- Patient Information
- Especially Tell Your Healthcare Provider If You Take:
- Colchicine Tablets Are A Prescription Medicine Used To:
- Who Should Not Take Colchicine Tablets?
- Before You Take Colchicine Tablets, Tell Your Healthcare Provider About All Your Medical Conditions, Including If You:
- How Should I Take Colchicine Tablets?
- What Should I Avoid While Taking Colchicine Tablets?
- What Are The Possible Side Effects Of Colchicine Tablets?
- Get Medical Help Right Away If You Have:
- How Should I Store Colchicine Tablets?
- Active Ingredient:
- Inactive Ingredients:
- Patients Should Be Advised To Take Colchicine 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 Is Missed:
- Patients 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:
Patient Information ⮝
Colchicine (KOL-chi-
Colchicine tablets can cause serious side effects or death if levels of colchicine are too high in your body.
- Taking certain medicines with colchicine tablets can cause your level of colchicine 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 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 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)
- cyclosporine (Neoral, Gengraf, Sandimmune)
- fosamprenavir (Lexiva) with ritonavir
- indinavir (Crixivan)
- ketoconazole (Nizoral)
- nefazodone (Serzone)
- ritonavir (Norvir)
- telithromycin (Ketek)
- clarithromycin (Biaxin)
- darunavir (Prezista)
- fosamprenavir (Lexiva)
- itraconazole (Sporanox)
- lopinavir/ritonavir (Kaletra)
- nelfinavir mesylate (Viracept)
- saquinavir mesylate (Invirase)
- 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.
- 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 out of the reach of children.
Colchicine Tablets Are A Prescription Medicine Used To: ⮝
- treat familial Mediterranean fever (FMF) in adults and children age four or older
Colchicine tablets are 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? ⮝
Do not take colchicine tablets 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.
Before You Take Colchicine Tablets, 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 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 passes into your breast milk. You and your healthcare provider should decide if you will take colchicine tablets or breastfeed. If you take colchicine tablets 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. Do not start a new medicine without talking to your healthcare provider.
Using colchicine tablets 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. Talk to your healthcare provider about whether the medications you are taking might interact with colchicine tablets and what side effects to look for.
How Should I Take Colchicine Tablets? ⮝
- Take colchicine tablets exactly as your healthcare provider tells you to take it.If you are not sure about your dosing,call your healthcare provider.
- Colchicine tablets can be taken with or without food.
- If you take too much colchicine tablets, go to the nearest hospital emergency room right away.
- Do not stop taking colchicine tablets 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.
- If you take colchicine tablets 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? ⮝
- Avoid eating grapefruit or drinking grapefruit juice while taking colchicine tablets. It can increase your chances of getting serious side effects.
What Are The Possible Side Effects Of Colchicine Tablets? ⮝
Colchicine tablets can cause serious side effects or even cause death.
Get Medical Help Right Away If You Have: ⮝
- Muscle weakness or pain
- Numbness or tingling in your fingers or toes
- Unusual bleeding or bruising
- Increased infections
- Feel weak or tired
- Pale or gray color to your lips, tongue or palms of your hands
- Severe diarrhea or vomiting
FMF:The most common side effects of colchicine tablets 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. 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 1-800-FDA-1088.
How Should I Store Colchicine Tablets? ⮝
- Store colchicine tablets at room temperature between 68 F and 77 F (20 C to 25 C).
- Keep colchicine tablets in a tightly closed container.
- Keep colchicine tablets out of the light.
Keep colchicine tabletsand all medicines out of the reach of children.
General Information about Colchicine Tablets
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use colchicine tablets for a condition for which it was not prescribed. Do not give colchicine tablets 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. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about colchicine tablets that is written for healthcare professionals.
For more information, go to www.amneal.com or call 1-877-835-5472.
Active Ingredient: ⮝
colchicine
Inactive Ingredients: ⮝
ethanol, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, macrogol, magnesium stearate, microcrystalline cellulose, polydextrose, pregelatinized starch (corn), purified water, sodium starch glycolate, titanium dioxide and triacetin.This Medication Guide has been approved by the U.S. Food and Drug Administration.
Trademarks are the property of their respective owners.
Distributed by:
Amneal Pharmaceuticals
Bridgewater, NJ 08807Rev. 08-2016-00
Patients Should Be Advised To Take Colchicine 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 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 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.
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 colchicine treatment.
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.
Distributed by:
Amneal Pharmaceuticals
Bridgewater, NJ 08807Rev. 08-2016-00
Patients 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.
- Highlights Of Prescribing Information
- Indications And Usage
- Dosage And Administration
- Dosage Forms And Strengths
- Contraindications
- Warnings And Precautions
- Adverse Reactions
- Drug Interactions
- Use In Specific Populations
- 1 Indications And Usage
- 2 Dosage And Administration
- 3 Dosage Forms And Strengths
- 4 Contraindications
- 5 Warnings And Precautions
- 6 Adverse Reactions
- 7 Drug Interactions
- 8 Use In Specific Populations
- 9 Drug Abuse And Dependence
- 10 Overdosage
- 11 Description
- 12 Clinical Pharmacology
- 13 Nonclinical Toxicology
- 14 Clinical Studies
- 16 How Supplied/storage And Handling
- Package Label.principal Display Panel
- 1 Indications & Usage
- 2 Dosage & Administration
- 3 Dosage Forms & Strengths
- 4 Contraindications
- 5 Warnings And Precautions
- 6 Adverse Reactions
- 7 Drug Interactions
- 8 Use In Specific Populations
- 9 Drug Abuse And Dependence
- 10 Overdosage
- 11 Description
- 12 Clinical Pharmacology
- 13 Nonclinical Toxicology
- 14 Clinical Studies
- 16 How Supplied/storage And Handling
- Package Label.principal Display Panel
Highlights Of Prescribing Information ⮝
These highlights do not include all the information needed to use COLCHICINE TABLETS safely and effectively. See full prescribing information for COLCHICINE TABLETS.
COLCHICINE tablets, for oral use
Initial U.S. Approval: 1961
Indications And Usage ⮝
Colchicine tablets, USP are an alkaloid indicated for:
- Familial Mediterranean fever (FMF) in adults and children 4 years or older (1.2).
Colchicine tablets, USP are not an analgesic medication and should not be used to treat pain from other causes.
Dosage And Administration ⮝
- FMF: Adults and children older than 12 years 1.2 to 2.4 mg; children 6 to 12 years 0.9 to 1.8 mg; children 4 to 6 years 0.3 to 1.8 mg (2.2, 2.3).
Colchicine tablets, USP are administered orally without regard to meals. See full prescribing information for dose adjustment regarding patients with impaired renal function (2.5), impaired hepatic function (2.6), the patient s age (2.3, 8.5) or use of co-administered drugs (2.4).
Dosage Forms And Strengths ⮝
- 0.6 mg tablets (3).
Contraindications ⮝
Patients with renal or hepatic impairment should not be given colchicine, USP in conjunction with P-gp or strong CYP3A4 inhibitors (5.3).
In these patients, life-threatening and fatal colchicine, USP toxicity has been reported with colchicine, USP taken in therapeutic doses (7).
Warnings And Precautions ⮝
- Fatal overdoses have been reported with colchicine in adults and children. Keep colchicine 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: Co-administration of colchicine with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death (5.3, 7).
- Neuromuscular toxicity: Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of colchicine (5.4, 7).
Adverse Reactions ⮝
FMF: Most common adverse reactions (up to 20%) are abdominal pain, diarrhea, nausea and vomiting. These effects are usually mild, transient and reversible upon lowering the dose (6).
To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions ⮝
Co-administration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of colchicine. The potential for drug-drug interactions must be considered prior to and during therapy. See full prescribing information for a complete list of reported and potential interactions (2.4, 5.3, 7).
Use In Specific Populations ⮝
- In the presence of mild to moderate renal or hepatic impairment, adjustment of dosing is not required for treatment of FMF, but patients should be monitored closely (2.5, 8.6).
- In FMF patients with severe renal impairment, start with 0.3 mg/day and any increase in dose should be done with close monitoring (2.5, 8.6).
- In patients with severe hepatic impairment, a dose reduction may be needed in FMF patients (2.5, 2.6, 8.6, 8.7).
- For FMF patients undergoing dialysis, the starting dose should be 0.3 mg per day and dosing can be increased with close monitoring (2.5, 8.6).
- Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus (8.1).
- Nursing Mothers: Caution should be exercised when administered to a nursing woman (8.3).
- Geriatric Use: The recommended dose of colchicine should be based on renal function (2.5, 8.5).
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 12/2018
1 Indications And Usage ⮝
1.2 Familial Mediterranean Fever (FMF)
Colchicine tablets, USP 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, USP is established for FMF. The dosing regimens for colchicine tablets, USP are different for each indication and must be individualized.
The recommended dosage of colchicine tablets, USP depends on the patient s age, renal function, hepatic function and use of co-administered drugs [see Dose Modification for Co-administration of Interacting Drugs (2.4)].
Colchicine tablets, USP are administered orally without regard to meals.
Colchicine tablets, USP are not an analgesic medication and should not be used to treat pain from other causes.
2.2 FMF
The recommended dosage of colchicine tablets, USP for FMF in adults is 1.2 mg to 2.4 mg daily.
Colchicine tablets, USP 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, USP dose may be administered in one to two divided doses.
2.3 Recommended Pediatric Dosage
FMF
The recommended dosage of colchicine tablets, USP 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 Co-administration of Interacting Drugs
Concomitant Therapy
Co-administration of colchicine tablets, USP 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, USP Dose Adjustment for Co-administration with Interacting Drugs if no Alternative Available*
Strong CYP3A4 Inhibitors
Drug
Noted or Anticipated
OutcomeFMF
Original
Intended
DosageAdjusted
DoseAtazanavir
Clarithromycin
Darunavir/
Ritonavir
Indinavir
Itraconazole
Ketoconazole
Lopinavir/
Ritonavir
Nefazodone
Nelfinavir
Ritonavir
Saquinavir
Telithromycin
Tipranavir/
RitonavirSignificant increase in
colchicine, USP plasma
levels*; fatal colchicine, USP toxicity has been
reported with
clarithromycin, a strong
CYP3A4 inhibitor.
Similarly, significant
increase in colchicine,
USP plasma levels is
anticipated with other
strong CYP3A4
inhibitors.Maximum
daily dose of
1.2 to 2.4 mgMaximum
daily dose of
0.6 mg (may
be given as
0.3 mg twice
a day)Moderate CYP3A4 Inhibitors
Drug
Noted or Anticipated
OutcomeFMF
Original
Intended
DosageAdjusted
DoseAmprenavir
Aprepitant
Diltiazem
Erythromycin
Fluconazole
Fosamprenavir
(pro-drug of
Amprenavir)
Grapefruit juice
VerapamilSignificant increase in
colchicine, USP plasma
concentration is
anticipated.
Neuromuscular toxicity
has been reported with
diltiazem and verapamil
interactions.Maximum
daily dose of
1.2 to 2.4 mgMaximum
daily dose of
1.2 mg (may
be given as
0.6 mg twice
a day)P-gp Inhibitors
Drug
Noted or Anticipated
OutcomeFMF
Original
Intended
DosageAdjusted
DoseCyclosporine
RanolazineSignificant increase in
colchicine, USP plasma
levels*; fatal colchicine,
USP toxicity has been
reported with
cyclosporine, a P-gp
inhibitor. Similarly,
significant increase in
colchicine, USP plasma
levels is anticipated
with other P-gp
inhibitors.Maximum
daily dose of
1.2 to 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, USP plasma concentrations [see Pharmacokinetics (12.3)]
Patients with renal or hepatic impairment should not be given colchicine tablets, USP 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, USP Dose Adjustment for Co-administration with Protease Inhibitors
Protease Inhibitor
Clinical Comment
w/Colchicine
Treatment of FMFAtazanavir sulfate
(Reyataz)Patients with renal
or hepatic
impairment should
not be given
colchicine, USP
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, USP
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, USP
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, USP
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, USP
with CrixivanMaximum 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, USP
with KaletraMaximum 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, USP
with ViraceptMaximum 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, USP
with NorvirMaximum 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, USP
with
Invirase/ritonavirMaximum 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, USP
with
Aptivus/ritonavirMaximum daily dose
of 0.6 mg (may be
given as 0.3 mg twice
a day)2.5 Dose Modification in Renal Impairment
Colchicine, USP 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:
[140-age (years) weight (kg)]
Clcr = ---------------------------------------- 0.85 for female patients
72 serum creatinine (mg/dL)
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 to 80 mL/min) and moderate (Clcr 30 to 50 mL/min) renal impairment should be monitored closely for adverse effects of colchicine tablets, USP. 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 And Strengths ⮝
0.6 mg tablets - purple capsule-shaped, film-coated tablets, scored on one side and debossed with A10 on the other side.
4 Contraindications ⮝
Patients with renal or hepatic impairment should not be given colchicine, USP in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors except fosamprenavir). In these patients, life-threatening and fatal colchicine, USP toxicity has been reported with colchicine, USP 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)]. Colchicine 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 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, 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 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 ⮝
Colchicine is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of colchicine. If colchicine is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of colchicine are likely. Fatal drug interactions have been reported.
Physicians should ensure that patients are suitable candidates for treatment with colchicine and remain alert for signs and symptoms of toxicities related to increased colchicine exposure as a result of a drug interaction. Signs and symptoms of colchicine toxicity should be evaluated promptly and, if toxicity is suspected, colchicine should be discontinued immediately.
Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.
Table 4. Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food Noted or Anticipated Outcome Clinical Comment HMG-Co A Reductase
Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatinPharmacokinetic 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 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. 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, 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 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 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.
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 Co-administration 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 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)].
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, USP 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, USP is given below.
Colchicine, USP occurs as a pale yellow powder that is soluble in water.
Colchicine tablets, USP are supplied for oral administration as purple, capsule-shaped, film-coated tablets, scored on one side and debossed with A10 on the other, containing 0.6 mg of the active ingredient colchicine, USP. Inactive ingredients: ethanol, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, macrogol, magnesium stearate, microcrystalline cellulose, polydextrose, pregelatinized starch (corn), purified water, sodium starch glycolate, titanium dioxide and triacetin.
USP Dissolution Test Pending.
12 Clinical Pharmacology ⮝
12.1 Mechanism of Action
The mechanism by which colchicine 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-1 . Additionally, colchicine disrupts cytoskeletal functions through inhibition of -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 to 2.5 hours). Following administration of the nonrecommended 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 ng/mL), occurring 1.3 to 1.4 hours post dose (range 0.5 to 3 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5.
Table 5. Mean (%CV) Pharmacokinetic Parameters in Healthy Adults Given Colchicine
Cmax (colchicine ng/mL) Tmax* (h) Vd/F (L) CL/F (L/hr) t1/2 (h) Colchicine 0.6 mg Single Dose (N=13) 2.5 (28.7) 1.5 (1 to 3) 341.5 (54.4) 54.1 (31) -- Colchicine 0.6 mg Twice Daily x 10 days (N =13) 3.6 (23.7) 1.3 (0.5 to 3) 1150 (18.7) 30.3 (19) 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 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 colchicine). 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 Co-administration 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 co-administration of other drugs with colchicine 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 Co-administration of Interacting Drugs [see Dose Modification for Co-administration of Interacting Drugs (2.4)].
Table 6. Drug Interactions: Pharmacokinetic Parameters for Colchicine Tablets in the Presence of the Co-Administered Drug
Co-administered Drug Dose of
Co-administered Drug
(mg)Dose of
Colchicine
(mg)N % Change in Colchicine
Concentrations from Baseline
(Range: Min to Max)Cmax AUC0-t Cyclosporine 100 mg
single dose0.6 mg
single dose23 270
(62 to 606.9)259
(75.8 to 511.9)Clarithromycin 250 mg twice daily,
7 days0.6 mg
single dose23 227.2
(65.7 to 591.1)281.5
(88.7 to 851.6)Ketoconazole 200 mg twice daily,
5 days0.6 mg
single dose24 101.7
(19.6 to 219)212.2
(76.7 to 419.6)Ritonavir 100 mg twice daily,
5 days0.6 mg
single dose18 184.4
(79.2 to 447.4)296
(53.8 to 924.4)Verapamil 240 mg daily,
5 days0.6 mg
single dose24 40.1
(-47.1 to 149.5)103.3
(-9.8 to 217.2)Diltiazem 240 mg daily,
7 days0.6 mg
single dose20 44.2
(-46 to 318.3)93.4
(-30.2 to 338.6)Azithromycin 500 mg 1 day, then
250 mg 4 days0.6 mg
single dose21 21.6
(-41.7 to 222)57.1
(-24.3 to 241.1)Grapefruit juice 240 mL twice daily,
4 days0.6 mg
single dose21 -2.55
(-53.4 to 55)-2.36
(-46.4 to 62.2)Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum 1/35) co-administered with colchicine (0.6 mg twice daily 14 days), hormone concentrations are not affected.
In healthy volunteers given theophylline co-administered with colchicine (0.6 mg twice daily 14 days), theophylline concentrations were not affected.
Table 7. Drug Interactions: Pharmacokinetic Parameters for Co-Administration of Drug in the Presence of Colchicine Tablets
Co-administered
DrugDose of
Co-administered
Drug (mg)Dose of
Colchicine
(mg)N % Change in Co-Administered
Drug Concentrations from Baseline
(Range: Min to Max)Cmax AUC0-t
Theophylline 300 mg (elixir)
single dose0.6 mg twice daily x 14 days 27 1.6
(-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 x 14 days 27* -6.7
(-40.3 to 44.7)-3
(-25.3 to 24.9)Norethindrone
(Ortho-Novum 1/35)0.94
(-37.3 to 59.4)-1.6
(-32 to 33.7)* Conducted in healthy adult females
AUC
13 Nonclinical Toxicology ⮝
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
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. 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 How Supplied/storage And Handling ⮝
16.1 How Supplied
Colchicine tablets, USP, 0.6 mg, are purple, capsule-shaped, film-coated tablets, scored on one side and debossed with A10 on the other side.
They are available as:
Bottles of 30: NDC 65162-710-03
Bottles of 90: NDC 65162-710-09
Bottles of 1000: NDC 65162-710-1116.2 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.
Package Label.principal Display Panel ⮝
COLCHICINE
colchicine tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65162-710 Route of Administration ORAL
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength COLCHICINE (UNII: SML2Y3J35T) (COLCHICINE - UNII:SML2Y3J35T) COLCHICINE 0.6 mg
Inactive Ingredients Ingredient Name Strength ALCOHOL (UNII: 3K9958V90M) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) HYPROMELLOSES (UNII: 3NXW29V3WO) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYDEXTROSE (UNII: VH2XOU12IE) STARCH, CORN (UNII: O8232NY3SJ) WATER (UNII: 059QF0KO0R) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)
Product Characteristics Color PURPLE Score 2 pieces Shape CAPSULE Size 8mm Flavor Imprint Code A10 Contains
Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65162-710-03 30 in 1 BOTTLE; Type 0: Not a Combination Product 09/30/2016 2 NDC:65162-710-09 90 in 1 BOTTLE; Type 0: Not a Combination Product 09/30/2016 3 NDC:65162-710-11 1000 in 1 BOTTLE; Type 0: Not a Combination Product 09/30/2016
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA204711 09/30/2016
Labeler - Amneal Pharmaceuticals LLC (123797875)
Establishment Name Address ID/FEI Business Operations Amneal Pharmaceuticals of New York, LLC 123797875 ANALYSIS(65162-710) , LABEL(65162-710) , MANUFACTURE(65162-710) , PACK(65162-710) Revised: 12/2018 Document Id: a1854945-4831-49b4-bf80-21220648dbbf 34391-3 Set id: 7daef7e2-888d-4116-81a9-2c02b9ef97ef Version: 8 Effective Time: 20181218 Amneal Pharmaceuticals LLC
1 Indications & Usage ⮝
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.
2.3 Recommended Pediatric Dosage
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 Atazanavir
Clarithromycin Darunavir/
Ritonavir
Indinavir Itraconazole
Ketoconazole Lopinavir/ Ritonavir
Nefazodone
Nelfinavir Ritonavir Saquinavir Telithromycin
Tipranavir/RitonavirSignificant 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 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day) Moderate CYP3A4 Inhibitors
FMF
Drug
Noted or Anticipated OutcomeOriginal 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 mg Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day) P-gp Inhibitors
FMFDrug Noted or Anticipated Outcome Original Intended Dosage Adjusted Dose Cyclosporine Ranolazine Significant 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 mg Maximum 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 Inhibitors
Protease 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 Ritonavir Patients 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:
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 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 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)]. 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 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 ⮝
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 Interactions
Concomitant Drug Class or Food
Noted or Anticipated Outcome
Clinical Comment
HMG-Co A Reductase Inhibitors:
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)
Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin
P-gp substrate; rhabdomyolysis has been reported
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. 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 Clinical Pharmacology ⮝
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-1 . Additionally, colchicine disrupts cytoskeletal functions through inhibition of -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
Cyclosporine
100 mg single dose
0.6 mg single dose
23
270.0
(62.0 to 606.9)
259.0
(75.8 to 511.9)
Clarithromycin
250 mg twice daily, 7 days
0.6 mg single dose
23
227.2
(65.7 to 591.1)
281.5
(88.7 to 851.6)
Ketoconazole
200 mg twice daily, 5 days
0.6 mg single dose
24
101.7
(19.6 to 219.0)
212.2
(76.7 to 419.6)
Ritonavir
100 mg twice daily, 5 days
0.6 mg single dose
18
184.4
(79.2 to 447.4)
296.0
(53.8 to 924.4)
Verapamil
240 mg daily, 5 days
0.6 mg single dose
24
40.1
(-47.1 to 149.5)
103.3
(-9.8 to 217.2)
Diltiazem
240 mg daily, 7 days
0.6 mg single dose
20
44.2
(-46.0 to 318.3)
93.4
(-30.2 to 338.6)
Azithromycin
500 mg 1 day, then 250 mg 4 days
0.6 mg single dose
21
21.6
(-41.7 to 222.0)
57.1
(-24.3 to 241.1)
Grapefruit juice
240 mL twice daily, 4 days
0.6 mg single dose
21
-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
Theophylline
300 mg (elixir)
single dose
0.6 mg twice daily 14 days
27
1.6
(-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 placebo
0.6 mg twice daily 14 days
27*
-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 AUC
13 Nonclinical Toxicology ⮝
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 How Supplied/storage And Handling ⮝
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 67877-589-30
Bottles of 60 NDC 67877-589-60
Bottles of 100 NDC 67877-589-01
Bottles of 250 NDC 67877-589-86
Bottles of 500 NDC 67877-589-05
Bottles of 1000 NDC 67877-589-10
Carton 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.
Package Label.principal Display Panel ⮝
NCD 67877-589-30
PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE ATTACHED
Rx Only
30 Tablets
NCD 67877-589-33
PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE ATTACHED
Rx Only
10 (1X10)Unit-dose Tablets
COLCHICINE
colchicine tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67877-589 Route of Administration ORAL
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength COLCHICINE (UNII: SML2Y3J35T) (COLCHICINE - UNII:SML2Y3J35T) COLCHICINE 0.6 mg
Inactive Ingredients Ingredient Name Strength 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)
Product Characteristics Color PURPLE Score 2 pieces Shape CAPSULE (capsule shaped) Size 8mm Flavor Imprint Code C6 Contains
Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67877-589-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 02/10/2019 2 NDC:67877-589-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 02/10/2019 3 NDC:67877-589-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/10/2019 4 NDC:67877-589-86 250 in 1 BOTTLE; Type 0: Not a Combination Product 02/10/2019 5 NDC:67877-589-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 02/10/2019 6 NDC:67877-589-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 02/10/2019 7 NDC:67877-589-33 1 in 1 CARTON 02/10/2019 7 10 in 1 BLISTER PACK; Type 0: Not a Combination Product
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA211250 02/10/2019
Labeler - Ascend Laboratories, LLC (141250469)
Establishment Name Address ID/FEI Business Operations Alkem Laboratories Limited 677605851 MANUFACTURE(67877-589) Revised: 2/2019 Document Id: 73956359-5dbd-4937-a0c9-5cd9099b04cd 34391-3 Set id: a4284783-fea6-4af2-9a8d-79c929176c05 Version: 3 Effective Time: 20190209 Ascend Laboratories, LLC
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