Sandoz Colchicine Product Monograph

SUMMARY PRODUCT INFORMATION:

Presentation: Tablet for oral administration available in bottles of 100’s for pharmacy and hospital use only.

Description: Yellow, round, biconvex tablet plain on one side and scored on the other side with the engraving “E” above and “0.6” below the score line.

Non-Medicinal Ingredients: Colloidal Silicon Dioxide, Lactose Monohydrate, Magnesium Stearate, Microcrystalline Cellulose, Pregelatinized Starch. Color composition: D&C Yellow No. 10 Aluminum Lake; FD&C Yellow No. 6 Aluminum Lake.

INDICATIONS

Sandoz COLCHICINE is indicated for gout therapy: prophylaxis and treatment of gout flares in adults.

CONTRAINDICATIONS

Sandoz COLCHICINE is contraindicated in patients with:

• impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor (clarithromycin, etc.).
• impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor (cyclosporin, etc.).
• a known hypersensitivity to colchicine.
• serious gastrointestinal, hepatic, renal and cardiac disease.

DOSAGE AND ADMINISTRATION

Oral administration dosages:

• Administer orally with water and maintain adequate fluid intake.
• May be administered without regard to meals.
• May need to supplement with Vitamin B12.
• Avoid grapefruit juice.
• Sandoz COLCHICINE is not an analgesic medication and should not be used to treat pain from other causes.

Treatment of gout flares with Sandoz COLCHICINE is not recommended in patients receiving prophylactic doses of Sandoz COLCHICINE and CYP3A4 inhibitors.

WARNINGS AND PRECAUTIONS

• Keep Sandoz COLCHICINE out of the reach of children. Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine.
• Sandoz COLCHICINE is a toxic substance and must be given only under physician’s care. Since the administration of Sandoz COLCHICINE is subject to wide variations, the prescribed dosage must be strictly followed.
• Colchicine is a substrate for both the cytochrome P450 3A isoform subfamily (CYP3A) and the efflux transporter, P-glycoprotein (P-gp), clarithromycin and other macrolides are known to inhibit CYP3A4 and P-gp. When Sandoz COLCHICINE and clarithromycin are administered together, inhibition of P-gp and/or CYP3A4 by clarithromycin may lead to increased exposure to Sandoz COLCHICINE which could result in clinically significant safety concerns. Patients should be monitored for clinical symptoms of colchicine toxicity. There have been post-marketing reports of colchicine toxicity with concurrent use of Sandoz COLCHICINE and clarithromycin. In patients with impaired renal function and/or who are elderly, Sandoz COLCHICINE and clarithromycin should not be used concurrently due to the risk of colchicine toxicity. Deaths have been reported in some of these patients.
• Blood dyscrasias: myelosuppression, leucopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported with colchicine used in therapeutic doses.
• Sandoz COLCHICINE must not be used by women who are pregnant or breastfeeding.
• Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or cyclosporine with Sandoz COLCHICINE may potentiate the development of myopathy. Once colchicine is stopped, the symptoms generally resolve within 1 week to several months.
• Sandoz COLCHICINE must be used with caution in aged and feeble patients and those with mild to moderate cardiac, renal, hepatic or gastrointestinal disease (see Contraindications).
• Periodic blood tests are suggested since prolonged administration of Sandoz COLCHICINE could cause blood dyscrasias.

ADVERSE REACTIONS

Post-marketing Experience

Serious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation, and impairment of renal, hepatic, circulatory, and central nervous systems. There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some of these patients (see WARNINGS AND PRECAUTIONS).

The following adverse reactions have been reported with colchicine. These have been generally reversible upon temporarily 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, hematuria, oliguria, vascular and renal disturbances

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

OVERDOSE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

The exact dose of colchicine that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a 4-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients overdosed on colchicine found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions, such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg.

Symptoms: 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 consequences. Extensive vascular damage may result in shock. Renal dysfunction may occur. Hematuria and oliguria are common manifestations. Muscular weakness is marked and ascending CNS paralysis may develop and delirium and convulsions may occur. Death is usually a result of 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: Induce emesis or perform gastric lavage. Symptomatic and supportive treatment. No specific antidote is known. Colchicine is not effectively removed by dialysis.

PHARMACOLOGY

Colchicine is an alkaloid extracted from plants of the genus Colchicum (Colchicum autumnale) and is a water soluble pale yellow powder which blackens with exposure to light.

Oral colchicine intake undergoes an entero-hepatic cycle. It is absorbed rapidly by the gastro-intestinal tract. The drug and its metabolites are distributed in the leucocytes, the kidneys, the liver, the spleen and the intestine.

Peak plasma concentration is obtained from 0.5 to 2 hours after ingestion. The half-life of this drug is approximately 20 minutes in the plasma and 60 hours in the leucocytes. The drug is 50% bound to proteins. The interleucocyte concentrations are higher than the concentrations in plasma.

Its metabolism is not well understood. Colchicine is metabolized in the liver and is excreted mainly in the feces; 10-20% of the drug finds its way in the urine. The colchicine binding results in its accumulation in tissues as soon as the daily dosage exceeds 1 mg, which, in turn, could result in toxic effects. A serious renal ailment could prolong the half-life for its elimination.

Colchicine crosses the placenta into the breast milk.

Although its exact mode of action in the relief of gout is not completely understood, colchicine is known to decrease the inflammatory response to urate crystal deposition by inhibiting migration of leukocytes, to interfere with urate deposition by decreasing lactic acid production by leukocytes, to interfere with kinin formation and to diminish phagocytosis and the subsequent anti-inflammatory response.

The anti-inflammatory effect of colchicine is relatively selective for acute gouty arthritis. It is neither analgesic nor a uricosuric and will not prevent progression to chronic gouty arthritis. It does have a prophylactic, suppressive effect that helps to reduce the incidence of acute attacks.

STORAGE:

Store between 15-30°C.

REFERENCES

1. 1. Borstad GC, Bryant LR, Abel MP, et al, “Colchicine for Prophylaxis of Acute Flares When Initiating Allopurinol for Chronic Gouty Arthritis,” J Rheumatol, 2004, 31(12):2429-32.
2. 2. Emmerson BT, “The Management of Gout,” N Engl J Med, 1996, 334(7):445-51
3. 3. Terkeltaub RA, “Gout,” N Engl J Med, 2003, 349(17):1647-55
4. 4. Wallace SL, Singer JZ, Duncan GJ, et al, “Renal Function Predicts Colchicine Toxicity: Guidelines for the Prophylactic Use of Colchicine in Gout,” J Rheumatol, 1991, 18(2):264-9
5. 5. AQhern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Doeas Colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301-4
6. 6. Arnold MH, Preston SJ, Buchanan WW. Comparison of the natural history of untreated acute gouty arthritis vs acute gouty arthritis treated with non-steroidal-anti-inflammatory drugs. Br J Clin Pharmacol 1988;26:4889
7. 7. Morris I, et al. Colchicine in acute gout. BMJ 2003;327:1275-6
8. 8. Morris I, et al. Colchicine in acute gout. BMJ 2004; 328:289
9. 9. Canadian Pharmacists Association Letter; September 2009; Vol 25
10. 10. Canadian Pharmacists Association Letter; Spetember 2009; 25(9):250903
11. 11. Canadian Pharmacists Association Letter; Spetember 2009; 27(12):271208
12. 12. Colcrys (Colchicine) Tablet, film coated [AR Scientific Inc.] DailyMed Label Information – Human Prescription Drug Label (http://dailymed.nlm.nih.gov)

REPORTING SIDE EFFECTS

You can report any suspected side effects associated with the use of health products to Health Canada by:

• Visiting the Web page on Adverse Reaction Reporting (https://www.canada.ca/en/health- canada/services/drugs-health-products/medeffect-canada/adverse-reaction-reporting.html) for information on how to report online, by mail or by fax; or
• Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to manage your side effects. The Canada Vigilance Program does not provide medical advice.

Sandoz Canada Inc.

Boucherville, Québec, Canada J4B 7K8

Questions or Concerns: 1-800-361-3062

medinfo@sandoz.com

^®Registered trademark used under licence by Sandoz Canada Inc.

Last revision: December 08, 2017