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probenecid-colchicine tablet

Out of Stock Manufacturer RISING PHARM 64980014901
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Uses

Gout Flare

Colchicine is used to relieve acute gout flares (acute attacks of gouty arthritis). Nonsteroidal anti-inflammatory agents (NSAIAs) (e.g., indomethacin, ibuprofen, naproxen, sulindac, piroxicam, ketoprofen) are as effective as, and better tolerated than, usual dosages of colchicine for short-term use in relieving acute attacks of gouty arthritis. Corticosteroids also are used to relieve acute attacks of gouty arthritis. Colchicine is considered a second-line agent; colchicine may be used for the treatment of acute gouty arthritis in patients who have not responded to or who cannot tolerate recommended therapies (i.e., NSAIAs, corticosteroids).

Colchicine should be initiated at the first sign of an acute gout flare. When colchicine is administered orally within 12 hours of the onset of an acute gout flare, 38% of patients receiving the drug in the currently recommended dosage have a favorable response.

Colchicine also is used in the prophylactic treatment of recurrent gout flares. Colchicine has no effect on plasma concentrations or urinary excretion of uric acid; therefore, concomitant administration of allopurinol or a uricosuric agent (e.g., febuxostat, probenecid, sulfinpyrazone) is necessary to decrease serum urate concentrations. Prophylactic doses of colchicine should be administered before the initiation of allopurinol or uricosuric therapy because sudden changes in serum urate concentrations may precipitate acute gout attacks. After the serum urate concentration has been reduced to the desired level and acute gout attacks have not occurred for 3-6 months (some clinicians suggest 1-12 months), colchicine may be discontinued and the patient may be treated with urate-lowering agents alone. Colchicine is frequently used in combination with probenecid to facilitate prophylactic therapy in patients with chronic gouty arthritis. The usefulness of the commercially available fixed-dosage preparation is limited, however, because the colchicine present exceeds the amount required by most patients.

Familial Mediterranean Fever

Colchicine is used in the management of familial Mediterranean fever. The drug has been used effectively for chronic prophylactic therapy to reduce the frequency and severity of the episodic attacks of painful serositis in patients with familial Mediterranean fever. Chronic prophylactic therapy reportedly is associated with marked amelioration of attacks (both frequency and severity) or remission in about 90% of patients with this condition, but therapy with the drug is not curative and manifestations of this condition return to pretreatment levels following discontinuance of colchicine. Chronic prophylactic therapy also appears to prevent amyloidosis, manifested by nephropathy, in patients with familial Mediterranean fever who lack evidence of amyloidosis when therapy is initiated. Colchicine appears to be effective in preventing amyloidosis regardless of whether patients continue to experience episodic attacks of serositis during chronic prophylactic therapy with the drug. Colchicine may prevent deterioration in patients in the proteinuric phase of the disease when amyloid involvement is minimal. The drug generally appears to be of limited value in altering the effects of amyloid deposits when clinical amyloidosis is evident, particularly when proteinuria has progressed to nephrosis, although a beneficial effect (e.g., restoration of serum albumin concentrations toward normal, slight improvement in renal function) may be evident in some patients.

Regulatory Actions Affecting Colchicine

Colchicine injection became available in the US in the 1950s and has been used for the treatment of acute attacks of gout. Colchicine injection preparations that have been commercially available have not been approved by the US Food and Drug Administration (FDA). Serious adverse events, some fatal, have been reported in patients receiving colchicine injection.(See Cautions: Adverse Effects.) Because of the potentially serious health risks associated with unapproved colchicine injection, FDA announced on February 8, 2008, 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.

Although commercially available, single-entity, oral preparations of colchicine also lacked FDA approval, FDA did not take action against colchicine tablets in February 2008; risks associated with use of the tablets are believed to be lower than those associated with use of the injection. In July 2009, FDA approved a single-ingredient oral colchicine preparation. During the review process, FDA identified 2 safety concerns associated with use of colchicine. Reports suggested that drug interactions play an important role in the development of colchicine toxicity. There also was evidence that the dosage of colchicine previously used for treatment of acute gout flares could be reduced without reducing the drug's efficacy. The labeling now includes extensive information on drug interactions and a new (lower) dosage for acute gout flare. Colchicine in fixed combination with probenecid is approved by the FDA for the management of recurrent gouty arthritis.

Dosage and Administration

Administration

Colchicine is administered orally without regard to meals. Colchicine has been administered by IV injection; however, IV preparations of colchicine have been withdrawn from the US market because of safety concerns.(See Uses: Regulatory Actions Affecting Colchicine and see Cautions.)

Patients receiving colchicine should be instructed on how to resume therapy in the event of a missed dose. Patients with gout who are receiving colchicine for treatment of an acute flare but not for prophylaxis of recurrent flares should be instructed to take the missed dose as soon as possible. Those receiving the drug to treat an acute gout flare during colchicine prophylaxis should be instructed to take the missed dose immediately and then wait 12 hours before resuming the previous dosing schedule. Patients receiving colchicine for treatment of familial Mediterranean fever or for prophylaxis of recurrent gout flares (without treatment for an acute gout flare) should be instructed to take the missed dose as soon as possible and then resume their usual dosing schedule, but not to take a double dose to make up for the missed dose.

Dosage

Dosage of colchicine depends on the patient's age, renal and hepatic function, and whether the drug is administered concomitantly with or within 14 days following therapy with drugs that affect hepatic metabolism or the P-glycoprotein transport system.

Treatment of Acute Gout Flare

The recommended oral dosage of colchicine for relief of an acute gout flare in patients who are not receiving concomitant therapy with a moderate or potent inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 or an inhibitor of the P-glycoprotein transport system, and who have not received such therapy during the prior 14 days, is 1.2 mg given at the first sign of flare followed by 0.6 mg one hour later. The maximum recommended dosage for treatment of acute gout flare is 1.8 mg administered over a one-hour period. Higher dosages of colchicine have not been shown to be more effective in relieving acute gout flares. Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed. Patients receiving colchicine for prevention of gout flares who are not receiving a CYP3A4 inhibitor also may receive colchicine (1.2 mg initially followed by 0.6 mg 1 hour later) to relieve an acute gout flare; following the 2-dose treatment course, 12 hours should elapse before prophylactic doses of the drug are resumed.

In patients receiving concomitant therapy with a potent inhibitor of CYP3A4, such as atazanavir, boceprevir, clarithromycin, darunavir with low-dose ritonavir (ritonavir-boosted darunavir), ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for relief of an acute gout flare is 0.6 mg given at the first sign of flare followed by 0.3 mg 1 hour later. Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed. Use of colchicine for the treatment of acute gout flares is not recommended in individuals receiving the drug for prevention of gout flares who also are receiving therapy with a CYP3A4 inhibitor.

In patients receiving concomitant therapy with a moderate inhibitor of CYP3A4, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for relief of an acute gout flare is a single 1.2-mg dose given at the first sign of flare. Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed. Use of colchicine for the treatment of acute gout flare is not recommended in individuals receiving the drug for prevention of gout flares who also are receiving therapy with a CYP3A4 inhibitor.

In patients receiving concomitant therapy with a drug that inhibits the P-glycoprotein transport system, such as cyclosporine or ranolazine, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for relief of an acute gout flare is a single 0.6-mg dose given at the first sign of flare. Additional courses of colchicine therapy for treatment of an acute gout flare should not be repeated until 3 days have elapsed.

The safety and efficacy of repeat courses of colchicine for treatment of acute gout flare have not been evaluated.

Prophylactic Treatment of Recurrent Gout Flare

The recommended oral dosage of colchicine for prophylaxis of recurrent gout flares in adults and adolescents older than 16 years of age who are not receiving concomitant therapy with a moderate or potent inhibitor of CYP3A4 or an inhibitor of the P-glycoprotein transport system, and who have not received such therapy during the prior 14 days, is 0.6 mg once or twice daily. The maximum recommended dosage is 1.2 mg daily.

In patients receiving concomitant therapy with a potent inhibitor of CYP3A4, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg daily or every other day.

In patients receiving concomitant therapy with a moderate inhibitor of CYP3A4, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg twice daily, 0.6 mg once daily, or 0.3 mg once daily.

In patients receiving concomitant therapy with a drug that inhibits the P-glycoprotein transport system, such as cyclosporine or ranolazine, and those who have received such therapy during the prior 14 days, the recommended oral dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg once daily or every other day.

Familial Mediterranean Fever

For management of familial Mediterranean fever in patients who are not receiving concomitant therapy with a moderate or potent inhibitor of CYP3A4 or an inhibitor of the P-glycoprotein transport system, and who have not received such therapy during the prior 14 days, colchicine may be given in a dosage of 1.2-2.4 mg daily in adults and adolescents older than 12 years of age, a dosage of 0.9-1.8 mg daily in children 6-12 years of age, and a dosage of 0.3-1.8 mg daily in children 4-6 years of age. The daily dosage may be given once daily or in 2 divided doses. Dosage of the drug may be increased in increments of 0.3 mg daily to the maximum recommended dosage. Alternatively, in patients experiencing intolerable adverse effects, dosage may be decreased in increments of 0.3 mg daily.

In adults and adolescents receiving concomitant therapy with a potent inhibitor of CYP3A4, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and those who have received such therapy during the prior 14 days, the maximum recommended dosage of colchicine for the management of familial Mediterranean fever is 0.6 mg daily; the daily dosage may be given as 0.3 mg twice daily.

In adults and adolescents receiving concomitant therapy with a moderate inhibitor of CYP3A4, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, and those who have received such therapy during the prior 14 days, the maximum recommended dosage of colchicine for the management of familial Mediterranean fever is 1.2 mg daily; the daily dosage may be given as 0.6 mg twice daily.

In adults and adolescents receiving concomitant therapy with a drug that inhibits the P-glycoprotein transport system, such as cyclosporine or ranolazine, and those who have received such therapy during the prior 14 days, the maximum recommended dosage of colchicine for the management of familial Mediterranean fever is 0.6 mg daily; the daily dosage may be given as 0.3 mg twice daily.

These maximum recommended dosages for patients with familial Mediterranean fever who are receiving CYP3A4 or P-glycoprotein inhibitors are intended for individuals for whom a dosage range of 1.2-2.4 mg daily would be appropriate in the absence of interacting drugs (i.e., adults and adolescents older than 12 years of age). The manufacturer currently makes no specific recommendations regarding maximum colchicine dosage in children 4-12 years of age who are receiving CYP3A4 or P-glycoprotein inhibitors.

Dosage in Renal and Hepatic Impairment

Dosage in Renal Impairment

Use of colchicine in combination with a potent CYP3A4 inhibitor, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with a P-glycoprotein inhibitor, such as cyclosporine or ranolazine, in patients with renal impairment is contraindicated.

Gout Flare

Use of colchicine for the treatment of an acute gout flare is not recommended in patients with renal impairment who are receiving the drug for prevention of gout flares.

Colchicine dosage adjustment is not needed in patients with mild (creatinine clearance 50-80 mL/minute) to moderate (creatinine clearance 30-50 mL/minute) renal impairment who are receiving the drug for treatment of an acute gout flare or for prophylaxis of recurrent gout flares; however, such patients should be monitored for adverse effects.

In patients with severe renal impairment, the recommended initial dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg daily; close monitoring is needed if the dosage is increased. When colchicine is used for the treatment of an acute gout flare in patients with severe renal impairment, dosage adjustment is not needed, but additional courses of colchicine therapy for acute gout flares should not be repeated until 2 weeks have elapsed. Alternative therapy should be considered for patients with severe renal impairment requiring repeat courses of therapy.

In patients who are undergoing dialysis, the recommended dosage of colchicine for prophylaxis of recurrent gout flares is 0.3 mg twice weekly; close monitoring is advised. When colchicine is used for the treatment of an acute gout flare in patients who are undergoing dialysis, the recommended dosage of colchicine is 0.6 mg at the first sign of flare. Additional courses of colchicine therapy for acute gout flares should not be repeated until 2 weeks have elapsed.

Familial Mediterranean Fever

Patients with mild (creatinine clearance 50-80 mL/minute) to moderate (creatinine clearance 30-50 mL/minute) renal impairment who are receiving colchicine for management of familial Mediterranean fever should be monitored for adverse effects. Dosage adjustment may be needed.

In patients with severe (creatinine clearance less than 30 mL/minute) renal impairment or undergoing dialysis, the recommended initial dosage of colchicine for management of familial Mediterranean fever is 0.3 mg daily. Dosage can be increased with careful monitoring.

Dosage in Hepatic Impairment

Use of colchicine in combination with a potent CYP3A4 inhibitor, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with a P-glycoprotein inhibitor, such as cyclosporine or ranolazine, in patients with hepatic impairment is contraindicated.

Gout Flare

Colchicine dosage adjustment is not needed in patients with mild to moderate hepatic impairment who are receiving the drug for treatment of an acute gout flare or for prophylaxis of recurrent gout flares; however, such patients should be monitored for adverse effects.

Dosage reduction should be considered in patients with severe hepatic impairment who are receiving colchicine for prophylaxis of recurrent gout flares. When colchicine is used for the treatment of an acute gout flare in patients with severe hepatic impairment, dosage adjustment is not needed, but additional courses of colchicine therapy for acute gout flares should not be repeated until 2 weeks have elapsed. Alternative therapy should be considered for patients with severe hepatic impairment requiring repeat courses of therapy.

Familial Mediterranean Fever

Patients with mild to moderate hepatic impairment who are receiving colchicine for management of familial Mediterranean fever should be monitored for adverse effects.

Dosage adjustment should be considered for patients with severe hepatic impairment who are receiving colchicine for management of familial Mediterranean fever.

Cautions

Adverse Effects

The most common adverse effects of oral colchicine therapy are nausea, abdominal discomfort, vomiting, and diarrhea. Pharyngolaryngeal pain has been reported.

Bladder spasm, paralytic ileus, stomatitis, hypothyroidism, nonthrombocytopenic purpura, and prostration have also been reported with colchicine therapy.

Myelosuppression, disseminated intravascular coagulation, and renal, hepatic, circulatory, and CNS cellular injury have been reported in patients receiving colchicine, generally in those receiving excessive dosages of the drug. Leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported. Death has occurred in one patient with normal renal and hepatic function who developed pancytopenia and bone marrow aplasia following IV administration of 10 mg of colchicine (IV preparations are no longer commercially available in the US) over a 5-day period.

Neuromuscular toxicity and rhabdomyolysis have been reported in patients receiving long-term colchicine therapy. Patients with renal dysfunction and geriatric patients, including those with normal renal and hepatic function, are at increased risk. Concomitant therapy with an HMG-CoA reductase inhibitor (statin), fibric acid derivative, or cyclosporine also may increase the risk for development of myopathy. Following discontinuance of colchicine, symptoms generally resolve within one week to several months.

Loss of body and scalp hair, rash, vesicular dermatitis, peripheral neuritis or neuropathy, myopathy, rhabdomyolysis, anuria, renal damage, hematuria, and one case of purpura have been reported with prolonged administration of colchicine. Colchicine may also cause increased serum concentrations of alkaline phosphatase, aminotransferases (AST, ALT), and creatine kinase (CK, creatine phosphokinase, CPK). Other reported adverse effects include sensory motor neuropathy, maculopapular rash, abdominal pain or cramping, lactose intolerance, myotonia, muscle weakness or pain, azoospermia, and oligospermia.

Serious adverse events have been reported in patients receiving IV colchicine. Many of these adverse effects were the result of colchicine toxicity. As of June 2007, the US Food and Drug Administration (FDA) was aware of 50 reports of adverse effects associated with use of IV colchicine; 23 of these events were fatal. Reported adverse effects included neutropenia, acute renal failure, thrombocytopenia, congestive heart failure, and pancytopenia. Three deaths were associated with use of compounded IV colchicine. Tests of vials from the same lot used to treat these 3 patients indicated that the concentration of colchicine was 4 mg/mL; labeling on the vial indicated that the concentration of colchicine was 0.5 mg/mL. Because of the potentially serious health risks associated with colchicine injection, FDA announced on February 8, 2008, that it would take enforcement action against all firms, including compounding pharmacies, attempting to manufacture, ship, or deliver colchicine injection.

Oral preparations containing colchicine remain on the market; risks associated with use of the tablets are believed to be lower than those associated with use of the injection.

Precautions and Contraindications

Concomitant use of colchicine with certain drugs is contraindicated or requires particular caution.(See Drug Interactions and also see Dosage and Administration: Dosage.)

Colchicine is contraindicated in patients with renal or hepatic impairment who are receiving a drug that inhibits the P-glycoprotein transport system or is a potent CYP3A4 inhibitor (see Dosage and Administration: Dosage in Renal and Hepatic Impairment); fatal or life-threatening colchicine toxicity has occurred in such patients following therapeutic doses of colchicine.

Pediatric Precautions

Safety and efficacy of colchicine for treatment of gout in children have not been established.

Safety and efficacy of colchicine for management of familial Mediterranean fever in children have been evaluated in uncontrolled studies. Long-term use of colchicine did not appear to affect growth in children with familial Mediterranean fever.

Geriatric Precautions

Clinical studies of colchicine for treatment of acute 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 and older to determine whether geriatric patients respond differently than younger patients. Drug dosage generally should be titrated carefully in geriatric patients with gout; the greater frequency of decreased renal function and of concomitant disease and drug therapy observed in geriatric patients also should be considered.

Pregnancy, Fertility, and Lactation

Pregnancy

Chromosomal aberrations have been reported in a limited number of patients receiving prolonged colchicine therapy. Colchicine crosses the placenta in humans and has been shown in animal reproduction and development studies to cause embryofetal toxicity, teratogenic effects, and altered postnatal development at exposure levels within or above the therapeutic range. Although there are no adequate and controlled studies to date in humans, results of one study suggest that patients receiving prolonged colchicine therapy may have a greater risk of producing trisomic offspring if conception occurs during therapy with the drug. Other clinicians, however, contend that this study is inconclusive and at most merely suggestive of a probable increased risk to the offspring. Data from a limited number of published studies indicate that use of colchicine for the treatment of familial Mediterranean fever in pregnant women was not associated with increased risk of miscarriage, stillbirth, or teratogenic effects. Colchicine should be used during pregnancy only if the potential benefits outweigh the risks.

The effect of colchicine on labor and delivery is not known.

Fertility

Colchicine has adversely affected spermatogenesis in humans and animals. Reversible azoospermia has been reported in a 36-year-old man who received 0.6 mg of colchicine twice daily for several months.

Lactation

Colchicine is distributed into milk.(See Pharmacokinetics: Distribution.) Limited information suggests that exclusively breast-fed infants receive less than 10% of the maternal weight-adjusted dose. Although the drug can affect GI cell renewal and permeability, some experts state that the actual amounts of the drug distributed into breast milk are not high enough to warrant cessation of nursing. No adverse effects have been reported to date in breast-fed infants of women receiving colchicine therapy who were observed over periods of up to 10 months. The American Academy of Pediatrics (AAP) states that the drug usually is compatible with breast-feeding. Some clinicians have suggested that exposure of the infant to the drug could be minimized by waiting 8-12 hours after a dose to breast-feed the infant. The manufacturer states that caution is advised; the infant should be observed for adverse effects.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Colchicine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. In vitro studies indicate that colchicine does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.

Concomitant use of colchicine with potent CYP3A4 inhibitors, such as atazanavir, boceprevir, clarithromycin, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, telithromycin, ritonavir-boosted tipranavir, lopinavir/ritonavir, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, or with moderate CYP3A4 inhibitors, such as aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir (without ritonavir), grapefruit juice, or verapamil, may result in substantially increased plasma concentrations of colchicine. If concomitant therapy is required, the dosage of colchicine must be reduced or treatment with colchicine may need to be interrupted.(See Dosage and Administration: Dosage.) Use of colchicine in combination with a potent CYP3A4 inhibitor in patients with renal or hepatic impairment is contraindicated.

Clarithromycin

An increase in plasma colchicine concentrations (227% increase in peak plasma concentration, 281% increase in area under the plasma concentration-time curve [AUC]) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with clarithromycin (250 mg twice daily for 7 days). Severe or fatal colchicine toxicity has been reported with concomitant clarithromycin and colchicine therapy.

Ketoconazole

An increase in plasma colchicine concentrations (102% increase in peak plasma concentration, 212% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with ketoconazole (200 mg twice daily for 5 days).

Ritonavir

An increase in plasma colchicine concentrations (184% increase in peak plasma concentration, 296% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with ritonavir (100 mg twice daily for 5 days).

Verapamil

An increase in plasma colchicine concentrations (40% increase in peak plasma concentration, 103% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with verapamil (240 mg daily for 5 days). Neuromuscular toxicity has been reported with concomitant verapamil and colchicine therapy.

Diltiazem

An increase in plasma colchicine concentrations (44% increase in peak plasma concentration, 93% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with diltiazem (240 mg daily for 7 days). Neuromuscular toxicity has been reported with concomitant diltiazem and colchicine therapy.

Grapefruit Juice

No substantial change in plasma concentrations of colchicine was observed when a single 0.6-mg dose of colchicine was administered concomitantly with grapefruit juice (240 mL twice daily for 4 days). However, when colchicine was given concomitantly with other moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil), substantial increases in plasma colchicine concentrations were reported. The manufacturer states that patients receiving colchicine should be advised not to consume grapefruit or grapefruit juice. If a moderate CYP3A4 inhibitor (including grapefruit juice) is given concomitantly with colchicine, the manufacturer recommends adjustment of colchicine dosage (see Dosage and Administration: Dosage).

Drugs Affecting the P-glycoprotein Transport System

Concomitant use of colchicine with drugs that inhibit the P-glycoprotein transport system, such as cyclosporine or ranolazine, results in substantially increased plasma concentrations of colchicine. If use of a P-glycoprotein inhibitor is required, the dosage of colchicine must be reduced or treatment with colchicine may need to be interrupted.(See Dosage and Administration: Dosage.) Use of colchicine in combination with a P-glycoprotein inhibitor in patients with renal or hepatic impairment is contraindicated.

Cyclosporine

Administration of a single 100-mg dose of cyclosporine, a P-glycoprotein inhibitor, concomitantly with a single 0.6-mg dose of colchicine resulted in increases in plasma colchicine concentrations (270% increase in peak plasma concentration, 259% increase in AUC). Fatal colchicine toxicity has been reported with concomitant cyclosporine and colchicine therapy. Concomitant use of cyclosporine and colchicine also may result in increased cyclosporine concentrations and additive nephrotoxic effects; therefore, renal function and blood concentrations of cyclosporine should be monitored and cyclosporine dosage should be adjusted accordingly if colchicine is initiated or discontinued or the colchicine dosage is altered in patients receiving cyclosporine.

Antilipemic Agents

Addition of an HMG-CoA reductase inhibitor (statin) or other lipid-lowering agents (e.g., fibric acid derivatives) to long-term therapy with colchicine or addition of colchicine to long-term therapy with these antilipemic agents has resulted in myopathy and rhabdomyolysis; death has been reported. Potential benefits and risks of such concomitant therapy should be weighed. Patients should be monitored for muscle pain, tenderness, and weakness, especially during the initial phase of such concomitant therapy.

Azithromycin

An increase in plasma colchicine concentrations (22% increase in peak plasma concentration, 57% increase in AUC) was observed when a single 0.6-mg dose of colchicine was administered concomitantly with azithromycin (500 mg initially, followed by 250 mg daily for 4 days).

Digoxin

Digoxin is a P-glycoprotein transport system substrate. Rhabdomyolysis has been reported in an individual receiving colchicine and digoxin concomitantly. Potential benefits and risks of concomitant therapy with colchicine and digoxin should be weighed. Patients should be monitored for muscle pain, tenderness, and weakness, especially during the initial phase of such concomitant therapy.

Estrogens or Progestins

Administration of an oral contraceptive (ethinyl estradiol 35 mcg with norethindrone 1 mg) concomitantly with colchicine (0.6 mg twice daily for 14 days) in healthy women did not alter the plasma concentrations of either the estrogen or the progestin.

Theophylline

No change in plasma concentrations of theophylline was observed when theophylline was administered concomitantly with colchicine (0.6 mg twice daily for 14 days) in healthy individuals.

Pharmacokinetics

Absorption

Following oral administration, colchicine is absorbed from the GI tract and is partially metabolized in the liver. The drug and its metabolites re-enter the intestinal tract via biliary secretions and the unchanged drug may be reabsorbed from the intestine. Following oral administration of colchicine 1.8 mg over 1 hour under fasting conditions, peak plasma concentrations of 6.2 ng/mL were reached in 1.8 hours. Following oral administration of 0.6 mg twice daily for 10 days, a mean peak plasma concentration of 3.6 ng/mL was reached at 1.3 hours after a dose. Administration of colchicine with food did not affect rate of absorption but decreased the extent of absorption by 15%. Absolute bioavailability is reported to be approximately 45%.

The presence of a secondary peak in colchicine concentrations, ranging from 39-155% of the height of the initial peak concentration, has been reported in some individuals 3-36 hours after oral administration and has been attributed to intestinal secretion and reabsorption and/or biliary circulation.

Distribution

Colchicine is about 39% bound to serum proteins, mainly albumin.

Colchicine crosses the placenta. Fetal plasma concentrations of the drug are reported to be approximately 15% of the maternal concentration.

Colchicine is distributed into milk. In a limited number of nursing women receiving long-term colchicine therapy at dosages of 1-1.5 mg daily, peak concentrations of the drug in milk were similar to serum concentrations and ranged from 1.9-8.6 ng/mL. Higher concentrations of the drug in milk (31, 24-27, or 10 ng/mL at 2, 4, or 7 hours, respectively, after a dose) have been reported in the absence of concurrent serum concentration data in a nursing woman receiving colchicine 1 mg daily.

Elimination

Following IV administration of a single therapeutic dose (IV preparations are no longer commercially available in the US), colchicine is rapidly removed from the plasma; plasma half-life is about 20 minutes. The drug has a half-life of about 60 hours in leukocytes.

Colchicine is demethylated in the liver by cytochrome P-450 (CYP) isoenzyme 3A4. In healthy individuals, 40-65% of an orally administered 1-mg dose of the drug is excreted unchanged in urine. Enterohepatic circulation and biliary excretion may occur. A half-life of 26.6-31.2 hours has been reported in healthy young adults receiving colchicine 0.6 mg orally twice daily. Colchicine is a substrate of the P-glycoprotein transport system. Colchicine is not removed by hemodialysis.

Clearance of colchicine is decreased in patients with renal impairment. In one study, patients with severe renal disease eliminated little or no colchicine or its metabolites in the urine, resulting in a prolonged plasma half-life. Total body clearance of colchicine was reduced by 75% in patients with end-stage renal disease requiring dialysis.

In patients with hepatic impairment, substantial interpatient variability in colchicine pharmacokinetics has been observed. In some patients with mild to moderate cirrhosis, clearance of colchicine was decreased substantially and plasma half-life was prolonged compared with healthy individuals; however, no consistent trends were observed in patients with primary biliary cirrhosis.

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