Mitigare

MITIGARE (colchicine) capsules are indicated for prophylaxis of gout flares in adults.

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 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.
  ). Maximum dose 1.2 mg/day.
• •MITIGARE is administered orally, without regard to meals (
  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.
  ).

0.6 mg capsules

• •In the presence of renal or hepatic impairment, patients should be monitored closely and dose adjustment should be considered as necessary .
• •Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus .
• •Lactation: Caution should be exercised when administered to a breastfeeding woman (
  8.2 Lactation

  Risk Summary

  Colchicine is present in human milk

  (see Data).

  Adverse events in breastfed infants have not been reported in the

  published literature after administration of colchicine to lactating women. There are no data on the effects of colchicine on

  milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s

  clinical need for MITIGARE and any potential adverse effects on the breastfed child from MITIGARE or from the

  underlying maternal condition.

  Data

  Human data

  Limited published data from case reports and a small lactation study demonstrate that colchicine is present in breastmilk.

  A systematic review of literature reported no adverse effects in 149 breastfed children. In a prospective observational

  cohort study, no gastrointestinal or other symptoms were reported in 38 colchicine-exposed breastfed infants.
  ).
• •Females and Males of Reproductive Potential: Advise males that MITIGARE
  may rarely and transiently impair fertility
  (
  8.3 Females and Males of Reproductive Potential

  Infertility

  Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare and may be reversible.
  )
• •Geriatric Use: The recommended dosage of colchicine should be based on renal/hepatic function .

• •
  Fatal overdoses
  have been reported with colchicine in adults and children. Keep MITIGARE out of the reach of children (
  5.1 Fatal Overdose

  Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine

  [see Overdosage]

  .  MITIGARE should be kept out of the reach of children.
  ,
  10 OVERDOSAGE

  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]
    .
  ).
• •
  Blood dyscrasias
  : Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported (
  5.2 Blood Dyscrasias

  Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.
  ).
• •Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine (
  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]

  .  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

  ]

  .
  ,
  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 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

  [see Warnings and Precautions]

  .

  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]

  .

  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.

  ,
  10 OVERDOSAGE

  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]
    .
  ).
• •
  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 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]

  .  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

  ]

  .
  ,
  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

  ]

  . 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 .

  7.1 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

  and

  Clinical Pharmacology

  ]

  .

  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

  ]

  .

  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

  and

  Clinical Pharmacology]

  .

  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]

  .

  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

  and

  Pharmacokinetics

  ]

  .
  ).
• •
  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 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.
  ,
  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

  ]

  . 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 .

  7.1 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

  and

  Clinical Pharmacology

  ]

  .

  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

  ]

  .

  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

  and

  Clinical Pharmacology]

  .

  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]

  .

  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

  and

  Pharmacokinetics

  ]

  .
  ).