Colchicine (Page 3 of 10)

5.4 Neuromuscular Toxicity

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, lovastatin, gemfibrozil, fenofibrate, fenofibric acid or benzafibrate (themselves associated with myotoxicity) or cyclosporine with colchicine tablets may potentiate the development of myopathy [see Drug Interactions (7)]. Once colchicine is stopped, the symptoms generally resolve within one week to several months.

6 ADVERSE REACTIONS

Prophylaxis of Gout Flares: The most commonly reported adverse reaction in clinical trials of colchicine for the prophylaxis of gout was diarrhea.

Treatment of Gout Flares: The most common adverse reactions reported in the clinical trial with colchicine tablets for treatment of gout flares were diarrhea (23%) and pharyngolaryngeal pain (3%).

FMF: Gastrointestinal tract adverse effects are the most frequent side effects in patients initiating colchicine tablets, usually presenting within 24 hours, and occurring in up to 20% of patients given therapeutic doses. Typical symptoms include cramping, nausea, diarrhea, abdominal pain and vomiting. These events should be viewed as dose-limiting if severe, as they can herald the onset of more significant toxicity.

6.1 Clinical Trials Experience in Gout

Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over one hour) of colchicine tablets compared to 77% of patients taking a nonrecommended high dose (4.8 mg over six hours) of colchicine and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with colchicine tablets treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the nonrecommended high-dose colchicine regimen but did not occur in the recommended low-dose colchicine tablets regimen.

Table 3. Number (%) of Patients with at Least One Drug-Related Treatment-Emergent Adverse Event with an Incidence of ≥ 2% of Patients in Any Treatment Group

MedDRA System Organ Class MedDRA Preferred Term

Colchicine Tablets Dose

Placebo

(N = 59)

n (%)

High (N= 52)

n (%)

Low (N = 74)

n (%)

Number of Patients with at Least One Drug-Related TEAE

40 (77)

27 (37)

16 (27)

Gastrointestinal Disorders

40 (77)

19 (26)

12 (20)

Diarrhea

40 (77)

17 (23)

8 (14)

Nausea

9 (17)

3 (4)

3 (5)

Vomiting

9 (17)

0

0

Abdominal Discomfort

0

0

2 (3)

General Disorders and Administration Site Conditions

4 (8)

1 (1)

1 (2)

Fatigue

2 (4)

1 (1)

1 (2)

Metabolic and Nutrition Disorders

0

3 (4)

2 (3)

Gout

0

3 (4)

1 (2)

Nervous System Disorders

1 (2)

1 (1.4)

2 (3)

Headache

1 (2)

1 (1)

2 (3)

Respiratory Thoracic Mediastinal Disorders

1 (2)

2 (3)

0

Pharyngolaryngeal Pain

1 (2)

2 (3)

0

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