Colchicine

COLCHICINE- colchicine capsule
Par Pharmaceutical, Inc.

1 INDICATIONS AND USAGE

Colchicine Capsules are indicated for prophylaxis of gout flares in adults.

Limitations of use: The safety and effectiveness of colchicine for acute treatment of gout flares during prophylaxis has not been studied.

Colchicine 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 colchicine is 0.6 mg once or twice daily. The maximum dose is 1.2 mg per day.

Colchicine is administered orally, without regard to meals.

3 DOSAGE FORMS AND STRENGTHS

0.6 mg capsules size 4 white/olive green hard gelatin capsules with a white opaque cap printed “par” in black ink, and an olive green body printed “080” in black ink.

4 CONTRAINDICATIONS

Patients with renal or hepatic impairment should not be given colchicine 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 colchicine.

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 )]. Colchicine 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 colchicine 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 colchicine 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:

D i gestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting

N eurological: sensory motor neuropathy

D ermatological: alopecia, maculopapular rash, purpura, rash

H e m atological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia

H epatobiliary: elevated AST, elevated ALT

Musculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis

R eproductive: azoospermia, oligospermia

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 colchicine with drugs that inhibit both P­ glycoprotein and CYP3A4 [See Contraindications (4 )]. Combining these dual inhibitors with colchicine 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 colchicine 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, colchicine should be discontinued immediately.

7.1 CYP3A4

The concomitant use of colchicine 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 coadministration of colchicine and a CYP3A4 inhibitor is necessary, the dose of colchicine 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 colchicine 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 coadministration of colchicine and a P-gp inhibitor is necessary, the dose of colchicine 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 C linical 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 colchicine. Complaints of muscle pain or weakness could be an indication to check serum creatinine kinase levels for signs of myopathy.

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