NDC 67877-589 Colchicine

Colchicine

NDC Product Code 67877-589

NDC Code: 67877-589

Proprietary Name: Colchicine Additional informationCallout TooltipWhat is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Colchicine Additional informationCallout TooltipWhat is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.


Product Characteristics
Color(s):
PURPLE (C48327)
Shape: CAPSULE (C48336)
Size(s):
8 MM
Imprint(s):
C6
Score: 2

Code Structure
  • 67877 - Ascend Laboratories, Llc
    • 67877-589 - Colchicine

NDC 67877-589-01

Package Description: 100 TABLET in 1 BOTTLE

NDC 67877-589-05

Package Description: 500 TABLET in 1 BOTTLE

NDC 67877-589-10

Package Description: 1000 TABLET in 1 BOTTLE

NDC 67877-589-30

Package Description: 30 TABLET in 1 BOTTLE

NDC 67877-589-33

Package Description: 1 BLISTER PACK in 1 CARTON > 10 TABLET in 1 BLISTER PACK

NDC 67877-589-60

Package Description: 60 TABLET in 1 BOTTLE

NDC 67877-589-86

Package Description: 250 TABLET in 1 BOTTLE

NDC Product Information

Colchicine with NDC 67877-589 is a a human prescription drug product labeled by Ascend Laboratories, Llc. The generic name of Colchicine is colchicine. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Ascend Laboratories, Llc

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug Additional informationCallout TooltipWhat kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.


Colchicine Active Ingredient(s)

Additional informationCallout TooltipWhat is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • COLCHICINE .6 mg/1

Inactive Ingredient(s)

Additional informationCallout TooltipAbout the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • FD&C RED NO. 40 (UNII: WZB9127XOA)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • POLYDEXTROSE (UNII: VH2XOU12IE)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • TRIACETIN (UNII: XHX3C3X673)

Administration Route(s)

Additional informationCallout TooltipWhat are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

Additional informationCallout TooltipWhat is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Cytochrome P450 3A4 Inhibitors - [MoA] (Mechanism of Action)
  • P-Glycoprotein Interactions - [MoA] (Mechanism of Action)

Product Labeler Information

Additional informationCallout TooltipWhat is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Ascend Laboratories, Llc
Labeler Code: 67877
FDA Application Number: ANDA211250 Additional informationCallout TooltipWhat is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. Additional informationCallout TooltipWhat is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 02-10-2019 Additional informationCallout TooltipWhat is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 Additional informationCallout TooltipWhat is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N Additional informationCallout TooltipWhat is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Colchicine Product Label Images

Colchicine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.2 Familial Mediterranean Fever (Fmf)

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

2 Dosage & Administration

The long-term use of colchicine is established for FMF.The recommended dosage of colchicine tablets depends on the patient’s age, renal function, hepatic function and use of coadministered drugs [see Dose Modification for Coadministration of Interacting Drugs (2.4)].Colchicine tablets are administered orally without regard to meals.Colchicine tablets are not an analgesic medication and should not be used to treat pain from other causes.

2.2 Fmf

The recommended dosage of colchicine tablets for FMF in adults is 1.2 mg to 2.4 mg daily.Colchicine tablets 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 colchicine tablets dose may be administered in one to two divided doses.

FMF The recommended dosage of colchicine tablets 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 to 6 years: 0.3 mg to 1.8 mg daily·                Children 6 to 12 years: 0.9 mg to 1.8 mg daily·                Adolescents older than 12 years: 1.2 mg to 2.4 mg daily

2.4 Dose Modification For Coadministration Of Interacting Drugs

Concomitant Therapy Coadministration of colchicine tablets 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 adjustments are as shown in the table below [see Drug Interactions (7)]Table 1. Colchicine tablets Dose Adjustment for Coadministration with Interacting Drugs if no Alternative Available*Strong CYP3A4 Inhibitors†       Drug   Noted or Anticipated Outcome FMFOriginal Intended DosageAdjusted Dose AtazanavirClarithromycin Darunavir/ Ritonavir‡Indinavir Itraconazole Ketoconazole Lopinavir/ Ritonavir‡Nefazodone   Nelfinavir Ritonavir Saquinavir Telithromycin    Tipranavir/Ritonavir‡Significant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with clarithromycin, a strong CYP3A4 inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other strong CYP3A4 inhibitors.Maximum daily dose of 1.2 – 2.4 mgMaximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Moderate CYP3A4 Inhibitors   FMF  Drug Noted or Anticipated Outcome Original Intended Dosage Adjusted Dose  Amprenavir‡Aprepitant Diltiazem Erythromycin Fluconazole Fosamprenavir‡   (pro-drug of Amprenavir)    Grapefruit juice VerapamilSignificant increase in colchicine plasma concentration is anticipated.Neuromuscular toxicity has been reported with diltiazem and verapamil interactions.Maximum daily dose of 1.2 – 2.4 mgMaximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) P-gp Inhibitors†   FMF DrugNoted or Anticipated Outcome Original Intended Dosage Adjusted Dose Cyclosporine RanolazineSignificant increase in colchicine plasma levels*; fatal colchicine toxicity has been reported with cyclosporine, a P-gp inhibitor. Similarly, significant increase in colchicine plasma levels is anticipated with other P-gp inhibitors. Maximum daily dose of 1.2 –2.4 mgMaximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day.*for magnitude of effect on colchicine plasma concentrations [see Pharmacokinetics (12.3)]†Patients with renal or hepatic impairment should not be given colchicine tablets in conjunction with strong CYP3A4 or P-gp inhibitors [see Contraindications (4)]‡When used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors [see Contraindications (4)]Table 2. Colchicine tablets Dose Adjustment for Coadministration with Protease InhibitorsProtease Inhibitor Clinical Comment  w/Colchicine ­Treatment of FMF Atazanavir sulfate (Reyataz)Patients with renal or hepatic impairment should not be given colchicine with Reyataz. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Darunavir (Prezista)Patients with renal or hepatic impairment should not be given colchicine with Prezista/ ritonavir.Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)Fosamprenavir (Lexiva) with RitonavirPatients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)Fosamprenavir (Lexiva)Patients with renal or hepatic impairment should not be given colchicine with Lexiva/ritonavir.Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)Indinavir (Crixivan)Patients with renal or hepatic impairment should not be given colchicine with Crixivan.Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)Lopinavir/ Ritonavir (Kaletra)Patients with renal or hepatic impairment should not be given colchicine with Kaletra. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)Nelfinavir mesylate (Viracept)Patients with renal or hepatic impairment should not be given colchicine with Viracept.Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)Ritonavir (Norvir)Patients with renal or hepatic impairment should not be given colchicine with Norvir.Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)Saquinavir mesylate (Invirase)Patients with renal or hepatic impairment should not be given colchicine with Invirase/ ritonavir.Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)Tipranavir (Aptivus)Patients with renal or hepatic impairment should not be given colchicine with Aptivus/ritonavir.Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)

2.5 Dose Modification In Renal Impairment

Colchicine dosing must be individualized according to the patient's renal function [see Renal Impairment (8.6)]. Clcr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula:FMFCaution 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 to 80 mL/min) and moderate (Clcr 30 to 50 mL/min) renal impairment should be monitored closely for adverse effects of colchicine tablets. Dose reduction may be necessary. For patients with severe renal failure (Clcr less than 30 mL/min), 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

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 & Strengths

0.6 mg tablets-Purple colored, capsule shaped, film coated tablets debossed with "C6" on one side and scored on other side.

4 Contraindications

Patients with renal or hepatic impairment should not be given colchicine tablets 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.

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 tablets should be kept out of the reach of children.

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 tablets may potentiate the development of myopathy [see Drug Interactions (7)]. Once colchicine is stopped, the symptoms generally resolve within one week to several months.

6 Adverse Reactions

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

6.2 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 neuropathyDermatological: alopecia, maculopapular rash, purpura, rash Digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomitingHematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemiaHepatobiliary: elevated AST, elevated ALTMusculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis Reproductive: azoospermia, oligospermia

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 tablets 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 tablets 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 tablets toxicity should be evaluated promptly and, if toxicity is suspected, colchicine tablets 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 InteractionsConcomitant Drug Class or FoodNoted or Anticipated OutcomeClinical CommentHMG-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, gemfibrozilDigitalis Glycosides: digoxinP-gp substrate; rhabdomyolysis has been reported

8.1 Pregnancy

Pregnancy Category C There are no adequate and well-controlled studies with colchicine in pregnant women. Colchicine crosses the human placenta. 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 colchicine tablets, 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 tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Labor & 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 breastfeeding 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 tablets 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 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 should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see Dose Modification for Coadministration of Interacting Drugs (2.4) and Pharmacokinetics (12.3)].

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.FMF Although, pharmacokinetics of colchicine in patients with mild (Clcr 50 to 80 mL/min) and moderate (Clcr 30 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 (Clcr less than 30 mL/min) and end-stage renal disease requiring dialysis, colchicine tablets 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 tablets [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)].FMF In patients with severe hepatic disease, dose reduction should be considered with careful monitoring [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 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 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.Colchicine Tablets, USP 0.6 mg are supplied for oral administration as Purple colored, capsule shaped, film coated tablets debossed with “C6” on one side and scored on other side., containing 0.6 mg of the active ingredient colchicine, USP. Inactive ingredients: 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.

12.1 Mechanism Of Action

The mechanism by which colchicine tablets 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.

12.3 Pharmacokinetics

Absorption In healthy adults, colchicine is absorbed when given orally, reaching a mean Cmax of  2.5 ng/mL (range 1.1 to 4.4 ng/mL) in one to two hours (range 0.5 to three hours) after a single dose administered under fasting conditions.Following oral administration of colchicine given as 1.8 mg colchicine over one 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 six 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 5.\Table 5. Mean (%CV) Pharmacokinetic Parameters in Healthy Adults Given colchicine tablets Cmax (Colchicine ng/mL) Tmax* (h) Vd/F (L) CL/F (L/hr) t1/2 (h) Colchicine tablets 0.6 mg Single Dose (N=13) 2.5(28.7)1.5(1.0 – 3.0)341.5(54.4)54.1(31.0)-­Colchicine tablets 0.6 mg Twice Daily x 10 Days (N=13) 3.6(23.7)1.3(0.5 – 3.0)1150(18.7)30.3(19.0)26.6(16.3)*Tmax mean (range)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 three 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 colchicine tablets with food has no effect on the rate of colchicine absorption but does decrease the extent of colchicine by approximately 15%. This is without clinical significance. Distribution The mean apparent volume of distribution in healthy young volunteers is 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% to 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-gp.Extracorporeal Elimination Colchicine is not removed by hemodialysis.Special Populations 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: 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 to 93), mean weight was 47 kg (38 to 61 kg) and mean creatinine clearance was 46 mL/min (range 25 to 75 mL/min). Mean peak plasma levels and AUC of colchicine were two times higher in elderly subjects compared to young healthy males.A pharmacokinetic study using a single oral dose of one 0.6 mg colchicine tablet was conducted in young healthy subjects (n=20) between the ages of 18 and 30 years and elderly subjects (n=18) between the ages of 60 and 70 years. Elderly subjects in this study had a median age of 62 years and a mean (±SD) age of 62.83 ± 2.83 years. A statistically significant difference in creatinine clearance (mean ± SD) was found between the two age groups (132.56 ± 23.16 mL/min for young vs. 87.02 ± 17.92 mL/min for elderly subjects, respectively). The following pharmacokinetic parameter values (mean ± SD) were observed for colchicine in the young and elderly subjects, respectively: AUC0-inf (ng/hr/mL) 22.39 ± 6.95 and 25.01 ± 6.92; Cmax (ng/mL) 2.61 ± 0.71 and 2.56 ± 0.97; Tmax (hr) 1.38 ± 0.42 and 1.25 ± 0.43; apparent elimination half-life (hr) 24.92 ± 5.34 and 30.06 ± 10.78; and clearance (mL/min) 0.0321 ± 0.0091 and 0.0292 ± 0.0071.Clinical studies with colchicine for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease or other drug therapy [see Dose Modification for Coadministration of Interacting Drugs (2.4) and Geriatric Use (8.5)].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 hours vs. 4.4 hours) 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 interpatient 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 (Child-Pugh C). Drug Interactions In Vitro Drug Interactions: 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 coadministration of other drugs with colchicine tablets on Cmax, AUC and Cmin are summarized in Table 6 (effect of other drugs on colchicine) and Table 7 (effect of colchicine on other drugs). For information regarding clinical recommendations, see Table 1 in Dose Modification for Coadministration of Interacting Drugs [see Dose Modification for Coadministration of Interacting Drugs (2.4)].Table 6. Drug Interactions: Pharmacokinetic Parameters for Colchicine tablets in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) Dose of Colchicine tablets (mg) N % Change in Colchicine Concentrations from Baseline (Range: Min - Max) Cmax AUC0-t Cyclosporine100 mg single dose0.6 mg single dose23270.0(62.0 to 606.9)259.0(75.8 to 511.9)Clarithromycin250 mg twice daily, 7 days0.6 mg single dose23227.2(65.7 to 591.1)281.5(88.7 to 851.6)Ketoconazole200 mg twice daily, 5 days0.6 mg single dose24101.7(19.6 to 219.0)212.2(76.7 to 419.6)Ritonavir100 mg twice daily, 5 days0.6 mg single dose18184.4(79.2 to 447.4)296.0(53.8 to 924.4)Verapamil240 mg daily, 5 days0.6 mg single dose2440.1(-47.1 to 149.5)103.3(-9.8 to 217.2)Diltiazem240 mg daily, 7 days0.6 mg single dose2044.2(-46.0 to 318.3)93.4(-30.2 to 338.6)Azithromycin500 mg × 1 day, then 250 mg × 4 days0.6 mg single dose2121.6(-41.7 to 222.0)57.1(-24.3 to 241.1)Grapefruit juice240 mL twice daily, 4 days0.6 mg single dose21-2.55(-53.4 to 55.0)-2.36(-46.4 to 62.2)Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum 1/35) coadministered with colchicine tablets (0.6 mg twice daily × 14 days), hormone concentrations are not affected.In healthy volunteers given theophylline coadministered with colchicine tablets (0.6 mg twice daily × 14 days), theophylline concentrations were not affected.Table 7. Drug Interactions: Pharmacokinetic Parameters for Coadministration of Drug in the Presence of Colchicine tablets Coadministered Drug Dose of Coadministered Drug (mg) Dose of colchicine tablets (mg) N % Change in Coadministered Drug Concentrations from Baseline (Range: Min - Max) Cmax AUC0-t Theophylline300 mg (elixir)single dose0.6 mg twice daily × 14 days271.6(-30.4 to 23.1)1.6(-28.5 to 27.1)Ethinyl Estradiol (Ortho-Novum 1/35)21-day cycle (active treatment)+ 7-day placebo0.6 mg twice daily × 14 days27* -6.7(-40.3 to 44.7)-3.0†(-25.3 to 24.9)Norethindrone (Ortho-Novum 1/35) 0.94(-37.3 to 59.4)-1.6†(-32.0 to 33.7)*Conducted in healthy adult females †AUCτ

13.1 Carcinogenesis,Mutagenesis,Impairment Of Fertility

Two-year studies were conducted in mice and rats to assess the carcinogenic potential of colchicine. No evidence of colchicine-related tumorigenicity was observed in mice or rats at colchicine oral doses up to 3 mg/kg/day and 2 mg/kg/day, respectively (approximately 6 and 8 times, respectively, the maximum recommended human dose of 2.4 mg on a mg/m2 basis).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 colchicine tablets. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. 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 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 six-month crossover study during which five patients discontinued due to study noncompliance. The 10 patients completing the study experienced five 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 four-month crossover study during which nine patients discontinued due to lack of efficacy while receiving placebo or study noncompliance. 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 six 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.

16.1 How Supplied

Colchicine tablets, USP 0.6 mg are purple colored, capsule shaped, film, coated tablets debossed with “C6” on one side and scored on other side.Bottles of 30                                                               NDC 67877-589-30Bottles of 60                                                               NDC 67877-589-60Bottles of 100                                                             NDC 67877-589-01Bottles of 250                                                             NDC 67877-589-86Bottles of 500                                                             NDC 67877-589-05Bottles of 1000                                                           NDC 67877-589-10Carton of 10 [10 (1 x 10 Unit-dose) Tablets]                NDC 67877-589-33

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

Advise the patient to read the FDA-approved (Medication Guide). Dosing InstructionsPatients should be advised to take colchicine tablets 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 colchicine tablets is missed:·                For FMF, take the dose as soon as possible and then return to the normal dosing schedule. However, if a dose is skipped the patient should not double the next dose.Fatal Overdose Instruct patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested colchicine. Colchicine tablets should be kept out of the reach of children.Blood Dyscrasias Patients should be informed that bone marrow depression with agranulocytosis, aplastic anemia and thrombocytopenia may occur with colchicine tablets.Drug and Food Interactions Patients should be advised that many drugs or other substances may interact with colchicine tablets 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 colchicine tablets treatment.Neuromuscular Toxicity Patients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with colchicine tablets alone or when it is used with certain other drugs. Patients developing any of these signs or symptoms must discontinue colchicine tablets and seek medical evaluation immediately.

Medication Guide

  • Colchicine Tablets, USP (KOL chi seen)Read the Medication Guide that comes with colchicine tablets, USP before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about colchicine tablets, USP when you start taking it and at regular checkups.What is the most important information that I should know about colchicine tablets, USP? • Colchicine tablets, USP can cause serious side effects or death if levels of colchicine tablets, USP are too high in your body. • Taking certain medicines with colchicine tablets, USP can cause your level of colchicine tablets, USP to be too high, especially if you have kidney or liver problems. • Tell your healthcare provider about all your medical conditions, including if you have kidney or liver problems. Your dose of colchicine tablets, USP may need to be changed. • Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. • Even medicines that you take for a short period of time, such as antibiotics, can interact with colchicine tablets, USP and cause serious side effects or death. • Talk to your healthcare provider or pharmacist before taking any new medicine. • Especially tell your healthcare provider if you take:atazanavir sulfate (Reyataz)  clarithromycin (Biaxin) cyclosporine (Neoral, Gengraf, Sandimmune) darunavir (Prezista) fosamprenavir (Lexiva) with ritonavir fosamprenavir (Lexiva) indinavir (Crixivan) itraconazole (Sporanox) ketoconazole (Nizoral) lopinavir/ritonavir (Kaletra) nefazodone (Serzone) nelfinavir mesylate (Viracept) ritonavir (Norvir) saquinavir mesylate (Invirase) telithromycin (Ketek)tipranavir (Aptivus)  Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. This is not a complete list of all the medicines that can interact with colchicine tablets, USP.Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.Keep colchicine tablets, USP out of the reach of children.What is colchicine tablets, USP?Colchicine tablets, USP is a prescription medicine used to:treat familial Mediterranean fever (FMF) in adults and children age 4 or olderColchicine tablets, USP is not a pain medicine, and it should not be taken to treat pain related to other conditions unless specifically prescribed for those conditions.Who should not take colchicine tablets, USP?Do not take colchicine tablets, USP if you have liver or kidney problems and you take certain other medicines. Serious side effects, including death, have been reported in these patients even when taken as directed. See “What is the most important information that I should know about colchicine tablets, USP?”What should I tell my healthcare provider before starting colchicine tablets, USP?See “What is the most important information that I should know about colchicine tablets, USP?”Before you take colchicine tablets, USP, tell your healthcare provider about all your medical conditions, including if you:have liver or kidney problems.are pregnant or plan to become pregnant. It is not known if colchicine tablets, USP will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.are breastfeeding or plan to breastfeed. colchicine tablets, USP passes into your breast milk. You and your healthcare provider should decide if you will take colchicine tablets, USP or breastfeed. If you take colchicine tablets, USP and breastfeed, you should talk to your child’s healthcare provider about how to watch for side effects in your child.Tell your healthcare provider about all the medicines you take, including ones that you may only be taking for a short time, such as antibiotics. See “What is the most important information that I should know about colchicine tablets, USP?” Do not start a new medicine without talking to your healthcare provider.Using colchicine tablets, USP with certain other medicines, such as cholesterol-lowering medications and digoxin, can affect each other, causing serious side effects. Your healthcare provider may need to change your dose of colchicine tablets, USP. Talk to your healthcare provider about whether the medications you are taking might interact with colchicine tablets, USP and what side effects to look for.How should I take colchicine tablets, USP?Take colchicine tablets, USP exactly as your healthcare provider tells you to take it. If you are not sure about your dosing, call your healthcare provider.Colchicine tablets, USP can be taken with or without food.If you take too much colchicine tablets, USP, go to the nearest hospital emergency room right away.Do not stop taking colchicine tablets, USP even if you start to feel better, unless your healthcare provider tells you.Your healthcare provider may do blood tests while you take colchicine tablets, USP. If you take colchicine tablets, USP daily and you miss a dose, then take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take two doses at the same time.What should I avoid while taking colchicine tablets, USP? • Avoid eating grapefruit or drinking grapefruit juice while taking colchicine tablets, USP. It can increase your chances of getting serious side effects.What are the possible side effects of colchicine tablets, USP?Colchicine tablets, USP can cause serious side effects or even cause death. See “What is the most important information that I should know about colchicine tablets, USP?” Get medical help right away if you have: Muscle weakness or painNumbness or tingling in your fingers or toesUnusual bleeding or bruisingIncreased infectionsFeel weak or tiredPale or gray color to your lips, tongue or palms of your handsSevere diarrhea or vomitingFMF: The most common side effects of colchicine tablets, USP in people who have FMF are abdominal pain, diarrhea, nausea and vomiting.Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of colchicine tablets, USP. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088.How should I store colchicine tablets, USP?Store colchicine tablets, USP at room temperature between 68°F and 77°F (20°C and 25°C).Keep colchicine tablets, USP in a tightly closed container.Keep colchicine tablets, USP out of the light.Keep colchicine tablets, USP and all medicines out of the reach of children. General Information about colchicine tablets, USPMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use colchicine tablets, USP for a condition for which it was not prescribed. Do not give colchicine tablets, USP to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about colchicine tablets, USP. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about colchicine tablets, USP that is written for healthcare professionals.What are the ingredients in colchicine tablets, USP? Active Ingredient: colchicine.Inactive Ingredients: 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.This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured in India by:Alkem Laboratories Limited H.O.: ALKEM HOUSE, Senapati Bapat Marg, Lower Parel, Mumbai – 400 013, INDIA.Distributed by:Ascend Laboratories, LLC Parsippany, NJ 07054.Revised: March, 2018PT 2919

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