Gloperba

1 INDICATIONS AND USAGE GLOPERBA ® (colchicine) Oral Solution is indicated for prophylaxis of gout flares in adults. GLOPERBA is indicated for prophylaxis of gout flares in adults ( 1 ). Limitations of use: The safety and effectiveness of GLOPERBA for acute treatment of gout flares during prophylaxis has not been studied. GLOPERBA is not an analgesic medication and should not be used to treat pain from other causes ( 1 ). Limitations of use: The safety and effectiveness of GLOPERBA for acute treatment of gout flares during prophylaxis has not been studied. GLOPERBA is not an analgesic medication and should not be used to treat pain from other causes.

2 DOSAGE AND ADMINISTRATION 0.6 mg (5 mL) once or twice daily. Maximum dose 1.2 mg/day. ( 2.1 ) GLOPERBA is administered orally, without regard to meals ( 2.1 ) 2.1 Gout Prophylaxis For prophylaxis of gout flares, the recommended dosage of GLOPERBA is 0.6 mg (5 mL) once or twice daily. The maximum dose is 1.2 mg/day. GLOPERBA is administered orally, without regard to meals.

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

5 WARNINGS AND PRECAUTIONS Fatal overdoses have been reported with colchicine in adults and children. Keep GLOPERBA out of the reach of children ( 5.1 , 10 ). Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported ( 5.2 ). Monitor for toxicity and, if present, consider lowering the dose, temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ). Drug interaction with CYP3A4 and P-gp inhibitors: Co-administration of colchicine with dual CYP3A4 and P-gp 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 lowering the dose, temporary interruption or discontinuation of GLOPERBA ( 5.4 , 6 ). 5.1 Fatal Overdose Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine [see Overdosage (10) ]. GLOPERBA 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 Drug Interactions Because colchicine is a substrate for both the CYP3A4 metabolizing enzyme and the P-gp efflux transporter, inhibition of either of these pathways may lead to colchicine related toxicity. Inhibition of both CYP3A4 and P-gp by dual inhibitors (i.e., clarithromycin) has been reported to produce life threatening or fatal colchicine toxicity due to significant increases in systemic colchicine levels. Therefore, concomitant use of GLOPERBA with inhibitors of both CYP3A4 and P-gp should be avoided. If treatment with colchicine is necessary, a reduced daily dose should be considered and the patient should be closely monitored for colchicine toxicity [see Drug Interactions (7) ]. Use of GLOPERBA in conjunction with drugs that inhibit both CYP3A4 and P-gp is contraindicated in patients with renal or hepatic impairment [see Contraindications (4) ]. 5.4 Neuromuscular Toxicity Colchicine induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment 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 stopped, the symptoms generally resolve within one week to several months.

7 DRUG INTERACTIONS Colchicine is a substrate of the CYP3A4 metabolizing enzyme and the P-glycoprotein (P-gp) efflux transporter. 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 GLOPERBA with drugs that inhibit both CYP3A4 and P-glycoprotein [see Contraindications (4) ] . Combining these dual inhibitors with GLOPERBA 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 GLOPERBA 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, consider lowering the dose, interruption or discontinuation of GLOPERBA. Co-administration of CYP3A4 or P-gp inhibitors or inhibitors of both CYP3A4 and P-gp (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 ( 7 ). Concomitant use of GLOPERBA and inhibitors of both CYP3A4 and P-gp should be avoided if possible. If co-administration with a CYP3A4 and P-gp inhibitor is required, the patients' dose of colchicine may need to be reduced or interrupted, and the patient should be monitored carefully for colchicine toxicity ( 7 ). 7.1 CYP3A4 The concomitant use of GLOPERBA 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 (12.3) ] . If co-administration of GLOPERBA and a CYP3A4 inhibitor is necessary, the dose of GLOPERBA 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 (12.3) ]. 7.2 P-Glycoprotein The concomitant use of GLOPERBA 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 (12.3) ] . If co-administration of GLOPERBA and a P-gp inhibitor is necessary, the dose of GLOPERBA 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 (12.3) ] . 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 GLOPERBA. Complaints of muscle pain or weakness could be an indication to check serum creatinine kinase levels for signs of myopathy. 7.4 Drug Interaction Studies Two pharmacokinetic studies evaluated the effects of co-administration of posaconazole (300 mg QD), ciprofloxacin (500 mg BID), amlodipine (5 to 10 mg QD), and carvedilol (20 to 40 mg QD) on the systemic levels of colchicine. GLOPERBA can be administered with amlodipine, carvedilol, and ciprofloxacin at the tested doses without a need for dose adjustment. However, the results should not be extrapolated to other co-administered drugs. Colchicine plasma levels were markedly elevated when GLOPERBA was co-administered with posaconazole. The recommended dose of GLOPERBA when co-administered with posaconazole is 0.24 mg (2 mL).

6 ADVERSE REACTIONS Gastrointestinal disorders are the most common adverse reactions with colchicine. These disorders are often the first signs of toxicity and may indicate that the colchicine dose needs to be reduced or therapy stopped. These disorders 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 systems. These toxicities most often occur with excessive accumulation or overdosage [see Overdosage (10) ] . The following adverse reactions have been reported with colchicine. These adverse reactions have been generally reversible upon interrupting treatment or lowering the dose of colchicine. Neurological: sensory motor neuropathy Dermatological: alopecia, maculopapular rash, purpura, rash Digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting 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 ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact SCILEX Pharmaceuticals, Inc. at 1-866-SCILEX3 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

8.1 Pregnancy Risk Summary Available human 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 adverse maternal or fetal outcomes (see Data ). Although animal reproduction and development studies were not conducted with GLOPERBA, published animal reproduction and development studies indicate that colchicine causes embryofetal toxicity and altered postnatal development at exposures within or above the clinical therapeutic range. The estimated 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 of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 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, Behçet'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.