Colchicine

Colchicine is an alkaloid indicated for:

• Prophylaxis and treatment of gout flares in adults (
  1.1  Gout Flares

  Colchicine tablets are indicated for prophylaxis and the treatment of acute gout flares.

  • Prophylaxis of Gout Flares:
    
    
    Colchicine tablets are indicated for prophylaxis of gout flares.

  • Treatment of Gout Flares:
    
    
    
    Colchicine tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.
  ).
• Familial Mediterranean fever (FMF) in adults and children 4 years or older (
  1.2  Familial
  Mediterranean Fever (FMF)

  Colchicine tablets are indicated in adults and children four years or older for treatment of familial Mediterranean fever (FMF).
  ).

The long-term use of colchicine is established for FMF and the prophylaxis of gout flares, but the safety and efficacy of repeat treatment for gout flares has not been evaluated. The dosing regimens for colchicine are different for each indication and must be individualized.

The recommended dosage of colchicine depends on the patient’s age, renal function, hepatic function and use of coadministered drugs

Colchicine tablets are administered orally without regard to meals.

Colchicine is not an analgesic medication and should not be used to treat pain from other causes.

Tablets: 0.6 mg colchicine, USP -  purple capsule-shaped, film-coated tablet with “

• In the presence of mild to moderate renal or hepatic impairment, adjustment of dosing is not required for treatment of gout flare, prophylaxis of gout flare and FMF, but patients should be monitored closely (
  8.6  Renal
  Impairment

  Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.

  Prophylaxis of Gout Flares

  For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring

  [see Dosage and Administration ]

  .

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks

  [see Dosage and Administration ]

  .

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 to 80 mL/min) and moderate (Cl_cr30 to 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Cl_crless than 30 mL/min) and end-stage renal disease requiring dialysis, colchicine may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• In patients with severe renal impairment for prophylaxis of gout flares, the starting dose should be 0.3 mg/day for gout flares, no dose adjustment is required, but a treatment course should be repeated no more than once every two weeks. In FMF patients, start with 0.3 mg/day, and any increase in dose should be done with close monitoring (
  8.6  Renal
  Impairment

  Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.

  Prophylaxis of Gout Flares

  For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring

  [see Dosage and Administration ]

  .

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks

  [see Dosage and Administration ]

  .

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 to 80 mL/min) and moderate (Cl_cr30 to 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Cl_crless than 30 mL/min) and end-stage renal disease requiring dialysis, colchicine may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• In patients with severe hepatic impairment, a dose reduction may be needed in prophylaxis of gout flares and FMF patients; while a dose reduction may not be needed in gout flares, a treatment course should be repeated no more than once every two weeks (
  8.6  Renal
  Impairment

  Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.

  Prophylaxis of Gout Flares

  For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring

  [see Dosage and Administration ]

  .

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks

  [see Dosage and Administration ]

  .

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 to 80 mL/min) and moderate (Cl_cr30 to 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Cl_crless than 30 mL/min) and end-stage renal disease requiring dialysis, colchicine may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ,
  8.7  Hepatic
  Impairment

  The clearance of colchicine may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment compared to healthy subjects

  [see Clinical Pharmacology ]

  .

  Prophylaxis of Gout Flares

  For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment

  [see Dosage and Administration ]

  .

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended colchicine dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, for the treatment of gout flares in patients with severe impairment, while the dose does not need to be adjusted, the treatment course should be repeated no more than once every two weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy

  [see Dosage and Administration ]

  .

  FMF

  In patients with severe hepatic disease, dose reduction should be considered with careful monitoring

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• For patients undergoing dialysis, the total recommended dose for prophylaxis of gout flares should be 0.3 mg given twice a week with close monitoring. For treatment of gout flares, the total recommended dose should be reduced to 0.6 mg (one tablet) x 1 dose and the treatment course should not be repeated more than once every two weeks. For FMF patients, the starting dose should be 0.3 mg/day and dosing can be increased with close monitoring (
  8.6  Renal
  Impairment

  Colchicine is significantly excreted in urine in healthy subjects. Clearance of colchicine is decreased in patients with impaired renal function. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease undergoing dialysis.

  Prophylaxis of Gout Flares

  For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring

  [see Dosage and Administration ]

  .

  Treatment of Gout Flares

  For treatment of gout flares in patients with mild (Cl_cr50 to 80 mL/min) to moderate (Cl_cr30 to 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of colchicine. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every two weeks. For patients with gout flares requiring repeated courses, consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (one tablet). For these patients, the treatment course should not be repeated more than once every two weeks

  [see Dosage and Administration ]

  .

  FMF

  Although pharmacokinetics of colchicine in patients with mild (Cl_cr50 to 80 mL/min) and moderate (Cl_cr30 to 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of colchicine. Dose reduction may be necessary. In patients with severe renal failure (Cl_crless than 30 mL/min) and end-stage renal disease requiring dialysis, colchicine may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of colchicine

  [see Clinical Pharmacology , Dosage and Administration ]

  .
  ).
• Females and Males of Reproductive Potential: Advise males that colchicine may transiently impair fertility (
  8.3 Females and Males of Reproductive Potential

  Infertility

  Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare and may be reversible. A case report indicated that azoospermia was reversed when therapy was stopped. Case reports and epidemiology studies in female subjects on colchicine therapy have not established a clear relationship between colchicine use and female infertility. However, since the progression of FMF without treatment may result in infertility, the use of colchicine needs to be weighed against the potential risks

  [see Nonclinical Toxicology ]

  .
  ).
• Geriatric Use: The recommended dose of colchicine should be based on renal function (
  8.5 Geriatric Use

  Clinical studies with colchicine for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy

  [see Dosage and Administration , Clinical Pharmacology ]

  .
  ).

• Fatal overdoses
  have been reported with colchicine in adults and children. Keep colchicine out of the reach of children (
  5.1  Fatal
  Overdose

  Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine

  [see Overdosage ]

  . Colchicine should be kept out of the reach of children.
  ,
  10 OVERDOSAGE

  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 four-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who 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.

  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 multiorgan failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one week after the initial ingestion.

  Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis

  [see Clinical Pharmacology ]

  .
  ).
• Blood dyscrasias:
  myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported (
  5.2  Blood
  Dyscrasias

  Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia and aplastic anemia have been reported with colchicine used in therapeutic doses.
  ).
• Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine (
  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

  Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted

  [see Drug Interactions ]

  . Use of colchicine in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir) is contraindicated in patients with renal or hepatic impairment

  [see Contraindications ]

  . 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 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, 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.

  • Prophylaxis of Gout Flares:
    The most commonly reported adverse reaction in clinical trials for the prophylaxis of gout was diarrhea.
  • Treatment of Gout Flares:
    The most common adverse reactions reported in the clinical trial for gout were diarrhea (23%) and pharyngolaryngeal pain (3%).
  • FMF:
    Most common adverse reactions (up to 20%) are abdominal pain, diarrhea, nausea and vomiting. These effects are usually mild, transient and reversible upon lowering the dose .

  To report SUSPECTED ADVERSE REACTIONS, contact

  Teva at 1-888-838-2872

  or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

  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 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 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 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 Dose		Pla c e bo
  	High (N=52)	Low (N=74)	(N=59)
  	n (%)	n (%)	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

  
  
  

  6.2 Postmarketing
  Experience

  Serious toxic manifestations associated with colchicine include myelosuppression, disseminated intravascular coagulation and injury to cells in the renal, hepatic, circulatory and central nervous systems.

  These most often occur with excessive accumulation or overdosage

  [see Overdosage (10)]

  .

  The following adverse reactions have been identified with colchicine. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of colchicine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  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
  ,
  10 OVERDOSAGE

  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 four-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who 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.

  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 multiorgan failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multiorgan injury may be accompanied by rebound leukocytosis and alopecia starting about one week after the initial ingestion.

  Treatment of colchicine poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Colchicine is not effectively removed by dialysis

  [see Clinical Pharmacology ]

  .
  ).
• Drug interaction P-gp and/or CYP3A4 inhibitors:
  Coadministration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death (
  5.3  Drug
  Interactions

  Colchicine is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient’s dose of colchicine may need to be reduced or interrupted

  [see Drug Interactions ]

  . Use of colchicine in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir) is contraindicated in patients with renal or hepatic impairment

  [see Contraindications .