Mitigare

1 INDICATIONS 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. • MITIGARE is an alkaloid 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 • The recommended dosage is 0.6 mg (one capsule) once or twice daily. Maximum dose 1.2 mg/day. • MITIGARE is administered orally, without regard to meals. 2.1. Recommended Dosage for Gout Prophylaxis For prophylaxis of gout flares, the recommended dosage of MITIGARE is 0.6 mg once or twice daily.

The maximum dosage is 1.2 mg per day. MITIGARE is administered orally, without regard to meals.

5 WARNINGS AND PRECAUTIONS • Fatal overdoses have been reported with colchicine in adults and children. Keep MITIGARE out of the reach of children ( 5.1 , 10 ). • Blood dyscrasias : Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported. • Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ). • Drug interaction with dual P-gp and CYP3A4 inhibitors : Co-administration of colchicine with dual P-gp and CYP3A4 inhibitors has resulted in life-threatening interactions and death ( 5.3 , 7 ). • Neuromuscular toxicity : Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of MITIGARE ( 5.4 , 7 ).

5.1Fatal Overdose Fatal

overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine . MITIGARE should be kept out of the reach of children.

5.2Blood Dyscrasias Myelosuppression,

leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.

5.3Interactions 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 . 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 .

5.4Neuromuscular 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.

Patients with renal or hepatic impairment should not be given MITIGARE with drugs that inhibit both P-glycoprotein and CYP3A4 inhibitors . 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. • Patients with renal or hepatic impairment should not be given MITIGARE in conjunction with drugs that inhibit both P-gp and CYP3A4. • Patients with both renal and hepatic impairment should not be given MITIGARE.

8.1Pregnancy Risk Summary Available

data from published literature on colchicine use in pregnancy over several decades have not identified any drug associated risks for major birth defects, miscarriage, or other adverse maternal or fetal outcomes . Colchicine crosses the human placenta. Although animal reproductive and developmental studies were not conducted with MITIGARE, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity, teratogenicity, and altered postnatal development at exposures within or above the clinical therapeutic range. The background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects or miscarriage in pregnant women with rheumatic diseases (such as rheumatoid arthritis, Behcet’s disease, or Familial Mediterranean Fever (FMF)) treated with colchicine at therapeutic doses during pregnancy.

Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications.

Gastrointestinal disorders are the most common adverse reactions with colchicine. They are often the first signs of toxicity and may indicate that the colchicine dosage 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 . 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 . 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 The most commonly reported adverse reactions with colchicine are gastrointestinal symptoms, including diarrhea, nausea, vomiting, and abdominal pain. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Specialty USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.