Ibuprofène Arrow may be available in the countries listed below.
Ingredient matches for Ibuprofène Arrow
Ibuprofen
Ibuprofen is reported as an ingredient of Ibuprofène Arrow in the following countries:
- France
International Drug Name Search
Sunday, 30 September 2012
Colchicine
Class: Antigout Agents
VA Class: MS400
CAS Number: 64-86-8
Brands: Colcrys
REMS:
FDA approved a REMS for colchicine to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of colchicine and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
Antigout and antimitotic agent.
Uses for Colchicine
Gout Flare
Treatment to relieve pain in attacks of acute gout flare (gouty arthritis).123 124 125 126 127 142 143 152 Initiate at the first sign of gout flare.152 Used as a second-line agent in patients who have not responded to or who cannot tolerate other recommended therapy (i.e., NSAIAs, corticosteroids).142 143
Prophylactic treatment of recurrent gout flare.152 Has no effect on plasma concentrations or urinary excretion of uric acid;123 124 129 130 143 146 use concomitantly with allopurinol or a uricosuric agent (e.g., febuxostat, probenecid, sulfinpyrazone) to decrease serum urate concentrations.123 124 129 130 143 146 Colchicine/probenecid fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.a
Familial Mediterranean Fever
Management of familial Mediterranean fever.100 103 104 105 106 107 108 109 110 111 149 152 Used for chronic prophylactic therapy to reduce frequency and severity of episodic attacks of painful serositis in patients with familial Mediterranean fever.100 103 104 105 106 107 108 109 149 150 152
Not curative; manifestations return to pretreatment levels following discontinuance.100 104 107 108 109
Chronic prophylactic therapy appears to prevent amyloidosis (manifested by nephropathy) when there is no evidence of it at initiation of therapy;100 appears to be effective for preventing amyloidosis regardless of whether patients continue to experience episodic attacks of serositis during chronic prophylactic therapy with the drug.149 150 May prevent deterioration during proteinuric phase of the disease (when amyloid involvement is minimal).100
Regulations Governing Colchicine Injection
On February 8, 2008, FDA announced that it would take enforcement action (e.g., seizure, injunction, other judicial proceeding) against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection because of potentially serious health risks associated with use of the injection.144 145 (See Serious Adverse Effects Related to Colchicine Injection under Cautions and see Preparations.)
Colchicine Dosage and Administration
General
Gout
Administer prophylactic doses of colchicine before initiation of allopurinol or uricosurics because sudden changes in serum urate concentrations may precipitate acute gout flare.124 125 127 129
May discontinue colchicine and use urate-lowering agents alone after serum urate concentration is reduced to the desired level, and acute gout flares have not occurred for 3–6 months (some clinicians suggest 1–12 months).124 126 143
Administration
Administer orally.152 Has been administered IV; parenteral preparation no longer available in the US.144 145 (See Serious Adverse Effects Related to Colchicine Injection under Cautions.)
Oral Administration
Initiate therapy for acute gout flare at the first sign of an attack.152
Administer without regard to meals.152
Dosage
Dosage depends on the patient’s age, renal and hepatic function, and recent (within 14 days) or concomitant use of moderate or potent CYP3A4 inhibitors or inhibitors of the P-glycoprotein transport system.152
Pediatric Patients
Prophylactic Treatment of Recurrent Gout Flares
Oral
Manufacturer states that adolescents ≥16 years of age may receive adult dosages.152
Familial Mediterranean Fever
Oral
Recommended dosage in children not receiving concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor depends on child’s age (see Table 1).152 Manufacturer makes no specific recommendations for children who are receiving or have recently received therapy with a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Dosage can be increased in increments of 0.3 mg daily to the maximum recommended dosage or decreased in decrements of 0.3 mg daily in individuals who develop intolerable adverse effects.152
Child’s Age (years) | Recommended Colchicine Dosage |
|---|---|
4–6 | 0.3–1.8 mg daily (given as 1 dose or 2 divided doses)152 |
6–12 | 0.9–1.8 mg daily (given as 1 dose or 2 divided doses)152 |
>12 | 1.2–2.4 mg daily (given as 1 dose or 2 divided doses)152 |
Adults
Treatment of Gout Flare
Oral
Recommended dosage of colchicine depends on whether patient is receiving or has recently (within 14 days) received a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system (see Table 2).152
Use of colchicine for treatment of gout flare is not recommended in patients receiving the drug for prevention of gout flare and also receiving a CYP3A4 inhibitor.152
Do not repeat courses of colchicine therapy (see Table 2) until 3 days have elapsed.152
Recent (within 14 days) or Concomitant Therapy | Recommended Colchicine Dosage |
|---|---|
No recent or concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor | 1.2 mg at first sign of flare followed by 0.6 mg one hour later;152 wait 12 hours before resuming prophylactic doses of colchicine152 |
Potent CYP3A4 inhibitor (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) | 0.6 mg at first sign of flare followed by 0.3 mg one hour later152 |
Moderate CYP3A4 inhibitor (aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil) | 1.2 mg at first sign of flare152 |
P-glycoprotein inhibitor (cyclosporine, ranolazine) | 0.6 mg at first sign of flare152 |
Prophylactic Treatment of Recurrent Gout Flares
Oral
Recommended dosage of colchicine depends on whether patient is receiving or has recently (within 14 days) received a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system (see Table 3).152
Recent (within 14 days) or Concomitant Therapy | Recommended Colchicine Dosage |
|---|---|
No recent or concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor | 0.6 mg once or twice daily (maximum 1.2 mg daily)152 |
Potent CYP3A4 inhibitor (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) | 0.3 mg daily or every other day152 |
Moderate CYP3A4 inhibitor (aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil) | 0.3 mg twice daily, 0.6 mg once daily, or 0.3 mg once daily152 |
P-glycoprotein inhibitor (cyclosporine, ranolazine) | 0.3 mg once daily or every other day152 |
Colchicine/Probenecid Fixed-Combination Therapy
Oral
Fixed-dosage preparation has limited usefulness for prophylactic therapy because colchicine present exceeds the amount required by most patients.a
Manufacturer recommends initial dosage of colchicine 0.5 mg in fixed combination with probenecid 500 mg (1 tablet) daily for 1 week, then 1 tablet twice daily.146 If gouty arthritis is not controlled or if 24-hour uric acid excretion is ≤700 mg, increase daily dosage by 1 tablet every 4 weeks as tolerated (generally not exceeding 4 tablets [colchicine 2 mg and probenecid 2 g] daily).146
If acute attacks have been absent ≥6 months and serum urate concentrations are controlled, manufacturer recommends reducing dosage by 1 tablet every 6 months as long as serum urate concentrations remain controlled.146
Familial Mediterranean Fever
Oral
Recommended dosage of colchicine depends on whether patient is receiving or has recently (within 14 days) received a moderate or potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system (see Table 4).152
Dosage can be increased in increments of 0.3 mg daily to the maximum recommended dosage or decreased in decrements of 0.3 mg daily in individuals who develop intolerable adverse effects.152
Recent (within 14 days) or Concomitant Therapy | Maximum Recommended Colchicine Dosage |
|---|---|
No recent or concomitant therapy with a moderate or potent CYP3A4 inhibitor or a P-glycoprotein inhibitor | 1.2–2.4 mg daily (given as 1 dose or 2 divided doses)152 |
Potent CYP3A4 inhibitor (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) | 0.6 mg daily (may be given as 0.3 mg twice daily)152 |
Moderate CYP3A4 inhibitor (aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil) | 1.2 mg daily (may be given as 0.6 mg twice daily)152 |
P-glycoprotein inhibitor (cyclosporine, ranolazine) | 0.6 mg daily (may be given as 0.3 mg twice daily)152 |
Special Populations
Hepatic Impairment
Contraindicated in patients with hepatic impairment who are receiving or have recently received therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Treatment of Gout Flare
Oral
Mild to moderate hepatic impairment: Dosage adjustment is not needed, but monitor for adverse effects.152
Severe hepatic impairment: Dosage adjustment is not needed, but do not repeat courses of colchicine therapy until 2 weeks have elapsed.152 Consider alternative therapy for patients requiring repeat courses of therapy.152
Prophylactic Treatment of Recurrent Gout Flares
Oral
Mild to moderate hepatic impairment: Dosage adjustment is not needed, but monitor for adverse effects.152
Severe hepatic impairment: Consider dosage reduction.152
Familial Mediterranean Fever
Oral
Mild to moderate hepatic impairment: Dosage adjustment is not needed, but monitor for adverse effects.152
Severe hepatic impairment: Consider dosage reduction.152
Renal Impairment
Contraindicated in patients with renal impairment who are receiving or have recently received therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Treatment of Gout Flare
Oral
Use of colchicine for treatment of gout flare is not recommended in patients with renal impairment who are receiving the drug for prevention of gout flares.152
Mild to moderate renal impairment (Clcr 50–80 or 30–50 mL/minute, respectively): Dosage adjustment is not needed, but monitor for adverse effects.152
Severe renal impairment (Clcr <30 mL/minute): Dosage adjustment is not needed, but do not repeat courses of colchicine therapy until 2 weeks have elapsed.152 Consider alternative therapy for patients requiring repeat courses of therapy.152
Dialysis: 0.6 mg at first sign of gout flare.152 Do not repeat courses of colchicine therapy until 2 weeks have elapsed.152
Prophylactic Treatment of Recurrent Gout Flares
Oral
Mild to moderate renal impairment (Clcr 50–80 or 30–50 mL/minute, respectively): Dosage adjustment is not needed, but monitor for adverse effects.152
Severe renal impairment (Clcr <30 mL/minute): Initial dosage is 0.3 mg daily; monitor closely if dosage is increased.152
Dialysis: Initial dosage is 0.3 mg twice weekly; monitor closely.152
Familial Mediterranean Fever
Oral
Mild to moderate renal impairment (Clcr 50–80 or 30–50 mL/minute, respectively): Monitor for adverse effects; dosage adjustment may be needed.152
Severe renal impairment (Clcr <30 mL/minute) or dialysis: Initial dosage is 0.3 mg daily; dosage can be increased with careful monitoring.152
Geriatric Patients
Select dosage with caution because of age-related decreases in renal function and concomitant disease and drug therapy.152
Cautions for Colchicine
Contraindications
Individuals with renal or hepatic impairment receiving a drug that inhibits the P-glycoprotein transport system or is a potent CYP3A4 inhibitor.152
Warnings/Precautions
Warnings
Overdosage-related Mortality
Cumulative IV doses >4 mg (e.g., 7 mg administered acutely) have resulted in irreversible multiple organ failure and death.122 148 Oral ingestion of as little as 7 mg has resulted in death, although larger oral doses have been survived.147 a
Serious Adverse Effects Related to Colchicine Injection
Serious adverse events, including some deaths, reported in patients receiving IV colchicine;144 145 148 many events associated with colchicine toxicity.144 145 As of June 2007, FDA was aware of 50 reports of adverse effects linked to IV colchicine; 23 of these events were fatal.144 145 Neutropenia, acute renal failure, thrombocytopenia, CHF, and pancytopenia reported.144 145 148
Compounded IV colchicine linked to 3 deaths.144 145 148 Compounded colchicine injection from the same lot as these patients received contained 8 times the labeled amount of colchicine.148
FDA is taking enforcement action against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection.145 Oral preparations containing colchicine remain on the market; risks believed to be lower with oral preparations.144 145 (See Preparations.)
Hematologic Effects
Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia reported.152
Drug Interactions
Concomitant use with certain drugs is contraindicated or requires particular caution.152 (See Interactions and also see Dosage under Dosage and Administration.)
Neuromuscular Effects
Neuromuscular toxicity and rhabdomyolysis reported with long-term use.152 Individuals with renal impairment and geriatric individuals are at increased risk.152 Concomitant use of certain drugs may increase risk of myotoxicity.152 (See Specific Drugs and Laboratory Tests under Interactions.)
General Precautions
Use of Fixed Combination
When colchicine is used in fixed combination with probenecid, consider the cautions, precautions, and contraindications associated with probenecid.146
Specific Populations
Pregnancy
Category C.152
Lactation
Distributed into milk.152 However, AAP states colchicine usually is compatible with breast-feeding;139 140 use caution.152
Pediatric Use
Safety and efficacy not established for gout.152
Safety and efficacy for familial Mediterranean fever in children evaluated in uncontrolled studies.152 Long-term use of colchicine did not appear to affect growth in children with familial Mediterranean fever.152
Geriatric Use
Clinical studies of colchicine for treatment of gout flares, prophylactic treatment of recurrent gout flares, or management of familial Mediterranean fever did not include sufficient numbers of patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.152
Select dosage carefully in geriatric patients with gout; consider the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients.152
Hepatic Impairment
Use with caution; dosage adjustment may be needed.152 (See Hepatic Impairment under Dosage and Administration.)
Contraindicated in patients with hepatic impairment receiving therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Renal Impairment
Use with caution; dosage adjustment may be needed.152 (See Renal Impairment under Dosage and Administration.)
Contraindicated in patients with renal impairment receiving therapy with a potent CYP3A4 inhibitor or an inhibitor of the P-glycoprotein transport system.152
Common Adverse Effects
Treatment of gout flare: Diarrhea, pharyngolaryngeal pain.152
Prophylactic treatment of recurrent gout flares: Diarrhea.152
Familial Mediterranean fever: Abdominal pain, diarrhea, nausea, vomiting.152
Interactions for Colchicine
Metabolized by CYP3A4.152 Does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.152
A P-glycoprotein substrate.152
Drugs Affecting Hepatic Microsomal Enzymes
CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased plasma colchicine concentrations); increased risk of colchicine toxicity.152 Fatal reactions reported with concomitant use of potent CYP3A4 inhibitors.152 Adjust colchicine dosage if patient is receiving or has recently (within 14 days) received therapy with a moderate or potent CYP3A4 inhibitor (see Dosage under Dosage and Administration).152 Concomitant use of colchicine and potent CYP3A4 inhibitors is contraindicated in renal or hepatic impairment.152
Drugs Affecting P-Glycoprotein Transport
P-glycoprotein inhibitors: Pharmacokinetic interaction (increased plasma concentrations of colchicine) likely; increased risk of colchicine toxicity.152 Fatal reactions reported.152 Adjust colchicine dosage if patient is receiving or has recently (within 14 days) received therapy with a P-glycoprotein inhibitor (see Dosage under Dosage and Administration).152 Concomitant use of colchicine and P-glycoprotein inhibitors is contraindicated in renal or hepatic impairment.152
Specific Drugs and Laboratory Tests
Drug or Test | Interaction | Comments |
|---|---|---|
Azithromycin | Increased plasma concentrations of colchicine152 | |
Clarithromycin | Decreased metabolism and increased plasma concentrations of colchicine; fatal colchicine toxicity reportedc 152 | Adjust colchicine dosage (see Dosage under Dosage and Administration),152 consider alternative anti-infective,c or substitute NSAIA for colchicine if clarithromycin is usedc Concomitant use contraindicated in renal or hepatic impairment152 |
Cyclosporine | Possible additive nephrotoxic effects; increased concentrations of cyclosporine in biological fluidd g h 152 Increased colchicine concentrations; fatal colchicine toxicity reported152 | Monitor concentration of cyclosporine in biologic fluid and renal function if colchicine is initiated, discontinued, or dosage altered; adjust cyclosporine dosage accordinglyd Adjust colchicine dosage (see Dosage under Dosage and Administration)152 Concomitant use contraindicated in renal or hepatic impairment152 |
Digoxin | Rhabdomyolysis reported152 | Weigh potential benefits and risks;120 152 monitor for muscle pain, tenderness, or weakness, especially during the initial phase of such concomitant therapy152 |
Diltiazem | Increased plasma concentrations of colchicine; neuromuscular toxicity reported152 | Adjust colchicine dosage (see Dosage under Dosage and Administration)152 |
Estrogens or progestins | Oral contraceptives: No change in plasma concentrations of ethinyl estradiol or norethindrone152 | |
Fibric acid derivatives (gemfibrozil, fenofibrate) | Addition of a fibrate to long-term colchicine therapy or addition of colchicine to long-term fibrate therapy has resulted in myopathy and rhabdomyolysis152 | Weigh potential benefits and risks; monitor for muscle pain, tenderness, or weakness, especially during the initial phase of such concomitant therapy152 |
Grapefruit juice | Minimal change in plasma concentration of colchicine reported152 | Dosage adjustment may be needed (see Dosage under Dosage and Administration)152 Advise patient to avoid grapefruit juice152 |
HMG-CoA reductase inhibitors (statins) | Addition of a statin to long-term colchicine therapy or addition of colchicine to long-term statin therapy has resulted in myopathy and rhabdomyolysis152 | Weigh potential benefits and risks; monitor for muscle pain, tenderness, or weakness, especially during the initial phase of such concomitant therapy152 |
Ketoconazole | Increased plasma concentrations of colchicine152 | Adjust colchicine dosage (see Dosage under Dosage and Administration)152 Concomitant use contraindicated in renal or hepatic impairment152 |
Ritonavir | Increased plasma concentrations of colchicine152 | Adjust colchicine dosage (see Dosage under Dosage and Administration)152 Concomitant use contraindicated in renal or hepatic impairment152 |
Theophylline | No change in plasma concentrations of theophylline152 | |
Verapamil | Increased plasma concentrations of colchicine; neuromuscular toxicity reported152 | Adjust colchicine dosage (see Dosage under Dosage and Administration)152 |
Colchicine Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed from the GI tract following oral administration.147 a f
Drug and metabolites reenter intestinal tract via biliary and intestinal secretions after partial metabolism in liver.147 152 a f
Unchanged drug may be reabsorbed from the intestine.a
Food
Administration with food did not affect rate of absorption but decreased extent of absorption by 15%.152
Plasma Concentrations
Following oral administration, peak plasma concentrations occur within 0.5–2 hours.f 152
Absolute bioavailability reported to be about 45%.152
Distribution
Extent
Crosses the placenta and is distributed into milk.139 152
Plasma Protein Binding
39% (mainly albumin).152
Elimination
Metabolism
Demethylated in the liver by CYP3A4.152
Elimination Route
40–65% recovered unchanged in urine.152 Not removed by hemodialysis.152
Half-life
26.6–31.2 hours.152
Special Populations
End-stage renal disease: Colchicine clearance is decreased and elimination half-life increased.152
Stability
Storage
Oral
Tablets
20–25°C.152 Protect from light.152
Actions
Has weak anti-inflammatory activity, but no analgesic activity.a
Has no effect on urinary excretion of uric acid or on serum urate concentration, solubility, or binding to serum proteins.a f
Mechanism of principal (antigout) effect is not completely known; drug appears to disrupt cytoskeletal functions through inhibition of β-tubulin polymerization into microtububules thus preventing activation, degranulation, and migration of neutrophils believed to mediate some gout symptoms.152
Mechanism of beneficial effects in familial Mediterranean fever not fully elucidated.152 Colchicine may interfere with the intracellular assembly of inflammasome complex in neutrophils and monocytes that mediates activation of interleukin-1β.152
Advice to Patients
Possibility of serious adverse effects.152
Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.152
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.152
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 0.6 mg | Colcrys (scored) | AR Scientific |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 500 mg Probenecid and Colchicine 0.5 mg* | Probenecid and Colchicine Tablets |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Colchicine-Probenecid 0.5-500MG Tablets (WATSON LABS): 30/$35.99 or 90/$95.97
Colcrys 0.6MG Tablets (AR SCIENTIFIC): 30/$169.99 or 90/$499.97
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
Only references cited for selected revisions after 1984 are available electronically.
100. Zemer D, Pras M, Sohar E et al. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986; 314:1001-5. [IDIS 213751] [PubMed 3515182]
101. Kaplan MM, Alling DW, Zimmerman HJ et al. A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med. 1986; 315:1448-54. [IDIS 223206] [PubMed 3537784]
102. Kaplan MM. Another treatment for primary biliary cirrhosis. Gastroenterology. 1987; 92:255-7. [IDIS 223601] [PubMed 3781194]
103. Anon. Colchicine for familial Mediterranean fever. FDA Drug Bull. 1983; 13:4.
104. Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med. 1972; 287:1302. [PubMed 4636899]
105. Ravid M, Robson M, Kedar I. Prolonged colchicine treatment in four patients with amyloidosis. Ann Intern Med. 1977; 87:568-70. [PubMed 921085]
106. Zemer D, Pras M, Sohar E et al. Colchicine in familial Mediterranean fever. N Engl J Med. 1976; 294:170-1. [IDIS 61568] [PubMed 1244524]
107. Dinarello CA, Wolff SM, Goldfinger SE et al. Colchicine therapy for familial Mediterranean fever: a double-blind trial. N Engl J Med. 1974; 291:934-7. [IDIS 47250] [PubMed 4606353]
108. Goldstein RC, Schwabe AD. Prophylactic colchicine therapy in familial Mediterranean fever: a controlled, double-blind study. Ann Intern Med. 1974; 31:792-4.
109. Zemer D, Revach M, Pras M et al. A controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med. 1974; 291:932-4. [IDIS 47249] [PubMed 4606109]
110. Wright DG, Wolff SM, Fauci AS et al. Efficacy of intermittent colchicine therapy in familial Mediterranean fever. Ann Intern Med. 1977; 86:162-5. [PubMed 319724]
111. Milano AM. Familial Mediterranean fever associated with menstruation: efficacy of intermittent colchicine therapy. Am J Gastroenterol. 1981; 76:363-4. [IDIS 165286] [PubMed 7198867]
112. Rojkind M, Uribe M, Kershenobich D. Colchicine and the treatment of liver cirrhosis. Lancet. 1973; 1:38-9.
113. Kershenobich D, Uribe M, Suarez GI et al. Colchicine, serum albumin, and alkaline phosphatase. Ann Intern Med. 1978; 89:144. [PubMed 352218]
114. Kershenobich D, Uribe M, Suarez GI et al. Treatment of cirrhosis with colchicine: a double-blind randomized trial. Gastroenterology. 1979; 77:532-6. [IDIS 109539] [PubMed 378754]
115. Tapalaga D, Dumitrascu D, Cotul S et al. Colchicine treatment effects on liver cirrhosis assessed by liver blood flow measurements. Rev Roum Med, Med Interne. 1986; 24:69-73.
116. Rojkind M, Mourelle M, Kershenobich D. Antiinflammatory and antifibrogenic activities of colchicine: treatment of liver cirrhosis. Prof Clin Biol Res. 1984; 154:475-89.
117. Kaplan MM. Primary biliary cirrhosis. N Engl J Med. 1987; 316:521-8. [IDIS 225770] [PubMed 3543682]
118. Kyle RA, Gertz MA, Greipp PR et al. A trial of three regimens for pirmary amyloidosis: colchicine alone, melphalan and prednisone and melphalan, prednisone, and colchicine. N Engl J Med. 1997; 336:1202-7. [IDIS 383378] [PubMed 9110907]
119. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med. 1997; 337:898-909. [IDIS 391785] [PubMed 9302305]
120. Skinner M, Anderson JJ, Simms R et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus chochicine only. Am J Med. 1996; 100:290-8. [IDIS 362735] [PubMed 8629674]
121. Abbott Laboratories. Colchicine tablets prescribing information. North Chicago, IL; 1991 Oct.
122. Bedford Laboratories. Colchicine injection, USP prescribing information. Bedford, OH; 1999 Apr.
123. Levy M, Spino M, Read SE. Colchicine: a state-of-the-art review. Pharmacotherapy. 1991; 11:196-211. [IDIS 385854] [PubMed 1862011]
124. Harris MD, Siegel LB, Alloway JA. Gout and hyperuricemia. Am Fam Physician. 1999; 59:925-34. [IDIS 424053] [PubMed 10068714]
125. Davis JC. A practical approach to gout. Postgrad Med. 1999; 106:115-23. [IDIS 437771] [PubMed 10533512]
126. Conaghan PG, Day RO. Risks and benefits of drugs used in the management and prevention of gout. Drug Saf. 1994; 11:252-8. [PubMed 7848545]
127. Star VL, Hochberg MC. Prevention and management of gout. Drugs. 1993; 45:212-22. [PubMed 7681372]
128. Emmerson BT. Management of gout. N Engl J Med. 1996; 334:1543-4.
129. Emmerson BT. Management of gout. N Engl J Med. 1996; 334:445-51. [IDIS 359541] [PubMed 8552148]
130. McGill NW. Gout and other crystal arthropathies. Med J Aust. 1997: 166:33-8.
131. Evans TI, Wheeler MT, Small E et al. A comprehensive investigation of inpatient intravenous colchicine use shows more education is needed. J Rheumatol. 1996: 23:143-8.
132. Roberts WN, Liang MH, Stern SH. Colchicine in acute gout: reassessment of risks and benefits. JAMA. 1987; 257:1920-2. [IDIS 227219] [PubMed 3820512]
133. Wallace SL, Singer JZ. Review: systemic toxicity associated with the intravenous administration of colchicine - guidelines for use. J Rheumatol. 1988; 15:495-9. [PubMed 3288754]
134. Baud FJ, Sabouraud A, Vicaut E et al. Treatment of severe colchicine overdose with colchicine-specific Fab fragments. N Engl J Med. 1995; 332:642-5. [IDIS 343981] [PubMed 7845428]
135. Ellenhorn MJ, Barceloux DG. Medical Toxicology. 2nd ed. Baltimore, MD: Williams & Wilkens; 1997: 1851-2.
136. Kubler PA. Fatal colchicine toxicity. Med J Aust. 2000; 172:498-9. [IDIS 447255] [PubMed 10901774]
137. Simons RJ, Kingma DW. Fatal colchicine toxicity. Am J Med. 1989; 86:356-7. [IDIS 252422] [PubMed 2919622]
138. Wallace SL, Singer JZ, Duncan GJ et al. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol. 1991; 18:264-9. [PubMed 2023222]
139. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and lactation. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: 379-81.
140. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics. 2001; 108:776-89. [IDIS 468574] [PubMed 11533352]
141. Ben-Chetrit E, Scherrmann JM, Levy M. Colchicine in breast milk of patients with familial Mediterranean fever. Arthritis Rheum. 1996; 39:1213-7.
142. Schlesinger N, Schumacher R, Catton M et al. Colchicine for acute gout. Cochrane Database of Systematic Reviews. 2006; Issue 4; Article no. CD006190.
143. Eggebeen AT. Gout: an update. Am Fam Physician. 2007; 76:801-8. [PubMed 17910294]
144. US Food and Drug Administration. Questions and answers about FDA’s enforcement action against unapproved injectable colchicine products. 2008 Feb 6. From FDA website. Accessed 2008 Feb 12.
145. Department of Health and Human Services: Food and Drug Administration. Drug products containing colchicine for injection; enforcement action dates. Notice [Docket No. FDA-2008-N-0014] Fed Regist. 2008; 73:7565-7.
146. Watson Laboratories. Probenecid and colchicine tablets prescribing information. Corona, CA; 2006 Mar.
147. Akyma Pharmaceuticals. Colchicine tablets 0.6 mg prescribing information. Glasgow, KY; 2005 Jan.
148. Centers for Disease Control and Prevention (CDC). Deaths from intravenous colchicine resulting from a compounding pharmacy error–Oregon and Washington, 2007. MMWR Morb Mortal Wkly Rep. 2007; 56:1050-2. [PubMed 17932481]
149. Kallinich T, Haffner D, Niehues T et al. Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics. 2007; 119:e474-83. [PubMed 17242135]
150. Lidar M, Livneh A. Familial Mediterranean fever: clinical, molecular and management advances. Neth J Med. 2007; 65:318-24. [PubMed 17954950]
151. Mikuls TR. Quality of care in gout: from measurement to improvement. Clin Exp Rheumatol. 2007; 25(Suppl 47):S114-9. [PubMed 17949564]
152. AR Scientific. Colcrys (colchicine, USP) tablets prescribing information. Philadelphia, PA; 2009 Sep.
153. US Food and Drug Administration. Information for healthcare professionals: new safety information for colchicine (marketed as Colcrys). July 30, 2009. From FDA website.
a. AHFS drug information 2008. McEvoy GK, ed. Colchicine. Bethesda, MD: American Society of Health-System Pharmacists; 2008:3679-82.
c. Clarithromycin (Biaxin)/colchicine. In: Hansten PD, Horn JR. Drug interactions analysis and management. St. Louis , MO: Wolters Kluwers Health, Inc; 2003 Oct:390.
d. Colchicine/cyclosporin (Neoral). In: Hansten PD, Horn JR. Drug interactions analysis and management. St. Louis , MO: Wolters Kluwers Health, Inc; 2004 Jul:390.
e. Colchicine/erythromycin. In: Hansten PD, Horn JR. Drug interactions analysis and management. St. Louis , MO: Wolters Kluwers Health, Inc; 2004 Jul:390.
f. Colchicine. In: Hardman JG, Limbird LE, Molinoff PB et al, eds. Goodman and Gilman’s the pharmacological basis of therapeutics. 9th ed
Carvedilol
Left Ventricular Dysfunction Following Myocardial Infarction
Carvedilol tablets USP are indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of ≤ 40% (with or without symptomatic heart failure) [see Clinical Studies (14.2)].
Hypertension
Carvedilol tablets USP are indicated for the management of essential hypertension [see Clinical Studies (14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2)].
Carvedilol Dosage and Administration
Carvedilol tablets USP should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.
Left Ventricular Dysfunction Following Myocardial Infarction
DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION. Treatment with Carvedilol tablets USP may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that Carvedilol tablets USP be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction.
Hypertension
DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of Carvedilol tablets USP is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full antihypertensive effect of Carvedilol tablets USP is seen within 7 to 14 days. Total daily dose should not exceed 50 mg.
Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of Carvedilol action.
Hepatic Impairment
Carvedilol tablets USP should not be given to patients with severe hepatic impairment [see Contraindications (4)].
Dosage Forms and Strengths
The tablets are available in the following strengths:
3.125 mg — White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side,
6.25 mg — White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side,
12.5 mg — White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side,
25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.
Contraindications
Carvedilol is contraindicated in the following conditions:
- Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of Carvedilol.
- Second or third degree AV block
- Sick sinus syndrome
- Severe bradycardia (unless a permanent pacemaker is in place)
- Patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating Carvedilol.
- Patients with severe hepatic impairment
- Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing Carvedilol.
Warnings and Precautions
Cessation of Therapy
Patients with coronary artery disease, who are being treated with Carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of Carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that Carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with Carvedilol abruptly even in patients treated only for hypertension or heart failure.
Bradycardia
In clinical trials, Carvedilol caused bradycardia in about 2% of hypertensive patients and 6.5% of myocardial infarction patients with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
Hypotension
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients.
In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving Carvedilol compared to 12.6% of placebo patients. Syncope was reported in 3.9% and 1.9% of patients, respectively. These events were a cause for discontinuation of therapy in 2.5% of patients receiving Carvedilol, compared to 0.2% of placebo patients.
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration (2.2, 2.3)]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.
Heart Failure/Fluid Retention
Worsening heart failure or fluid retention may occur during up-titration of Carvedilol. If such symptoms occur, diuretics should be increased and the Carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the Carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, Carvedilol.
Non-allergic Bronchospasm
Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers. Carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if Carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.
In clinical trials, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that Carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.
Glycemic Control in Type 2 Diabetes
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.
Studies designed to examine the effects of Carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.
In a study designed to examine the effects of Carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus, Carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies (14.4)].
Peripheral Vascular Disease
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
Deterioration of Renal Function
Rarely, use of Carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure < 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when Carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of Carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.
Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Thyrotoxicosis
β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.
Pheochromocytoma
In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although Carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of Carvedilol to patients suspected of having pheochromocytoma.
Prinzmetal’s Variant Angina
Agents with non-selective β-blocking activity may provoke chest pain in patients with Prinzmetal’s variant angina. There has been no clinical experience with Carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of Carvedilol to patients suspected of having Prinzmetal’s variant angina.
Risk of Anaphylactic Reaction
While taking ß-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
Intraoperative Floppy Iris Syndrome
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (Carvedilol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.
Adverse Reactions
Clinical Studies Experience
Carvedilol has been evaluated for safety in patients with left ventricular dysfunction following myocardial infarction and in hypertensive patients. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse events reported for each of these patient populations are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks).
Left Ventricular Dysfunction Following Myocardial Infarction: Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 patients who received Carvedilol and 980 who received placebo. Approximately 75% of the patients received Carvedilol for at least 6 months and 53% received Carvedilol for at least 12 months. Patients were treated for an average of 12.9 months and 12.8 months with Carvedilol and placebo, respectively.
The following adverse events were reported with a frequency of > 1% but ≤ 3% and more frequently with Carvedilol: Flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of patients. In this database, the only cause of discontinuation > 1%, and occurring more often on Carvedilol was hypotension (1.5% on Carvedilol, 0.2% on placebo).
Hypertension: Carvedilol has been evaluated for safety in hypertension in more than 2,193 patients in US clinical trials and in 2,976 patients in international clinical trials.
Approximately 36% of the total treated population received Carvedilol for at least 6 months. Most adverse events reported during therapy with Carvedilol were of mild to moderate severity. In US controlled clinical trials directly comparing Carvedilol in doses up to 50 mg (n = 1,142) to placebo (n = 462), 4.9% of patients receiving Carvedilol discontinued for adverse events versus 5.2% of placebo patients. Although there was no overall difference in discontinuation rates, discontinuations were more common in the Carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in US placebo-controlled trials increased with increasing dose of Carvedilol. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25 mg to 50 mg.
Table 1 shows adverse events in US placebo-controlled clinical trials for hypertension that occurred with an incidence of ≥ 1% regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients.
| ||
Carvedilol (n = 1,142) | Placebo (n = 462) | |
| Cardiovascular | ||
| Bradycardia | 2 | - |
| Postural hypotension | 2 | - |
| Peripheral edema | 1 | - |
| Central Nervous System | ||
| Dizziness | 6 | 5 |
| Insomnia | 2 | 1 |
| Gastrointestinal | ||
| Diarrhea | 2 | 1 |
| Hematologic | ||
| Thrombocytopenia | 1 | - |
| Metabolic | ||
| Hypertriglyceridemia | 1 | - |
Dyspnea and fatigue were also reported in these studies, but the rates were equal or greater in patients who received placebo.
The following adverse events not described above were reported as possibly or probably related to Carvedilol in worldwide open or controlled trials with Carvedilol in patients with hypertension.
Incidence > 0.1% to ≤ 1%
Cardiovascular: Peripheral ischemia, tachycardia.
Central and Peripheral Nervous System: Hypokinesia.
Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions (6.2)].
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability.
Respiratory System: Asthma [see Contraindications (4)].
Reproductive, male: Decreased libido.
Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction.
Special Senses: Tinnitus.
Urinary System: Micturition frequency increased.
Autonomic Nervous System: Dry mouth, sweating increased.
Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia
Hematologic: Anemia, leukopenia.
The following events were reported in ≤ 0.1% of patients and are potentially important:
Complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
Laboratory Abnormalities
Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with Carvedilol. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between patients treated with Carvedilol and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with Carvedilol. In a long-term, placebo-controlled trial in severe heart failure, patients treated with Carvedilol had lower values for hepatic transaminases than patients treated with placebo, possibly because improvements in cardiac function induced by Carvedilol led to less hepatic congestion and/or improved hepatic blood flow.
Carvedilol has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive patients.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Carvedilol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders: Aplastic anemia.
Immune System Disorders: Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria).
Renal and Urinary Disorders: Urinary incontinence.
Respiratory, Thoracic and Mediastinal Disorders: Interstitial pneumonitis.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
Drug Interactions
CYP2D6 Inhibitors and Poor Metabolizers
Interactions of Carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of Carvedilol [see Clinical Pharmacology (12.3)]. Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.
Hypotensive Agents
Patients taking both agents with β-blocking properties and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Concomitant administration of clonidine with agents with β-blocking properties may potentiate blood-pressure and heart rate-lowering effects. When concomitant treatment with agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Cyclosporine
Modest increases in mean trough cyclosporine concentrations were observed following initiation of Carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of Carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
Digitalis Glycosides
Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and Carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing Carvedilol [see Clinical Pharmacology (12.5)].
Inducers/Inhibitors of Hepatic Metabolism
Rifampin reduced plasma concentrations of Carvedilol by about 70% [see Clinical Pharmacology (12.5)]. Cimetidine increased AUC by about 30% but caused no change in Cmax[see Clinical Pharmacology (12.5)].
Amiodarone
Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and P glycoprotein, increased concentrations of the S(-) enantiomer of Carvedilol by at least 2-fold [see Clinical Pharmacology (12.5)].
The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with Carvedilol may enhance the β-blocking properties of Carvedilol resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is added to pre-existing treatment with the other.
Calcium Channel Blockers
Conduction disturbance (rarely with hemodynamic compromise) has been observed when Carvedilol is co-administered with diltiazem. As with other agents with β-blocking properties, if Carvedilol is to be administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.
Insulin or Oral Hypoglycemics
Agents with β-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)].
Anesthesia
If treatment with Carvedilol is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [see Overdosage (10)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Studies performed in pregnant rats and rabbits given Carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Studies in rats have shown that Carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.
Pediatric Use
Effectiveness of Carvedilol in patients younger than 18 years of age has not been established.
In a double-blind trial, 161 children (mean age 6 years, range 2 months to 17 years; 45% less than 2 years old) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction < 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of Carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of patients treated with Carvedilol and at twice the rate of placebo-treated patients included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
Geriatric Use
Of the 975 myocardial infarction patients randomized to Carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.
Of the 2,065 hypertensive patients in US clinical trials of efficacy or safety who were treated with Carvedilol, 21% (436) were 65 years of age or older. Of 3,722 patients receiving Carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.
With the exception of dizziness in hypertensive patients (incidence 8.8% in the elderly versus 6% in younger patients), no overall differences in the safety or effectiveness (see Figure 2) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Overdosage
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion. The following agents may be administered:
for excessive bradycardia: Atropine, 2 mg IV.
to support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect.
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7 to 10 hour half-life of Carvedilol.
Cases of overdosage with Carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.
Carvedilol Description
Carvedilol, USP is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. Carvedilol, USP is a racemic mixture with the following structure:
Carvedilol tablets USP are film-coated tablets containing 3.125 mg, 6.25 mg, 12.5 mg or 25 mg of Carvedilol. The 3.125 mg, 6.25 mg and 25 mg tablets are white film coated circular shaped tablets. The 12.5 mg tablets are white film coated capsule shaped tablets. Inactive ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone and titanium dioxide.
Carvedilol, USP is a white to off-white powder with a molecular weight of 406.5 and a molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS without pancreatin, pH 7.5).
The product meets USP Dissolution test 2.
Carvedilol - Clinical Pharmacology
Mechanism of Action
Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.
Pharmacodynamics
Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the beneficial effects of Carvedilol in patients with left ventricular dysfunction following an acute myocardial infarction is not established.
Hypertension: The mechanism by which β-blockade produces an antihypertensive effect has not been established.
β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that Carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that Carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.
Due to the α1-receptor blocking activity of Carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when Carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].
In hypertensive patients with normal renal function, therapeutic doses of Carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after Carvedilol and placebo.
Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.
Pharmacokinetics
Carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of Carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking Carvedilol with food should minimize the risk of orthostatic hypotension.
Carvedilol is extensively metabolized. Following oral administration of radiolabelled Carvedilol to healthy volunteers, Carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of Carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than Carvedilol for β-blockade.
Compared to Carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for Carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-Carvedilol approximately 2 to 3 times higher than S(-)-Carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-Carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-Carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of Carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-Carvedilol. Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-Carvedilol compared to extensive metabolizers. In contrast, plasma levels of S(-)-Carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-Carvedilol. The pharmacokinetics of Carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.
Specific Populations
Geriatric: Plasma levels of Carvedilol average about 50% higher in the elderly compared to young subjects.
Hepatic Impairment: Compared to healthy subjects, patients with severe liver impairment (cirrhosis) exhibit a 4 to 7 fold increase in Carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.
Renal Impairment: Although Carvedilol is metabolized primarily by the liver, plasma concentrations of Carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of Carvedilol were observed in hypertensive patients with moderate to severe renal impairment compared to a control group of hypertensive patients with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in patients with impaired renal function.
Consistent with its high degree of plasma protein-binding, Carvedilol does not appear to be cleared significantly by hemodialysis.
Drug-Drug Interactions
Since Carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of Carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes.
Amiodarone: In a pharmacokinetic study conducted in 106 Japanese patients with heart failure, coadministration of small loading and maintenance doses of amiodarone with Carvedilol resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-) Carvedilol [see Drug Interactions (7.6)].
Cimetidine: In a pharmacokinetic study conducted in 10 healthy male subjects, cimetidine (1,000 mg/day) increased the steady-state AUC of Carvedilol by 30% with no change in Cmax [see Drug Interactions (7.5)].
Digoxin: Following concomitant administration of Carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 hypertensive patients [see Drug Interactions (7.4)].
Glyburide: In 12 healthy subjects, combined administration of Carvedilol (25 mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction for either compound.
Hydrochlorothiazide: A single oral dose of Carvedilol 25 mg did not alter the pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 patients with hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of Carvedilol.
Rifampin: In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days) decreased the AUC and Cmax of Carvedilol by about 70% [see Drug Interactions (7.5)].
Torsemide: In a study of 12 healthy subjects, combined oral administration of Carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differences in their pharmacokinetics compared with administration of the drugs alone.
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
In 2-year studies conducted in rats given Carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), Carvedilol had no carcinogenic effect.
Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.
At doses ≥ 200 mg/kg/day (≥ 32 times the MRHD as mg/m2) Carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
Clinical Studies
Lef
Subscribe to:
Posts (Atom)