Label

HIGHLIGHTS OF PRESCRIBING INFORMATION
----------------------------- ADVERSE REACTIONS -------------------------------
These highlights do not include all the information needed to use
Gout Flares: Most common adverse reaction is diarrhea (23%) and
colchicine safely and effectively. See full prescribing information for
COLCRYSTM.
FMF: Most common adverse reactions (up to 20%) are abdominal pain,
COLCRYSTM (colchicine, USP) tablets for Oral use
diarrhea, nausea, and vomiting. These effects are usually mild, transient, and Initial U.S. Approval: 1961
---------------------------- INDICATIONS AND USAGE --------------------------
COLCRYS (colchicine, USP) tablets are an alkaloid indicated for
To report SUSPECTED ADVERSE REACTIONS, contact Mutual
Pharmaceutical Company, Inc. at 1-888-351-3786 or
or FDA at 1-800-FDA-1088 or
• Familial Mediterranean fever (FMF) in adults and children 4 years or www.fda.gov/medwatch.
COLCRYS is not an analgesic medication and should not be used to treat pain ------------------------------ DRUG INTERACTIONS ------------------------------
Coadministration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or ----------------------- DOSAGE AND ADMINISTRATION ----------------------
cyclosporine) have been demonstrated to alter the concentration of • Gout Flares: 1.2 mg (2 tablets) at the first sign of a gout flare followed
COLCRYS. The potential for drug-drug interactions must be considered prior by 0.6 mg (1 tablet) one hour later (2.1). to and during therapy. See full prescribing information for a complete list of reported and potential interactions (2.4, 5.3, 7). FMF: Adults and Children older than 12 years 1.2 – 2.4 mg; Children 6
to 12 years 0.9 – 1.8 mg; Children 4 to 6 years 0.3 – 1.8 mg. (2.2, 2.3).
---------------------- USE IN SPECIFIC POPULATIONS -----------------------
Give total daily dose in one or two divided doses (2.2). • In patients with severe hepatic or renal impairment, close monitoring is Increase or decrease the dose as indicated and as tolerated recommended in both gout flares and FMF patients; a dose reduction may in increments of 0.3 mg/day, not to exceed the maximum not be needed in gout flares but should be considered in FMF patients, based on the patient’s estimated creatinine clearance. (2.5, 2.6, 8.6, 8.7) • See full prescribing information for dose adjustment regarding patients • In the presence of renal impairment, dosing for gout flares should be with impaired renal function (2.5) or hepatic function (2.6). repeated no more than once every two weeks, whereas dosing for FMF --------------------- DOSAGE FORMS AND STRENGTHS ---------------------
should be continued but adjusted based upon the patients estimated • For patients undergoing dialysis, the total recommended dose for gout flares ----------------------------- CONTRAINDICATIONS ------------------------------
should be reduced to 0.6 mg (1 tablet) x 1 dose, whereas for FMF patients Patients with renal or hepatic impairment should not be given COLCRYS in the starting dose should be 0.3 mg per day. For gout flares, a treatment conjunction with P-gp or strong CYP3A4 inhibitors (5.3). In these patients, course should be repeated no more than once every 2 weeks with no life-threatening and fatal colchicine toxicity has been reported with colchicine increase in dosage but for FMF patients, dosing can be increased with close ---------------------- WARNINGS AND PRECAUTIONS ------------------------
• Pregnancy: Use only if the potential benefit justifies the potential risk to the • Fatal overdoses have been reported with colchicine in adults and children. Keep COLCRYS out of the reach of children (5.1, 10). • Nursing Mothers: Caution should be exercised when administered to a • Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported. • Geriatric Use: The recommended dose of colchicine should be based on Monitor for toxicity and if present consider temporary interruption or discontinuation of colchicine (5.2, 5.3, 5.4, 6, 10). See 17 for PATIENT COUNSELING INFORMATION and Medication
• Drug interaction P-gp and/or CYP3A4 inhibitors: Coadministration with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death (5.3, 7). Revised: 7/2009
• Neuromuscular toxicity: Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of COLCRYS. (5.4, 7). FULL PRESCRIBING INFORMATION: CONTENTS*
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
9 DRUG ABUSE AND DEPENDENCE
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
2.4 Dose Modification for Co-administration of Interacting Drugs 2.5 Dose Modification in Renal Impairment 2.6 Dose Modification in Hepatic Impairment 13 NONCLINICAL TOXICOLOGY
DOSAGE FORMS AND STRENGTHS
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CONTRAINDICATIONS
14 CLINICAL STUDIES
WARNINGS AND PRECAUTIONS
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
ADVERSE REACTIONS
DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
*Sections or subsections omitted from the full prescribing information are not FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Gout Flares
COLCRYSTM (colchicine, USP) tablets are indicated for treatment of acute gout flares when taken at the first
sign of a flare.
1.2 Familial Mediterranean fever (FMF)
COLCRYSTM (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of
familial Mediterranean fever (FMF).
2 DOSAGE AND ADMINISTRATION
The long term use of colchicine is established for FMF but the safety and efficacy of repeat treatment in
gout flares has not been evaluated. The dosing regimens for COLCRYS are different for the two
indications and must be individualized.
The recommended dosage of COLCRYS depends on the patient’s age, renal function, hepatic function, and use of other co-administered drugs [see Dose Modification for Co-administration of Interacting Drugs (2.4)]. COLCRYS tablets are administered orally, without regard to meals. COLCRYS is not an analgesic medication and should not be used to treat pain from other causes. Gout Flares
The recommended dose of COLCRYS for treatment of a gout flare is 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1 hour period. The recommended dosage of COLCRYS for FMF in adults is 1.2 mg to 2.4 mg daily. COLCRYS should be increased as needed to control disease and as tolerated in increments of 0.3 mg/day to a maximum recommended daily dose. If intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day. The total daily COLCRYS dose may be administered in one to two divided doses. Recommended Pediatric Dosage
Gout Flares:
COLCRYS is not recommended for pediatric use in gout flares.
FMF:
The recommended dosage of COLCRYS for FMF in pediatric patients 4 years of age and older is based on age.
The following daily doses may be given as a single or divided dose twice daily:
• Children 4 – 6 years: 0.3 mg to 1.8 mg daily • Children 6 – 12 years: 0.9 mg to 1.8 mg daily • Adolescents older than 12 years: 1.2 mg to 2.4 mg daily Dose Modification for Co-administration of Interacting Drugs
Concomitant Therapy:
Co-administration with drugs known to inhibit CYP3A4 and/or P-glycoprotein (P-gp) increases the risk of
colchicine-induced toxic effects (Table 1). If patients are taking or have recently completed treatment with
drugs listed in Table 1 within the prior 14 days, the dose of COLCRYS should be reduced as shown below[See
DRUG INTERACTIONS (7)].
Table 1: COLCRYS Dose Adjustment for Co-administration with Interacting Drugs
if no Alternative Available1
Noted or Anticipated
Clinical Comment
Strong CYP3A4 Inhibitors
Gout Flares
dose, followed by 0.3 mg 0.6 mg (may be given in colchicine plasma levels is anticipated with other strong CYP3A4 inhibitors. Moderate CYP3A4
Inhibitors
amprenavir, aprepitant,
Gout Flares
P-gp Inhibitors
Gout Flares
repeated no earlier than 3 as 0.3 mg twice a day) significant increase in colchicine plasma levels is anticipated with other P-gp inhibitors. 1 For magnitude of effect on colchicine plasma concentrations [See Pharmacokinetics (12.3)] 2.5 Dose Modification in Renal Impairment
Clcr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula: [140-age (years) × weight (kg)] Clcr = --------------------------------------- × 0.85 for female patients 72 × serum creatinine (mg/dL) Gout Flares:
For treatment of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to
moderate (Clcr 30 – 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 dose does not need to be adjusted, but a treatment course should be repeated no more
than once every 2 weeks. For these patients, requiring repeated courses, consideration should be given to
alternate therapy. For patients undergoing dialysis, the total recommended dose for gout flares should be
reduced to a single dose of 0.6 mg (1 tablet). For these patients, a treatment course should not be repeated more
than once every 2 weeks [See Clinical Pharmacology (12.3) and Renal Impairment (8.6)].
FMF:
Caution should be taken in dosing patients with moderate and severe renal impairment and in patients
undergoing dialysis. For these patients, the dosage should be reduced [See Clinical Pharmacology (12.3)].
Patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment should be
monitored closely for adverse effects of COLCRYS. Dose reduction may be necessary. For patients with severe
renal failure (Clcr less than 30 mL/minute), start with 0.3 mg/day; any increase in dose should be done with
adequate monitoring of the patient for adverse effects of colchicine. [See Renal Impairment (8.6)]. For patients
undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day. Dosing can be
increased with close monitoring. Any increase in dose should be done with adequate monitoring of the patient
for adverse effects of colchicine [See Clinical Pharmacology (12.3) and Renal Impairment (8.6)].
2.6 Dose Modification in Hepatic Impairment
Gout Flares
For treatment 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.
However, in patients with severe impairment, the dose does not need to be adjusted, but a treatment course
should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses,
consideration should be given to alternate therapy. [See Hepatic Impairment (8.7)].
FMF:
Patients with mild to moderate hepatic impairment should be monitored closely for adverse effects of
colchicine. Dose reduction should be considered in patients with severe hepatic impairment. [See Hepatic
Impairment (8.7)].
3 DOSAGE FORMS AND STRENGTHS
0.6 mg tablets — purple capsule-shaped, film-coated with AR 374 debossed on one side and scored on the other side 4 CONTRAINDICATIONS
Patients with renal or hepatic impairment should not be given colchicine in conjunction with P-gp or strong CYP3A4 inhibitors. In these patients, life-threatening and fatal colchicine toxicity has been reported with colchicine taken in therapeutic doses. 5 WARNINGS AND PRECAUTIONS
5.1 Fatal Overdose
Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested
colchicine. [See OVERDOSAGE (10)]. COLCRYS should be kept out of the reach of children.
5.2 Blood Dyscrasias
Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia with
colchicine used in therapeutic doses have been reported.
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 COLCRYS in
conjunction with P-gp or strong CYP3A4 inhibitors 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,
gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or
cyclosporine may potentiate the development of myopathy [See DRUG INTERACTIONS (7)]. Once colchicine
is stopped, the symptoms generally resolve within 1 week to several months.
6 ADVERSE REACTIONS
Gout Flares: The most common adverse reaction is diarrhea (23%). Pharyngolaryngeal pain was seen in 3% of patients 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.
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 1 hour) compared to 77% of patients taking a non-recommended high-dose (4.8 mg over 6 hours) and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 2, diarrhea is associated with 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. Number (%) of Patients with at Least One Drug-Related Treatment Emergent Adverse Events with
an Incidence of ≥ 2% of Patients in Any Treatment Group
MedDRA System Organ Class
Colchicine Dose
MedDRA Preferred Term
High (N=52)
Low (N=74)
Number of Patients with at Least One Drug-Related TEAE General Disorders and Administration Site Conditions Respiratory Thoracic Mediastinal Disorders 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 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
7 DRUG 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 3 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. Other Potentially Significant Drug Interactions
Concomitant Drug
Noted or anticipated Outcome
Clinical Comment
Class or Food
HMG-Co A Reductase
Weigh the potential benefits and risks and Inhibitors:
carefully monitor patients for any signs or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of Other Lipid Lowering
Drugs:
fibrates, gemfibrozil
Digitalis Glycosides:
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the
human placenta. While not studied in the treatment of gout flares, data from a limited number of published
studies found no evidence of an increased risk of miscarriage, stillbirth, or teratogenic effects among pregnant
women using colchicine to treat familial Mediterranean fever (FMF). Although animal reproductive and
developmental studies were not conducted with COLCRYS, published animal reproduction and development
studies indicate that colchicine causes embryofetal toxicity, teratogenicity, and altered postnatal development at
exposures within or above the clinical therapeutic range. Colchicine should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.
8.2 Labor and Delivery
The effect of colchicine on labor and delivery is unknown.
8.3 Nursing Mothers
Colchicine is excreted into human milk. Limited information suggests that exclusively breastfed infants receive
less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse
effects in breast-feeding infants of mothers taking colchicine, colchicine can affect gastrointestinal cell renewal
and permeability. Caution should be exercised and breastfeeding infants should be observed for adverse effects
when colchicine is administered to a nursing woman.
8.4 Pediatric Use
The safety and efficacy of colchicine in children of all ages with FMF has been evaluated in uncontrolled
studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with
colchicine. Gout is rare in pediatric patients, safety and effectiveness of colchicine in pediatric patients has not
been established.
8.5 Geriatric Use
Clinical studies with colchicine for 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 Dose Modification for
Co-administration of Interacting Drugs (2.4)].
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.
Gout Flares
For patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment,
adjustment of the dose recommended for treatment of gout flares is not required. However, in patients with
severe renal failure dose reduction should be considered with careful monitoring as necessary and the treatment
course should be repeated no more than once every 2 weeks. Colchicine is not removed by hemodialysis. For
patients undergoing dialysis, the total recommended dose for gout flares should be reduced to a single dose of
0.6 mg (1 tablet). A treatment course should not be repeated more than once every 2 weeks with no increase in
dosage. [See Pharmacokinetics (12.3) and Dose Modification in Renal Impairment (2.5)].
FMF
Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 –
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 (Clcr less than 30 mL/minute)
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
Pharmacokinetics (12.3) and Dose Modification in Renal Impairment (2.5)].
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 Pharmacokinetics (12.3)]. Nonetheless,
colchicine (0.6 mg twice daily) administered long-term to patients with Stage 3 cirrhosis (fibrosis) has been
well tolerated.
In patients with mild to moderate hepatic impairment, adjustment of the dose recommended for treatment of gout flares or FMF is not required, but patients should be monitored closely for adverse effects of colchicine [See Pharmacokinetics (12.3) and Dose Modification in Hepatic Impairment (2.6)]. Gout Flares
In patients with severe hepatic disease, dose reduction should be considered with careful monitoring as
necessary and the treatment course should be repeated no more than once every 2 weeks. [See
Pharmacokinetics (12.3) and Dose Modification in Hepatic Impairment (2.6)].
FMF
In patients with severe hepatic disease, dose reduction should be considered with careful monitoring as
necessary. [See Pharmacokinetics (12.3) and Dose Modification in Hepatic Impairment (2.6)].
9 DRUG ABUSE AND DEPENDENCE
Tolerance, abuse, or dependence with colchicine has not been reported.
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 4-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 multi-organ failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 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 Pharmacokinetics (12.3)]. 11 DESCRIPTION
Colchicine is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3, 10-tetramethoxy-9-oxobenzo
[alpha] heptalen-7-yl) acetamide with a molecular formula of C22H25NO6 and a molecular weight of 399.4. The
structural formula of colchicine is given below.
Colchicine occurs as a pale yellow powder that is soluble in water. COLCRYSTM (colchicine USP) tablets is supplied for oral administration as purple, film-coated, capsule-shaped tablets (0.1575” × 0.3030”), debossed with ‘AR 374’ on one side and scored on the other, containing 0.6 mg of the active ingredient colchicine USP. Inactive ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin. 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which COLCRYS exerts its beneficial effect in patients with FMF has not been fully
elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the
inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β.
Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into
microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils thought to
mediate some gout symptoms.
12.3 Pharmacokinetics
Absorption
In healthy adults, COLCRYS is absorbed when given orally, reaching a mean Cmax of 2.5 ng/mL (range 1.1 to
4.4 ng/mL) in 1 to 2 hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.
Following oral administration of COLCRYS given as 1.8 mg colchicine over 1 hour to healthy, young adults under fasting conditions, colchicine appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1.0 to 2.5 hours). Following administration of the non-recommended high-dose regimen (4.8 mg over 6 hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours). After 10 days on a regimen of 0.6 mg twice daily peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours post-dose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 4 below. Mean (%CV) Pharmacokinetic Parameters in Healthy Adults Given COLCRYS max (colchicine ng/mL)
CL/F (L/hr)
COLCRYS 0.6 mg Single Dose (N=13)
COLCRYS 0.6 mg b.i.d. x 10 days (N =13)
CL= Dose/AUC0-t (Calculated from mean values) Vd = CL/Ke (Calculated from mean values) In some subjects, secondary colchicine peaks are seen, occurring between 3 and 36 hours post-dose and ranging from 39% to 155% of the height of the initial peak. These observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation. Absolute bioavailability is reported to be approximately 45%. Administration of COLCRYS with food has no effect on the rate of colchicine absorption, but did decrease the extent of colchicine by approximately 15%. This is without clinical significance. The mean apparent volume of distribution in healthy young volunteers was approximately 5 to 8 L/kg. Colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration. Colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). Colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum. [See Pregnancy (8.1) and Nursing Mothers (8.3)] Metabolism Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2- and 3-DMC, respectively), and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2- and 3-DMC. Plasma levels of these metabolites are minimal (less than 5% of parent drug). Elimination/Excretion In healthy volunteers (n=12) 40 – 65% of 1 mg orally administered colchicine was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in colchicine elimination. Following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. Colchicine is a substrate of P-glycoprotein (P-gp). Extracorporeal Elimination: Colchicine is not removed by hemodialysis. There is no difference between men and women in the pharmacokinetic disposition of colchicine. Pediatric Patients: Pharmacokinetics of colchicine was not evaluated in pediatric patients. Elderly: Pharmacokinetics of colchicine has not been determined in elderly patients. A published report described the pharmacokinetics of 1 mg oral colchicine tablet in four elderly women compared to six young healthy males. The mean age of the four elderly women was 83 years (range 75 – 93), mean weight was 47 kg (38 – 61 kg) and mean creatinine clearance was 46 mL/min (range 25 – 75 mL/min). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males. However, it is possible that the higher exposure in the elderly subjects was due to decreased renal function. Renal impairment: Pharmacokinetics of colchicine in patients with mild and moderate renal impairment is not known. A published report described the disposition of colchicine (1 mg) in young adult men and women with FMF who had normal renal function or end-stage renal disease requiring dialysis. Patients with end-stage renal disease had 75% lower colchicine clearance (0.17 vs 0.73 L/hr/kg) and prolonged plasma elimination half-life (18.8 hrs vs 4.4 hrs) as compared to subjects with FMF and normal renal function [See Dose Modification in Renal Impairment (2.5) and Renal Impairment (8.6)]. Hepatic impairment: Published reports on the pharmacokinetics of IV colchicine in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis, and normal renal function suggest wide inter-patient variability. In some subjects with mild to moderate cirrhosis, the clearance of colchicine is significantly reduced and plasma half-life prolonged compared to healthy subjects. In subjects with primary biliary cirrhosis, no consistent trends were noted. [See Dose Modification in Hepatic Impairment (2.6) and Hepatic Impairment (8.7)]. No pharmacokinetic data are available for patients with severe hepatic impairment In vitro studies in human liver microsomes have shown that colchicine is not an inhibitor or inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 activity. In vivo drug interactions: The effects of co-administration of other drugs with COLCRYS on Cmax, AUC, and Cmin are summarized in Table 5 (effect of other drugs on colchicine) and Table 6 (effect of colchicine on other drugs). For information regarding clinical recommendations, see Table 1 in Dose Modification for Co-administration of Interacting Drugs (2.4)]. Drug Interactions: Pharmacokinetic Parameters for Colchicine in the Presence of the Co-Administered % Change in Colchicine
administered
Concentrations from Baseline
administered
(Range: Min - Max)
Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum® 1/35) co administered with COLCRYS (0.6 mg b.i.d. × 14 days), hormone concentrations are not affected. In healthy volunteers given theophylline coadministered with COLCRYS (0.6 mg b.i.d. x 14 days), theophylline concentrations were not affected. Drug Interactions: Pharmacokinetic Parameters for Co-Administration of Drug in the Presence of COLCRYS (colchicine, USP) tablets Dose of Co-
Dose of COLCRYS
% Change in Co-Administered Drug Concentrations from Baseline
administered
administered
(Range: Min - Max)
1 Conducted in healthy adult females 2 AUCτ 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies of colchicine have not been conducted. Due to the potential for colchicine to produce
aneuploid cells (cells with an unequal number of chromosomes), there is theoretically an increased risk of
malignancy.
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 COLCRYS. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Reproductive , 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. Case reports and epidemiology studies in human male subjects on colchicine therapy indicated that infertility from colchicine is rare. 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. 14 CLINICAL STUDIES
The efficacy of a low dosage regimen of oral colchicine (COLCRYS total dose 1.8 mg over 1 hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, 1 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 1 hour [1.8 mg total] followed by 5 placebo doses hourly); or placebo (2 capsules, then 1 capsule hourly × 6 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 pre-treatment 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 7. Number (%) of Responders Based on Target Joint Pain Score at 24 Hours Post First Dose
COLCRYS Dose
Responders n (%)
% Difference in Proportions
Low-dose
High-dose
Low-dose
High-dose
vs Placebo
vs Placebo
Figure 1 below shows the percentage of patients achieving varying degrees of improvement in pain from baseline at 24 hours. Pain Relief on Low and High Doses of COLCRYS and Placebo (Cumulative)
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 6-month crossover study during which 5 patients discontinued due to study non-compliance. The 10 patients completing the study experienced 5 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 4-month crossover study during which 9 patients discontinued due to lack of efficacy while receiving placebo or study non-compliance. 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 6 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
COLCRYSTM (colchicine, USP) tablets 0.6 mg, are purple, film-coated, capsule-shaped tablets, debossed with ‘AR 374’ on one side and scored on the other side. 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
17.1 Dosing Instructions
Patients should be advised to take COLCRYS 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 COLCRYS is missed,
then patients being treated for gout flare or FMF should take the dose as soon as possible and then patients with
FMF should return to their normal schedule. However, if a dose is skipped the patient should not double the
next dose.
17.2 Blood Dyscrasias
Patients should be informed that bone marrow depression with agranulocytosis, aplastic anemia, and
thrombocytopenia may occur.
17.3 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 COLCRYS
treatment.
17.4 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.
17.5 Medication Guide

Source: http://www.affmf.com/app/download/6033063076/colcrys+usa+colchicine.pdf?t=1332673971