Drug Interactions (7)].
Use of GLOPERBA in conjunction with drugs that inhibit both CYP3A4 and P-gp is contraindicated inpatients with renal or hepatic impairment [see Contraindications (4)].
5.4 Neuromuscular Toxicity
Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatmentin therapeutic doses, especially in combination with other drugs known to cause this effect. Patients withimpaired renal function and elderly patients, even those with normal renal and hepatic function, are atincreased risk. Once colchicine treatment is stopped, the symptoms generally resolve within one week toseveral months.
6 ADVERSE REACTIONS
Gastrointestinal disorders are the most common adverse reactions with colchicine. These disorders are often thefirst signs of toxicity and may indicate that the colchicine dose needs to be reduced or therapy stopped. Thesedisorders include diarrhea, nausea, vomiting, and abdominal pain.
Colchicine has been reported to cause neuromuscular toxicity, which may present as muscle pain or weakness[see Warnings and Precautions (5.4)].
Toxic manifestations associated with colchicine include myelosuppression, disseminated intravascularcoagulation and injury to cells in the renal, hepatic, circulatory and central nervous systems. These toxicitiesmost often occur with excessive accumulation or overdosage [see Overdosage (10)].
The following adverse reactions have been reported with colchicine. These adverse reactions have beengenerally reversible upon interrupting treatment or lowering the dose of colchicine.
Neurological: sensory motor neuropathy
Dermatological: alopecia, maculopapular rash, purpura, rashDigestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomitingHematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemiaHepatobiliary: elevated AST, elevated ALTMusculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysisReproductive: azoospermia, oligospermia
7 DRUG INTERACTIONS
Colchicine is a substrate of the CYP3A4 metabolizing enzyme and the P-glycoprotein (P-gp) effluxtransporter. Fatal drug interactions have been reported when colchicine is administered with clarithromycin, adual inhibitor of CYP3A4 and P- glycoprotein. Toxicities have also been reported when colchicine is
administered with inhibitors of CYP3A4 that may not be potent inhibitors of P-gp (e.g., grapefruit juice,erythromycin, verapamil), or inhibitors of P-gp that may not be potent inhibitors of CYP3A4 (e.g.,cyclosporine).
Patients with renal or hepatic impairment should not be given GLOPERBA with drugs that inhibit bothCYP3A4 and P-glycoprotein [see Contraindications (4)].
Combining these dual inhibitors with GLOPERBA inpatients with renal and hepatic impairment has resulted in life-threatening or fatal colchicine toxicity.
Physicians should ensure that patients are suitable candidates for treatment with GLOPERBA and remainalert for signs and symptoms of toxic reactions associated with increased colchicine exposure due to druginteractions. Signs and symptoms of colchicine toxicity should be eva luated promptly and, if toxicity issuspected, consider lowering the dose, interruption or discontinuation of GLOPERBA.
7.1 CYP3A4
The concomitant use of GLOPERBA and CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole,gr |
