MITIGARE- colchicine capsule
Hikma Americas, Inc.
1. INDICATION S AND USAGE
MITIGARE� (colchicine) capsules are indicated for prophylaxis of gout flares in adults.
Limitations of use: The safety and effectiveness of MITIGARE� for acute treatment of gout flares during prophylaxis has not been studied.
MITIGARE� is not an analgesic medication and should not be used to treat pain from other causes.
2. DOSAGE AND ADMINISTRATION
2.1. Gout Prophylaxis
For prophylaxis of gout flares, the recommended dosage of MITIGARE� is 0.6 mg once or twice daily. The maximum dose is 1.2 mg per day.
MITIGARE� is administered orally, without regard to meals.
3. DOSAGE FORMS AND STRENGTHS
0.6 mg capsules - No. 4 Dark Blue/Light Blue Hard Gelatin Capsules printed "West-ward 118" in white ink.
4. CONTRAINDICATIONS
Patients with renal or hepatic impairment should not be given MITIGARE� with drugs that inhibit both P-glycoprotein and CYP3A4 inhibitors [See Drug Interactions (7)]. Combining these dual inhibitors with colchicine in patients with renal or hepatic impairment has resulted in life-threatening or fatal colchicine toxicity.
Patients with both renal and hepatic impairment should not be given MITIGARE�.
5. WARNINGS AND PRECAUTIONS
5.1 Fatal Overdose
Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [See Overdosage (10)]. MITIGARE� should be kept out of the reach of children.
5.2 Blood Dyscrasias
Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.
5.3 Interactions with CYP3A4 and P- gp Inhibitors
Because colchicine is a substrate for both the CYP3A4 metabolizing enzyme and the P-glycoprotein efflux transporter, inhibition of either of these pathways may lead to colchicine-related toxicity. Inhibition of both CYP3A4 and P-gp by dual inhibitors such as clarithromycin has been reported to produce life-threatening or fatal colchicine toxicity due to significant increases in systemic colchicine levels. Therefore, concomitant use of MITIGARE� and inhibitors of CYP3A4 or P-glycoprotein should be avoided [See Drug Interactions (7)]. If avoidance is not possible, reduced daily dose should be considered and the patient should be monitored closely for colchicine toxicity. Use of MITIGARE� in conjunction with drugs that inhibit both P-gp and CYP3A4 is contraindicated in patients with renal or hepatic impairment [See Contraindications (4)].
5.4 Neuromuscular Toxicity
Neuromuscular toxicity and rhabdomyolysis have been reported from chronic treatment with colchicine in therapeutic doses, especially in combination with other drugs known to cause this effect. Patients with impaired renal function and elderly patients (even those with normal renal and hepatic function) are at increased risk. Once colchicine treatment is ceased, the symptoms generally resolve within 1 week to several months.
6. ADVERSE REACTIONS
Gastrointestinal disorders are the most common adverse reactions with colchicine. They are often the first signs of toxicity and may indicate that the colchicine dose needs to be reduced or therapy stopped. These 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 intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous system. These most often occur with excessive accumulation or overdosage [see Overdosage ( 10) ].
The following reactions have been reported with colchicine. These have been generally reversible by interrupting treatment or lowering the dose of colchicine:
Digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting
Neurological: sensory motor neuropathy
Dermatological: alopecia, maculopapular rash, purpura, rash
Hematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia
Hepatobiliary: elevated AST, elevated ALT
Musculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis
Reproductive: azoospermia, oligospermia
To report SUSPECTED ADVERSE REACTIONS, contact Hikma Americas, Inc. at 1-877-233-2001 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
7. DRUG INTERACTIONS
Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp), and the CYP3A4 metabolizing enzyme. Fatal drug interactions have been reported when colchicine is administered with clarithromycin, a dual 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 MITIGARE� with drugs that inhibit both P-glycoprotein and CYP3A4 [See Contraindications (4)]. Combining these dual inhibitors with MITIGARE� in patients 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 MITIGARE� and remain alert for signs and symptoms of toxic reactions associated with increased colchicine exposure due to drug interactions. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, MITIGARE� should be discontinued immediately.
7.1 CYP3A4
The concomitant use of MITIGARE� and CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, grapefruit juice, erythromycin, verapamil, etc.) should be avoided due to the potential for serious and life-threatening toxicity [See Warnings and Precautions (5.3) and Clinical Pharmacology (12)].
If co-administration of MITIGARE� and a CYP3A4 inhibitor is necessary, the dose of MITIGARE� should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [See Clinical Pharmacology (12)].
7.2 P-glycoprotein
The concomitant use of MITIGARE� and inhibitors of P-glycoprotein (e.g. clarithromycin, ketoconazole, cyclosporine, etc.) should be avoided due to the potential for serious and life-threatening toxicity [See Warnings and Precautions (5.3) and Clinical Pharmacology (12)].
If co-administration of MITIGARE� and a P-gp inhibitor is necessary, the dose of MITIGARE� should be adjusted by either reducing the daily dose or reducing the dose frequency, and the patient should be monitored carefully for colchicine toxicity [See Clinical Pharmacology (12)].
7.3 HMG-CoA Reductase Inhibitors and Fibrates
Some drugs such as HMG-CoA reductase inhibitors and fibrates may increase the risk of myopathy when combined with MITIGARE�. Complaints of muscle pain or weakness could be an indication to check serum creatinine kinase levels for signs of myopathy.
7.4 Drug-Drug Interaction Studies
Four pharmacokinetic studies evaluated the effects of co-administration of voriconazole (200 mg BID), fluconazole (200 mg QD), cimetidine (800 mg BID), and propafenone (225 mg BID) on systemic levels of colchicine. Colchicine can be administered with these drugs at the tested doses without a need for dose adjustment. However, these results should not be extrapolated to other co-administered drugs [See Drug-Drug Interactions ( 7.1, 7.2) and Pharmacokinetics (12.3)].
