Colchicine (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two year studies were conducted in mice and rats to assess the carcinogenic potential of colchicine. No evidence of colchicine-related tumorigenicity was observed in mice or rats at colchicine oral doses up to 3 and 2 mg/kg/day, respectively (approximately six and eight times, respectively, the maximum recommended human dose of 2.4 mg on a mg/m2 basis).

Mutagenesis

Colchicine was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomal aberration assay in cultured human white blood cells, colchicine treatment resulted in the formation of micronuclei. Since published studies demonstrated that colchicine induces aneuploidy from the process of mitotic nondisjunction without structural DNA changes, colchicine is not considered clastogenic, although micronuclei are formed.

Impairment of Fertility

No studies of colchicine effects on fertility were conducted with colchicine. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division and normal cleavage in females when exposed to colchicine. Colchicine administered to pregnant animals resulted in fetal death and teratogenicity. These effects were dose-dependent, with the timing of exposure critical for the effects on embryofetal development. The nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.

14 CLINICAL STUDIES

The evidence for the efficacy of colchicine in patients with chronic gout is derived from the published literature. Two randomized clinical trials assessed the efficacy of colchicine 0.6 mg twice a day for the prophylaxis of gout flares in patients with gout initiating treatment with urate-lowering therapy. In both trials, treatment with colchicine decreased the frequency of gout flares.

The efficacy of a low-dosage regimen of oral colchicine (colchicine total dose 1.8 mg over one hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, one week, dose-comparison study. Patients meeting American College of Rheumatology criteria for gout were randomly assigned to three groups: high-dose colchicine (1.2 mg, then 0.6 mg hourly × 6 hours

[4.8 mg total]); low-dose colchicine (1.2 mg, then 0.6 mg in one hour [1.8 mg total] followed by five placebo doses hourly); or placebo (two capsules, then one capsule hourly × six hours). Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity (11-point Likert scale) and adverse events over 72 hours. The efficacy of colchicine was measured based on response to treatment in the target joint, using patient self-assessment of pain at 24 hours following the time of first dose as recorded in the diary. A responder was one who achieved at least a 50% reduction in pain score at the 24-hour post dose assessment relative to the pretreatment score and did not use rescue medication prior to the actual time of 24-hour post dose assessment.

Rates of response were similar for the recommended low-dose treatment group (38%) and the non-recommended high-dose group (33%) but were higher as compared to the placebo group (16%) as shown in Table 8.

Table 8. Number (%) of Responders Based on Target Joint Pain Score at 24 Hours Post First Dose

Colchicine Dose

Responders n (%)

Placebo

n (%)

(n=58)

% Differences in Proportion

Low-Dose

(n=74)

High-Dose

(n=52)

Low-Dose vs Placebo (95% CI)

High-Dose vs Placebo (95% CI)

28 (38%)

17 (33%)

9 (16%)

22 (8, 37)

17 (1, 33)

Figure 1 shows the percentage of patients achieving varying degrees of improvement in pain from baseline at 24 hours.

Figure 1 Pain Relief on Low and High Doses of Colchicine and Placebo (Cumulative)

1
(click image for full-size original)

The evidence for the efficacy of colchicine in patients with FMF is derived from the published literature. Three randomized, placebo-controlled studies were identified. The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.

One of the studies randomized 15 patients with FMF to a six month crossover study during which five patients discontinued due to study noncompliance. The ten patients completing the study experienced five attacks over the course of 90 days while treated with colchicine compared to 59 attacks over the course of 90 days while treated with placebo. Similarly, the second study randomized 22 patients with FMF to a four month crossover study during which nine patients discontinued due to lack of efficacy while receiving placebo or study noncompliance. The 13 patients completing the study experienced 18 attacks over the course of 60 days while treated with colchicine compared to 68 attacks over the course of 60 days while treated with placebo. The third study was discontinued after an interim analysis of six of the 11 patients enrolled had completed the study; results could not be confirmed.

Open-label experience with colchicine in adults and children with FMF is consistent with the randomized, controlled trial experience and was utilized to support information on the safety profile of colchicine and for dosing recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Colchicine tablets, USP, 0.6 mg, are purple, capsule-shaped, film-coated tablets, scored on one side and debossed with ”A10” on the other side.

They are available as:

Bottles of 30: NDC 65162-710-03
Bottles of 90: NDC 65162-710-09
Bottles of 1,000: NDC 65162-710-11

16.2 Storage

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from light.

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Dosing Instructions

Patients should be advised to take colchicine as prescribed, even if they are feeling better. Patients should not alter the dose or discontinue treatment without consulting with their doctor. If a dose of colchicine is missed:

  • For treatment of a gout flare when the patient is not being dosed for prophylaxis, take the missed dose as soon as possible.
  • For treatment of a gout flare during prophylaxis, take the missed dose immediately, wait 12 hours, then resume the previous dosing schedule.
  • For prophylaxis without treatment for a gout flare, or FMF, take the dose as soon as possible and then return to the normal dosing schedule. However, if a dose is skipped the patient should not double the next dose.

Fatal Overdose

Instruct patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. Colchicine should be kept out of the reach of children.

Blood Dyscrasias

Patients should be informed that bone marrow depression with agranulocytosis, aplastic anemia and thrombocytopenia may occur with colchicine.

Drug and Food Interactions

Patients should be advised that many drugs or other substances may interact with colchicine and some interactions could be fatal. Therefore, patients should report to their healthcare provider all of the current medications they are taking and check with their healthcare provider before starting any new medications, particularly antibiotics. Patients should also be advised to report the use of nonprescription medication or herbal products. Grapefruit and grapefruit juice may also interact and should not be consumed during colchicine treatment.

Neuromuscular Toxicity

Patients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with colchicine alone or when it is used with certain other drugs. Patients developing any of these signs or symptoms must discontinue colchicine and seek medical evaluation immediately.

Infertility

Advise males of reproductive potential that colchicine may rarely and transiently impair fertility [see Use in Specific Populations (8.3)].

Distributed by:
Amneal Pharmaceuticals LLC Bridgewater, NJ 08807

Rev. 05-2020-02

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