Alkaloid

Colcrys

Approved 29 Jul 2009OralTablet

The FDA lists this product in 3 strengths and forms.

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Indications

COLCRYS (colchicine, USP) tablets are an alkaloid indicated for:

Prophylaxis and treatment of gout flares in adults ( 1.1 ).
Familial Mediterranean fever (FMF) in adults and children 4 years or older ( 1.2 ). COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

1.1Gout Flares

COLCRYS (colchicine, USP) tablets are indicated for prophylaxis and the treatment of acute gout flares.

Prophylaxis of Gout Flares: COLCRYS is indicated for prophylaxis of gout flares.
Treatment of Gout Flares: COLCRYS tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.

1.2Familial Mediterranean Fever (FMF)

COLCRYS (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).

Contraindications

Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir). In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses. Patients with renal or hepatic impairment should not be given COLCRYS in conjunction with P-gp or strong CYP3A4 inhibitors ( 5.3 ).

In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses ( 7 ).

Warnings and precautions

Fatal overdoses have been reported with colchicine in adults and children. Keep COLCRYS out of the reach of children ( 5.1 , 10 ).
Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported ( 5.2 ).
Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ).
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 , 7 ).

At a glance

Brand name: Colcrys
Active substance: colchicine
Pharmacologic class: Alkaloid
Route: Oral
Dosage form: Tablet
Applicant: Takeda Pharms USA
Status: Discontinued
FDA approval: 29 Jul 2009
Application: NDA022352-001

Indications

COLCRYS (colchicine, USP) tablets are an alkaloid indicated for:

Prophylaxis and treatment of gout flares in adults ( 1.1 ).
Familial Mediterranean fever (FMF) in adults and children 4 years or older ( 1.2 ). COLCRYS is not an analgesic medication and should not be used to treat pain from other causes.

1.1Gout Flares

COLCRYS (colchicine, USP) tablets are indicated for prophylaxis and the treatment of acute gout flares.

Prophylaxis of Gout Flares: COLCRYS is indicated for prophylaxis of gout flares.
Treatment of Gout Flares: COLCRYS tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.

1.2Familial Mediterranean Fever (FMF)

COLCRYS (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).

Contraindications

In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses ( 7 ).

Warnings and precautions

Fatal overdoses have been reported with colchicine in adults and children. Keep COLCRYS out of the reach of children ( 5.1 , 10 ).
Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia and aplastic anemia have been reported ( 5.2 ).
Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine ( 5.2 , 5.3 , 5.4 , 6 , 10 ).
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 , 7 ).

Interactions

COLCRYS (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 COLCRYS 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 COLCRYS 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 COLCRYS toxicity should be evaluated promptly and, if toxicity is suspected, COLCRYS 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) P-gp substrate; rhabdomyolysis has been reported 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 Coadministration 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 full prescribing information for a complete list of reported and potential interactions ( 2.4 , 5.3 , 7 ).

Adverse reactions

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 Takeda Pharmaceuticals America, Inc. at 1-877-825-3327 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 COLCRYS 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 COLCRYS, 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.

6.1Clinical 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 COLCRYS 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 COLCRYS 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 COLCRYS 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 COLCRYS 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

6.2Postmarketing 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 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 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

Colcrys

Indications

1.1Gout Flares

1.2Familial Mediterranean Fever (FMF)

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Colcrys

Indications

1.1Gout Flares

1.2Familial Mediterranean Fever (FMF)

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Fatal Overdose

5.2Blood Dyscrasias

5.3Drug Interactions

5.4Neuromuscular Toxicity

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Category C.

Adverse reactions

6.1Clinical Trials Experience in Gout

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information