Pharmacology & Pharmacy, 2010, 1, 39-41
doi:10.4236/pp.2010.12006 Published Online October 2010 (http://www.SciRP.org/journal/pp)
Copyright © 2010 SciRes. PP
39
Colchicine-Induced Rhabdomyolysis and Possible
Amiodarone Interaction
——Colchicine-Induced Rhabdomyolysis
Chaker Ben Salem1, Jaballah Sakhri2, Neila Fathallah1, Besma Trimech3, Houssem Hmouda4,
Bouraoui Kamel1
1Department of Clinical Pharmacology, Faculty of Medicine of Sousse, Sousse, Tunisia; 2Department of Surgery, Farhat Hached
Hospital, Sousse, Tunisia; 3Department of Cardiology, Farhat Hached Hospital, Sousse, Tunisia; 4Medical Intensive Care Unit,
Sahloul Hospital, Sousse, Tunisia.
Email: bensalem.c@gmail.com
Received August 10th, 2010; revised August 25th, 2010; accepted September 5th, 2010.
ABSTRACT
Objective: To report a case of drug interaction leading to rhabdomyolysis. Case Summary: A 65-year old woman suf-
fering from chronic atrial fibrillation was treated with amiodarone and acenocoumarol. Two weeks after administration
of conventional dosage of colchicine for pericarditis, the patient developed rhabdomyolysis. colchicine-induced rhab-
domyolysis was suspected. Colchicine was stopped and the patient underwent supportive therapy. Clinical symptoms
improved rapidly. Discussion: Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with
chronic treatment in therapeutic doses. Concomitant use of several drugs with colchicine may potentiate the develop-
ment of myopathy. In our case, a co-administration of colchicine, a well known substrate of cytochrome P450 3A4 and
P-glycoprotein, and amiodarone had possibly precipitated rhabdomyolysis. Amiodarone may increase colchicine
toxicity by a dual mechanism. Amiodarone inhibits P-glycoprotein which may theoretically result in increased intrace-
llular colchicine concentrations and decreased hepatic and renal excretion of the drug. Conclusion: Amiodarone may
potentiate the development of colchicine-induced rhabdomyolysis.
Keywords: Colchicine, Rhabdomyolysis, Amiodarone, Interaction
1. Introduction
Colchicine is an anti-inflammatory drug widely used in
the treatment of a large panel of inflammatory diseases
and particularly gout. Colchicine may induce many side
effects, principally gastrointestinal adverse effects in-
cluding abdominal pain, vomiting, and diarrhea. It may
cause much more severe reactions such as bone marrow
depression, myoneuropathy and myopathy. Rhabdomyo-
lysis is a rare and lifethreatening adverse effect of col-
chicine. We report a case of rhabdomyolysis possibly in-
duced by colchicine and concomitant use of amiodarone.
2. Case Report
A 65-year old woman suffering from chronic atrial fib-
rillation treated with amiodarone (200 mg daily; 5 days
per week) and acenocoumarol (0.25 mg daily). She also
received captopril (25 mg daily); furosemide (40 mg
daily); molsidomine (75 mg daily) and spironolactone
(50 mg daily) for ischemic cardiomyopathy. Colchicine
therapy (1 mg daily) has been started two weeks before
admission for pericarditis. She was admitted to cardiol-
ogy department for management of over-anticoagulation
by acenocoumarol manifested by epistaxis and melena.
On admission, the patient was afebrile. The relevant
physical findings were atrial fibrillation without signs of
acute decompensated heart failure. The patient also re-
ported myalgia and diffuse muscle weakness. Both sen-
sation and coordination were intact. She had no recent
viral illness and she denied any change from her normal
level of activity. No alcohol ingestion, illicit drugs, or
trauma were present. There were no signs of liver insuf-
ficiency or for thyroid disease.
Laboratory tests revealed the following: international
normalized ratio (INR) at 6.5 UI/l, creatine kinase (CK)
at 5780 UI/L (normal range: 40-150 U/L) and aldolase at
3700 UI/L (normal range: 06-16 UI/L). Blood cell count,
renal function, liver enzymes, potassium and troponin
Colchicine-Induced Rhabdomyolysis and Possible Amiodarone Interaction
Copyright © 2010 SciRes. PP
40
serum levels were within normal range. Viral tests did
not disclose any viral infection. Based on clinical and
biological findings, colchicine-induced rhabdomyolysis
was suspected. Muscle biopsy was not performed be-
cause of high INR. Colchicine was stopped and the pa-
tient underwent supportive therapy. The other drugs were
given continuously. Clinical symptoms improved rapidly
with a progressive decrease in CK and aldolase levels.
Few days later, CK level decreased to 384 UI/L, and al-
dolase level to 100 UI/L. However, the patient died from
ventricular fibrillation.
3. Discussion
Colchicine-induced neuromuscular toxicity and rhabdo-
myolysis have been reported with chronic treatment in
therapeutic doses. Patients with renal dysfunction and
elderly patients, even those with normal renal and hepatic
function, are at increased risk. Concomitant use of ator-
vastatin, simvastatin, pravastatin, lovastatin, fluvastatin,
gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate
(themselves associated with myotoxicity) or cyclosporine
may potentiate the development of myopathy [1-4].
Colchicine is a well known substrate of cytochrome
P450 3A4 (CYP3A4) in the liver and gastrointestinal (GI)
tract, along with P-glycoprotein efflux pumps (P-gp) in
the GI tract. Potent CYP3A4 inhibitors such as clarithro-
mycin, cyclosporine, diltiazem, erythromycin, grapefruit
juice, itraconazole, ketoconazole, and verapamil may
increase colchicine levels and the subsequent risk of
toxicity [5]. Many CYP3A4 inhibitors also inhibit P-gp,
which could further increase this effect.
Amiodarone is a well known CYP3A4 and P-gp
inhibitor [6,7]. This inhibition is primarily because of its
active metabolite, desethylamiodarone, which noncom-
petitively inhibits 3A4. Thus, Amiodarone co-administra-
tion may increase colchicine toxicity by a dual mechanism.
Amiodarone inhibits P-glycoprotein which may theoreti-
cally result in increased intracellular colchicine concen-
trations and decreased hepatic and renal excretion of the
drug. Amiodarone may also interact with CYP3A4 to
decrease the hepatic elimination of colchicine. Several
drugs increase the potential for colchicine toxicity via
dual modulation of CYP3A4 and P-gp [8]. These include
the macrolide antibiotics erythromycin and
clarithro-mycin, and the statins (lovastatin, simvastatin,
atorvastatin).
Based on the Naranjo probability scale, it is probable
that colchicine caused this patient's rhabdomyolysis, and
the Horn drug interaction probability scale indicates a
possible interaction between colchicine and amiodarone
[9,10]. Our case highlights a previously unknown drug
interaction. Rhabdomyolysis developed few days after
starting standard dose of colchicine in a patient without
renal insufficiency.
The FDA recently reviewed the safety of oral colchicine
[5]. New drug interactions have been identified with this
agent. Oral colchicine was linked to 169 cases of fatal
toxicity. One-hundred seventeen cases occured in pa-
tients taking therapeutic doses, and over half of these 117
cases involved concomitant use of clarithromycin.
Colchicine-induced rhabdomyolysis is an acute life-
threatening disease. The main goal of treatment is to stop
muscle destruction. The rapid withdrawal of the drug is
crucial. Once colchicine is stopped, the symptoms gener-
ally resolve within 1 week to several months [5].
The exact mechanism of colchicine-induced myoneu-
ropathy is still unclear. Colchicine affects microtubular
cell function, it may cause disruption of axonal transport
and organelle trafficking in both nerve and muscle cells
at the bases of clinical deficits. Electromyography shows
fibrillations, positive sharp waves, and low-amplitude
distal motor and sensory potentials. If performed, muscle
biopsy shows characteristic vacuolar myopathy with no
associated necrosis. In another side, the over-antico-
agulation by acenocoumarol manifested by epistaxis and
melena (reason for admission) may be precipitated by
amiodarone co-administration. The potentiation of aceno-
coumarol anticoagulant effect by amiodarone is well es-
tablished. In our patient, concomitant medications such
as captopril, furosemide, molsidomine and spironolac-
tone seem to not interfere with colchicine. These drugs
are not known to be CYP3A4 or P-gp inhibitor.
At present, colchicine has been recommended by the
2004 European guidelines on the management of peri-
cardial diseases for acute (class IIa) and recurrent peri-
carditis (class I), but its use is still unlabeled and in-
formed consent is required for prescription [11].
The indication of treatment with colchicine should be
carefully considered especially in poly-medicated patients.
Patients should be informed that muscle pain or weak-
ness may occur with colchicine alone or when it is used
with certain other drugs such as amiodarone. Patients
should be educated to report symptoms of myopathy
immediately to physicians who may decide to discon-
tinue colchicine treatment.
4. Conclusions
Our case suggests a possible interaction between colchi-
cine and amiodarone that appears theoretically possible
but not yet confirmed. We recommend that further in
vivo studies be completed to definitively identify the
mechanism of the interaction amiodarone-colchicine.
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