Colchicine

The long-term use of colchicine, USP 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 tablets, USP are different for each indication and must be individualized.

The recommended dosage of colchicine tablets, USP depends on the patient’s age, renal function, hepatic function and use of co-administered drugs

Colchicine tablets, USP are administered orally without regard to meals.

Colchicine tablets, USP are not an analgesic medication and should not be used to treat pain from other causes.

Tablets: 0.6 mg colchicine - purple capsule-shaped, film-coated tablets, scored on one side and debossed with “A10” on the other side.

• 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 (10)

  ].

  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 (12.3)]

  .
  .
• 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 (7)

  ].

  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 (4)

  ].
   
  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 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 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 (6).

  To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 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 non-recommended 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 non-recommended 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		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

  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 (12.3)]

  .
  .
• Drug interaction P-gp and/or CYP3A4 inhibitors:
  Co-administration 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 (7)

  ].

  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 (4)

  ].
   
  7  DRUG INTERACTIONS

  Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.

  Physicians should ensure that patients are suitable candidates for treatment with colchicine and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, colchicine should be discontinued immediately.

  Table 4

  provides recommendations as a result of other potentially significant drug interactions.

  Table 1

  provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.

  Table 4. Other Potentially Significant Drug Interactions

  Concomitant Drug Class or  Food	Noted or Anticipated Outcome	Clinical Comment
  HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a  stable long-term regimen of the other has  resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent  the occurrence of severe myopathy.
  Other Lipid-Lowering Drugs: fibrates, gemfibrozil
  Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

  Co-administration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy. See FPI for a complete list of reported and potential interactions (2.4, 5.3, 7).

  .
• Neuromuscular toxicity:
  Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of colchicine
  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 may potentiate the development of myopathy

  [see Drug Interactions (7)].

  Once colchicine is stopped, the symptoms generally resolve within one week to several months.
   
  7  DRUG INTERACTIONS

  Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.

  Physicians should ensure that patients are suitable candidates for treatment with colchicine and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, colchicine should be discontinued immediately.

  Table 4

  provides recommendations as a result of other potentially significant drug interactions.

  Table 1

  provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.

  Table 4. Other Potentially Significant Drug Interactions

  Concomitant Drug Class or  Food	Noted or Anticipated Outcome	Clinical Comment
  HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a  stable long-term regimen of the other has  resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent  the occurrence of severe myopathy.
  Other Lipid-Lowering Drugs: fibrates, gemfibrozil
  Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

  Co-administration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy. See FPI for a complete list of reported and potential interactions (2.4, 5.3, 7).

  .

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

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

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.

Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.

Physicians should ensure that patients are suitable candidates for treatment with colchicine and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, colchicine should be discontinued immediately.