simvastatina y amiodarona.
RESUMEN DEL CASO: Un hombre blanco de 63 años de edad con diabetes
dependiente de insulina subyacente, con una cirugía de circunvalación
de la arteria coronaria reciente y hemiplejía post-operatoria, fue tratado
con aspirina, metoprolol, furosemida, nitroglicerina, y simvastatina.
Debido a una fibrilación atrial reciente, se comenzó anticoagulación oral
con fenprocumona y tratamiento anti-arrítmico con amiodarona. Cuatro
semanas después del inicio de simvastatina y 2 semanas después de
comenzar amiodarona, el paciente desarrolló dolor muscular difuso con
debilidad muscular generalizada. Pruebas de laboratorio revelaron un
aumento significativo en la cinasa de creatina (CK) alcanzando un valor
máximo de 40 392 U/L. Debido a una interacción de fármacos entre
simvastatina y amiodarona sospechada, ambos medicamentos fueron
descontinuados. Durante los próximos 8 días, la CK se normalizó y el
paciente tuvo una recuperación sin incidentes. Una evaluación objetiva
de causalidad reveló que la miopatía estuvo relacionada probablemente
a la simvastatina.
DISCUSIÓN: La miopatía es una rara pero potencialmente severa reacción
adversa de fármacos asociada con las estatinas. En adición a dosis altas
de estatinas, el uso concomitante de fibratos, co-morbilidades definidas,
y el uso concurrente de inhibidores del citocromo P450 (CYP) son
importantes factores de riesgo. Esto es especialmente relevante si las
estatinas matabolizadas predominantemente por CYP3A4 se combinan
con inhibidores de esta isoenzima. Amiodarona es un inhibidor potente
de varios CYPs diferentes, incluyendo el CYP3A4.
CONCLUSIONES: El evitar el uso concomitante de fármacos que
potencialmente pueden inhibir el metabolismo dependiente de CYP (ej.
amiodarona) o la eliminación de las estatinas podría disminuir el riesgo
de miopatía asociado con las estatinas. Alternativamente, si la terapia
con un fármaco que posee una inhibición potente de CYP es inevitable,
la selección de una estatina sin metabolismo CYP relevante como
pravastatina, fluvastatina, o rosuvastatina debe ser considerada.
Brenda R Morand
RÉSUMÉ
OBJECTIF: Rapporter un cas de myopathie sévère associée à l’utilisation
concomitante de simvastatine et d’amiodarone.
RÉSUMÉ: Un homme caucasien de 63 ans avec une histoire de diabète
insulino-dépendant, un pontage aorto-coronarien récent et une
hémiplégie post-opératoire était traité avec l’aspirine, le métoprolol, le
furosémide, la nitroglycérine, et la simvastatine. A cause de fibrillation
auriculaire récurrente, une anticoagulation avec le phenprocoumon et un
traitement anti-arythmique à l’amiodarone furent initiés. Quatre
semaines après le début de la simvastatine et 2 semaines après le début
de l’amiodarone, le patient a développé des douleurs musculaires
diffuses associées à de la faiblesse. Une investigation biochimique a
révélé une augmentation significative des enzymes CK atteignant une
valeur de 40 392 U/L. Une interaction entre la simvastatine et
l’amiodarone fut suspectée et les 2 médicaments furent cessés. Les CK
se sont normalisées dans les 8 jours suivants et le patient a récupéré sans
difficulté. Une évaluation objective de cause à effet a révélé que la
myopathie était probablement reliée à la simvastatine.
DISCUSSION: La myopathie est un effet rare mais potentiellement sévère
associé à la simvastatine. Outre les fortes doses de statines, l’utilisation
concomitante des fibrates ou d’inhibiteurs du cytochrome P-450 (CYP),
et des comorbidités sont des facteurs de risque additionnels. Ceci est
particulièrement important puisque les statines sont principalement
métabolisées par le CYP3A4 et que l’amiodarone en est un puissant
inhibiteur.
CONCLUSIONS: Éviter l’utilisation concomitante de médicaments pouvant
inhiber le métabolisme via les cytochromes peut réduire le risque de
myopathie associé aux statines. De plus, si une telle combinaison est
inévitable, le choix d’une statine avec peu de métabolisme via le
cytochrome telle la pravastatine peut s’avérer un choix judicieux.
Marc M Perreault