Mitigare Drug Information

• (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 ( 1 ). 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.

• The recommended dosage is 0.6 mg (one capsule) once or twice daily ( 2 ). Maximum dose 1.2 mg/day.
• MITIGARE is administered orally, without regard to meals ( 2 ). 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.

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.

• 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.
• Co-administration of P-gp or CYP3A4 inhibitors or inhibitors of both P-gp and CYP3A4 (e.g., clarithromycin or cyclosporine) have been reported to lead to colchicine toxicity. The potential for drug-drug interactions must be considered prior to and during therapy.
• Concomitant use of MITIGARE and inhibitors of CYP3A4 or P-gp should be avoided if possible. If co-administration of MITIGARE and an inhibitor of CYP3A4 or P-gp is necessary, the dose of MITIGARE should be reduced and the patient should be monitored carefully for colchicine toxicity ( 7 , 12.3 ). 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 )] .

Pregnancy 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 (see Data). 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.

Pediatric Use Gout is rare in pediatric patients; the safety and effectiveness of MITIGARE in pediatric patients has not been evaluated in controlled studies.

• 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.
• Patients with renal or hepatic impairment should not be given MITIGARE in conjunction with drugs that inhibit both P-gp and CYP3A4 ( 4 ).
• Patients with both renal and hepatic impairment should not be given MITIGARE ( 4 ).

• The dose of colchicine that would induce significant toxicity for an individual is unknown. Fatalities have been reported in patients after ingesting a dose as low as 7 mg over a 4-day period, while other patients have reportedly survived after ingesting more than 60 mg. A review of 150 patients who overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder adverse reactions, such as gastrointestinal symptoms, whereas those who ingested from 0.5 to 0.8 mg/kg had more severe adverse reactions, including myelosuppression. There was 100% mortality among patients who ingested more than 0.8 mg/kg.
• The first stage of acute colchicine toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen.
• Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multi-organ failure and its associated consequences. Death usually results from respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion.
• Treatment of colchicine overdose should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by hemodialysis [ see Pharmacokinetics ( 12.3 )] .