Lengout

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Lengout uses


1 INDICATIONS AND USAGE

Lengout tablets are an alkaloid indicated for:

  • Prophylaxis and Treatment of Gout Flares in adults (1.1).
  • Familial Mediterranean fever (FMF) in adults and children 4 years or older (1.2).

Lengout is not an analgesic medication and should not be used to treat pain from other causes.

1.1 Gout Flares

Lengout® (colchicine, USP) tablets are indicated for prophylaxis and the treatment of acute gout flares.

  • Prophylaxis of Gout Flares:

    Lengout is indicated for prophylaxis of gout flares.

  • Treatment of Gout Flares:

    Lengout tablets are indicated for treatment of acute gout flares when taken at the first sign of a flare.

1.2 Familial Mediterranean fever

Lengout® (colchicine, USP) tablets are indicated in adults and children 4 years or older for treatment of familial Mediterranean fever (FMF).

2 DOSAGE AND ADMINISTRATION

The long term use of Lengout is established for FMF and the prophylaxis of gout flares but the safety and efficacy of repeat treatment for gout flares has not been evaluated. The dosing regimens for Lengout are different for each indication and must be individualized.

The recommended dosage of Lengout depends on the patient's age, renal function, hepatic function, and use of co-administered drugs [see Dose Modification for Co-administration of Interacting Drugs ].

Lengout tablets are administered orally, without regard to meals.

Lengout is not an analgesic medication and should not be used to treat pain from other causes.

  • Gout Flares:
    • Prophylaxis of Gout Flares: 0.6 mg once or twice daily in adults and adolescents older than 16 years of age (2.1). Maximum dose 1.2 mg/day.
    • Treatment of Gout Flares: 1.2 mg (2 tablets) at the first sign of a gout flare followed by 0.6 mg (1 tablet) one hour later (2.1).
  • FMF: Adults and Children older than 12 years 1.2 – 2.4 mg; Children 6 to 12 years 0.9 – 1.8 mg; Children 4 to 6 years 0.3 – 1.8 mg (2.2, 2.3).
    • Give total daily dose in one or two divided doses (2.2).
    • Increase or decrease the dose as indicated and as tolerated in increments of 0.3 mg/day, not to exceed the maximum recommended daily dose (2.2).

Lengout tablets are administered orally, without regard to meals.

2.1 Gout Flares

Prophylaxis of Gout Flares:

The recommended dosage of Lengout for prophylaxis of gout flares for adults and adolescents older than 16 years of age is 0.6 mg once or twice daily. The maximum recommended dose for prophylaxis of gout flares is 1.2 mg/day.

Treatment of Gout Flares:

The recommended dose of Lengout for treatment of a gout flare is 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Higher doses have not been found to be more effective. The maximum recommended dose for treatment of gout flares is 1.8 mg over a 1 hour period. Lengout may be administered for treatment of a gout flare during prophylaxis at doses not to exceed 1.2 mg (2 tablets) at the first sign of the flare followed by 0.6 mg (1 tablet) one hour later. Wait 12 hours and then resume the prophylactic dose.

2.2 FMF

The recommended dosage of Lengout for FMF in adults is 1.2 mg to 2.4 mg daily.

Lengout should be increased as needed to control disease and as tolerated in increments of 0.3 mg/day to a maximum recommended daily dose. If intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day. The total daily Lengout dose may be administered in one to two divided doses.

2.3 Recommended Pediatric Dosage

Prophylaxis and Treatment of Gout Flares:

Lengout is not recommended for pediatric use in prophylaxis or treatment of gout flares.

FMF:

The recommended dosage of Lengout for FMF in pediatric patients 4 years of age and older is based on age. The following daily doses may be given as a single or divided dose twice daily:

  • Children 4 – 6 years: 0.3 mg to 1.8 mg daily
  • Children 6 – 12 years: 0.9 mg to 1.8 mg daily
  • Adolescents older than 12 years: 1.2 mg to 2.4 mg daily

2.4 Dose Modification for Co-administration of Interacting Drugs

Concomitant Therapy:

Co-administration of Lengout with drugs known to inhibit CYP3A4 and/or P-glycoprotein increases the risk of colchicine-induced toxic effects (Table 1). If patients are taking or have recently completed treatment with drugs listed in Table 1 within the prior 14 days, the dose adjustments are as shown on the table below [see DRUG INTERACTIONS (7) ].

Strong CYP3A4 InhibitorsPatients with renal or hepatic impairment should not be given Lengout in conjunction with strong CYP3A4 or P-gp inhibitors [see CONTRAINDICATIONS (4) ].
Drug Noted or Anticipated Outcome Gout Flares FMF
Prophylaxis of Gout Flares Treatment of Gout Flares
Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose
Atazanavir

Clarithromycin

Darunavir/

RitonavirWhen used in combination with Ritonavir, see dosing recommendations for strong CYP3A4 inhibitors [see CONTRAINDICATIONS (4) ].

Indinavir

Itraconazole Ketoconazole

Lopinavir/

Ritonavir

Nefazodone

Nelfinavir

Ritonavir

Saquinavir Telithromycin

Tipranavir/

Ritonavir

Significant increase in Lengout plasma levels; fatal Lengout toxicity has been reported with clarithromycin, a strong CYP3A4 inhibitor. Similarly, significant increase in Lengout plasma levels is anticipated with other strong CYP3A4 inhibitors. 0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

1.2 mg

(2 tablets) followed by 0.6 mg

(1 tablet)

1 hour later. Dose to be repeated no earlier than

3 days.

0.6 mg

(1 tablet) ×

1 dose, followed by 0.3 mg

(1/2 tablet)

1 hour later. Dose to be repeated no earlier than

3 days.

Maximum daily dose of 1.2 – 2.4 mg Maximum daily dose of 0.6 mg (may be given as

0.3 mg twice a day)

Moderate CYP3A4 Inhibitors
Drug Noted or Anticipated Outcome Gout Flares FMF
Prophylaxis of Gout Flares Treatment of Gout Flares
Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose
Amprenavir Aprepitant

Diltiazem Erythromycin Fluconazole Fosamprenavir

(pro-drug of

Amprenavir)

Grapefruit Juice Verapamil

Significant increase in Lengout plasma concentration is anticipated. Neuromuscular toxicity has been reported with diltiazem and verapamil interactions. 0.6 mg twice a day

0.6 mg once a day

0.3 mg twice a day or 0.6 mg once a day

0.3 mg once a day

1.2 mg

(2 tablets) followed by 0.6 mg

(1 tablet)

1 hour later. Dose to be repeated no earlier than

3 days.

1.2 mg

(2 tablets) ×

1 dose. Dose to be repeated no earlier than

3 days.

Maximum daily dose of 1.2 – 2.4 mg. Maximum daily dose of 1.2 mg (may be given as

0.6 mg twice a day)

P-gp Inhibitors
Drug Noted or Anticipated Outcome Gout Flares FMF
Prophylaxis of Gout Flares Treatment of Gout Flares
Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose Original Intended Dosage Adjusted Dose
Cyclosporine Ranolazine Significant increase in Lengout plasma levels; fatal Lengout toxicity has been reported with cyclosporine, a

P-gp inhibitor. Similarly, significant increase in Lengout plasma levels is anticipated with other P-gp inhibitors.

0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

1.2 mg

(2 tablets) followed by 0.6 mg

(1 tablet)

1 hour later. Dose to be repeated no earlier than

3 days.

0.6 mg

(1 tablet) ×

1 dose. Dose to be repeated no earlier than

3 days.

Maximum daily dose of 1.2 – 2.4 mg Maximum daily dose of 0.6 mg (may be given as

0.3 mg twice a day)

Protease Inhibitor Clinical Comment w/Colchicine – Prophylaxis of Gout Flares w/Colchicine –

Treatment of Gout Flares

w/Colchicine – Treatment of FMF
Atazanavir sulfate

(Reyataz)

Patients with renal or hepatic impairment should not be given Lengout with Reyataz. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Darunavir (Prezista) Patients with renal or hepatic impairment should not be given Lengout with Prezista/ritonavir. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Fosamprenavir (Lexiva) with Ritonavir Patients with renal or hepatic impairment should not be given Lengout with Lexiva/ritonavir. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Fosamprenavir (Lexiva) Patients with renal or hepatic impairment should not be given Lengout with Lexiva/ritonavir. Original dose Adjusted dose 1.2 mg (2 tablets) × 1 dose. Dose to be repeated no earlier than 3 days. Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day)
0.6 mg twice a day 0.3 mg twice a day or 0.6 mg once a day
0.6 mg once a day 0.3 mg once a day
Indinavir (Crixivan) Patients with renal or hepatic impairment should not be given Lengout with Crixivan. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Lopinavir/Ritonavir (Kaletra) Patients with renal or hepatic impairment should not be given Lengout with Kaletra. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Nelfinavir mesylate (Viracept) Patients with renal or hepatic impairment should not be given Lengout with Viracept. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Ritonavir (Norvir) Patients with renal or hepatic impairment should not be given Lengout with Norvir. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Saquinavir mesylate (Invirase) Patients with renal or hepatic impairment should not be given Lengout with Invirase/ritonavir. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day

Tipranavir (Aptivus)

Patients with renal or hepatic impairment should not be given Lengout with Aptivus/ritonavir. Original dose Adjusted dose 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (1/2 tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day)
0.6 mg twice a day

0.6 mg once a day

0.3 mg once a day

0.3 mg once every other day


Treatment of gout flares with Lengout is not recommended in patients receiving prophylactic dose of Lengout and CYP3A4 inhibitors.

2.5 Dose Modification in Renal Impairment

Lengout dosing must be individualized according to the patient's renal function [see Renal Impairment (8.6) ].

Clcr in mL/minute may be estimated from serum creatinine (mg/dL) determination using the following formula:

Clcr = [140-age (years) × weight (kg)] × 0.85 for female patients
72 × serum creatinine (mg/dL)

Gout Flares:

Prophylaxis of Gout Flares:

For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of Lengout. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ].

Treatment of Gout Flares:

For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of Lengout. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ].

Treatment of gout flares with Lengout is not recommended in patients with renal impairment who are receiving Lengout for prophylaxis.

FMF:

Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing dialysis. For these patients, the dosage should be reduced [see Clinical Pharmacology (12.3) ]. Patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment should be monitored closely for adverse effects of Lengout. Dose reduction may be necessary. For patients with severe renal failure (Clcr less than 30 mL/minute), start with 0.3 mg/day; any increase in dose should be done with adequate monitoring of the patient for adverse effects of Lengout [see Renal Impairment (8.6) ]. For patients undergoing dialysis, the total recommended starting dose should be 0.3 mg (half tablet) per day. Dosing can be increased with close monitoring. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of Lengout [see Clinical Pharmacology (12.3) and Renal Impairment (8.6) ].

2.6 Dose Modification in Hepatic Impairment

Gout Flares

Prophylaxis of Gout Flares:

For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of Lengout. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment [see Hepatic Impairment (8.7) ].

Treatment of Gout Flares:

For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of Lengout. However, for the treatment of gout flares in patients with severe impairment while the dose does not need to be adjusted, but a treatment course should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy [see Hepatic Impairment (8.7) ].

Treatment of gout flares with Lengout is not recommended in patients with hepatic impairment who are receiving Lengout for prophylaxis.

FMF:

Patients with mild to moderate hepatic impairment should be monitored closely for adverse effects of Lengout. Dose reduction should be considered in patients with severe hepatic impairment [see Hepatic Impairment (8.7) ].

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3 DOSAGE FORMS AND STRENGTHS

0.6 mg tablets - purple capsule-shaped, film-coated with AR 374 debossed on one side and scored on the other side.

  • 0.6 mg tablets (3).

4 CONTRAINDICATIONS

Patients with renal or hepatic impairment should not be given Lengout in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir). In these patients, life-threatening and fatal Lengout toxicity has been reported with Lengout taken in therapeutic doses.

Patients with renal or hepatic impairment should not be given Lengout in conjunction with P-gp or strong CYP3A4 inhibitors (5.3). In these patients, life-threatening and fatal Lengout toxicity has been reported with Lengout taken in therapeutic doses (7).

5 WARNINGS AND PRECAUTIONS

  • Fatal overdoses have been reported with Lengout in adults and children. Keep Lengout out of the reach of children.
  • Blood dyscrasias: myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, and aplastic anemia have been reported (5.2).
  • Monitor for toxicity and if present consider temporary interruption or discontinuation of Lengout (5.2, 5.3, 5.4, 6, 10).
  • Drug interaction P-gp and/or CYP3A4 inhibitors: Co-administration of Lengout with P-gp and/or strong CYP3A4 inhibitors has resulted in life-threatening interactions and death (5.3, 7).
  • Neuromuscular toxicity: Myotoxicity including rhabdomyolysis may occur, especially in combination with other drugs known to cause this effect. Consider temporary interruption or discontinuation of Lengout (5.4, 7).

5.1 Fatal Overdose

Fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested Lengout [see OVERDOSAGE (10) ]. Lengout should be kept out of the reach of children.

5.2 Blood Dyscrasias

Myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported with Lengout used in therapeutic doses.

5.3 Drug Interactions

Lengout is a P-gp and CYP3A4 substrate. Life-threatening and fatal drug interactions have been reported in patients treated with Lengout given with P-gp and strong CYP3A4 inhibitors. If treatment with a P-gp or strong CYP3A4 inhibitor is required in patients with normal renal and hepatic function, the patient's dose of Lengout may need to be reduced or interrupted [see DRUG INTERACTIONS ]. Use of Lengout in conjunction with P-gp or strong CYP3A4 inhibitors (this includes all protease inhibitors, except fosamprenavir) is contraindicated in patients with renal or hepatic impairment [see CONTRAINDICATIONS (4) ].

5.4 Neuromuscular Toxicity

Colchicine-induced neuromuscular toxicity and rhabdomyolysis have been reported with chronic treatment in therapeutic doses. Patients with renal dysfunction and elderly patients, even those with normal renal and hepatic function, are at increased risk. Concomitant use of atorvastatin, simvastatin, pravastatin, fluvastatin, lovastatin, gemfibrozil, fenofibrate, fenofibric acid, or benzafibrate (themselves associated with myotoxicity) or cyclosporine with Lengout may potentiate the development of myopathy [see DRUG INTERACTIONS (7) ]. Once Lengout is stopped, the symptoms generally resolve within 1 week to several months.

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6 ADVERSE REACTIONS

Prophylaxis of Gout Flares: The most commonly reported adverse reaction in clinical trials for the prophylaxis of gout was diarrhea.

Treatment of Gout Flares: The most common adverse reactions reported in the clinical trial for gout were diarrhea and pharyngolaryngeal pain (3%).

FMF: Most common adverse reactions (up to 20%) are abdominal pain, diarrhea, nausea, and vomiting. These effects are usually mild, transient, and reversible upon lowering the dose (6).

To report SUSPECTED ADVERSE REACTIONS, contact Mutual Pharmaceutical Company, Inc. at 1-888-351-3786 or drugsafetyLengouturlpharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Prophylaxis of Gout Flares:

The most commonly reported adverse reaction in clinical trials of Lengout for the prophylaxis of gout was diarrhea.

Treatment of Gout Flares:

The most common adverse reactions reported in the clinical trial with Lengout for treatment of gout flares were diarrhea (23%) and pharyngolaryngeal pain (3%).

FMF:

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

6.1 Clinical Trials Experience in Gout

Because clinical studies are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug, and may not predict the rates observed in a broader patient population in clinical practice.

In a randomized, double-blind, placebo-controlled trial in patients with a gout flare, gastrointestinal adverse reactions occurred in 26% of patients using the recommended dose (1.8 mg over 1 hour) of Lengout compared to 77% of patients taking a non-recommended high-dose (4.8 mg over 6 hours) of Lengout and 20% of patients taking placebo. Diarrhea was the most commonly reported drug-related gastrointestinal adverse event. As shown in Table 3, diarrhea is associated with Lengout treatment. Diarrhea was more likely to occur in patients taking the high-dose regimen than the low-dose regimen. Severe diarrhea occurred in 19% and vomiting occurred in 17% of patients taking the non-recommended high-dose Lengout regimen but did not occur in the recommended low-dose Lengout regimen.

MedDRA System Organ Class Lengout Dose Placebo
MedDRA Preferred Term High (N=52)

n (%)

Low (N=74)

n (%)

(N=59)

n (%)

Number of Patients with at Least One Drug-Related TEAE 40 (77) 27 (37) 16 (27)
Gastrointestinal Disorders 40 (77) 19 (26) 12 (20)
Diarrhea 40 (77) 17 (23) 8 (14)
Nausea 9 (17) 3 (4) 3 (5)
Vomiting 9 (17) 0 0
Abdominal Discomfort 0 0 2 (3)
General Disorders and Administration Site Conditions 4 (8) 1 (1) 1 (2)
Fatigue 2 (4) 1 (1) 1 (2)
Metabolic and Nutrition Disorders 0 3 (4) 2 (3)
Gout 0 3 (4) 1 (2)
Nervous System Disorders 1 (2) 1 (1.4) 2 (3)
Headache 1 (2) 1 (1) 2 (3)
Respiratory Thoracic Mediastinal Disorders 1 (2) 2 (3) 0
Pharyngolaryngeal Pain 1 (2) 2 (3) 0

6.2 Postmarketing Experience

Serious toxic manifestations associated with Lengout include myelosuppression, disseminated intravascular coagulation, and injury to cells in the renal, hepatic, circulatory, and central nervous systems.

These most often occur with excessive accumulation or overdosage [see OVERDOSAGE (10) ].

The following adverse reactions have been reported with Lengout. These have been generally reversible upon temporarily interrupting treatment or lowering the dose of Lengout.

  • Neurological: sensory motor neuropathy
  • Dermatological: alopecia, maculopapular rash, purpura, rash
  • Digestive: abdominal cramping, abdominal pain, diarrhea, lactose intolerance, nausea, vomiting
  • Hematological: leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, aplastic anemia
  • Hepatobiliary: elevated AST, elevated ALT
  • Musculoskeletal: myopathy, elevated CPK, myotonia, muscle weakness, muscle pain, rhabdomyolysis
  • Reproductive: azoospermia, oligospermia
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7 DRUG INTERACTIONS

Lengout (colchicine) is a substrate of the efflux transporter P-glycoprotein (P-gp). Of the cytochrome P450 enzymes tested, CYP3A4 was mainly involved in the metabolism of Lengout. If Lengout is administered with drugs that inhibit P-gp, most of which also inhibit CYP3A4, increased concentrations of Lengout are likely. Fatal drug interactions have been reported.

Physicians should ensure that patients are suitable candidates for treatment with Lengout and remain alert for signs and symptoms of toxicities related to increased Lengout exposure as a result of a drug interaction. Signs and symptoms of Lengout toxicity should be evaluated promptly and, if toxicity is suspected, Lengout should be discontinued immediately.

Table 4 provides recommendations as a result of other potentially significant drug interactions. Table 1 provides recommendations for strong and moderate CYP3A4 inhibitors and P-gp inhibitors.

Concomitant Drug Class or Food Noted or anticipated Outcome Clinical Comment
HMG-Co A Reductase Inhibitors:

atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin

Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs:

fibrates, gemfibrozil

Digitalis Glycosides:

digoxin

P-gp substrate; rhabdomyolysis has been reported

Co-administration of P-gp and/or CYP3A4 inhibitors (e.g., clarithromycin or cyclosporine) have been demonstrated to alter the concentration of Lengout. The potential for drug-drug interactions must be considered prior to and during therapy. See full prescribing information for a complete list of reported and potential interactions (2.4, 5.3, 7).

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8 USE IN SPECIFIC POPULATIONS

  • In the presence of mild to moderate renal or hepatic impairment, adjustment of dosing is not required for treatment of gout flare, prophylaxis of gout flare, and FMF but patients should be monitored closely.
  • In patients with severe renal impairment for prophylaxis of gout flares the starting dose should be 0.3 mg/day, for gout flares no dose adjustment is required but a treatment course should be repeated no more than once every 2 weeks. In FMF patients, start with 0.3 mg/day and any increase in dose should be done with close monitoring (2.5, 8.6).
  • In patients with severe hepatic impairment, a dose reduction may be needed in prophylaxis of gout flares and FMF patients; while a dose reduction may not be needed in gout flares, a treatment course should be repeated no more than once every 2 weeks (2.5, 2.6, 8.6, 8.7).
  • For patients undergoing dialysis, the total recommended dose for prophylaxis of gout flares should be 0.3 mg given twice a week with close monitoring. For treatment of gout flares, the total recommended dose should be reduced to 0.6 mg (1 tablet) × 1 dose and the treatment course should not be repeated more than once every two weeks. For FMF patients the starting dose should be 0.3 mg per day and dosing can be increased with close monitoring (2.5, 8.6).
  • Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus (8.1).
  • Nursing Mothers: Caution should be exercised when administered to a nursing woman (8.3).
  • Geriatric Use: The recommended dose of Lengout should be based on renal function (2.5, 8.5).

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with Lengout in pregnant women. Lengout crosses the human placenta. While not studied in the treatment of gout flares, data from a limited number of published studies found no evidence of an increased risk of miscarriage, stillbirth, or teratogenic effects among pregnant women using Lengout to treat familial Mediterranean fever (FMF). Although animal reproductive and developmental studies were not conducted with Lengout, published animal reproduction and development studies indicate that Lengout causes embryofetal toxicity, teratogenicity, and altered postnatal development at exposures within or above the clinical therapeutic range. Lengout should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Labor and Delivery

The effect of Lengout on labor and delivery is unknown.

8.3 Nursing Mothers

Lengout is excreted into human milk. Limited information suggests that exclusively breast-fed infants receive less than 10 percent of the maternal weight-adjusted dose. While there are no published reports of adverse effects in breast-feeding infants of mothers taking Lengout, Lengout can affect gastrointestinal cell renewal and permeability. Caution should be exercised and breast-feeding infants should be observed for adverse effects when Lengout is administered to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of Lengout in children of all ages with FMF has been evaluated in uncontrolled studies. There does not appear to be an adverse effect on growth in children with FMF treated long-term with Lengout. Gout is rare in pediatric patients, safety and effectiveness of Lengout in pediatric patients has not been established.

8.5 Geriatric Use

Clinical studies with Lengout for prophylaxis and treatment of gout flares and for treatment of FMF did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient with gout should be cautious, reflecting the greater frequency of decreased renal function, concomitant disease, or other drug therapy [see Dose Modification for Co-administration of Interacting Drugs ].

8.6 Renal Impairment

Lengout is significantly excreted in urine in healthy subjects. Clearance of Lengout is decreased in patients with impaired renal function. Total body clearance of Lengout was reduced by 75% in patients with end-stage renal disease undergoing dialysis.

Prophylaxis of Gout Flares:

For prophylaxis of gout flares in patients with mild (estimated creatinine clearance Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of Lengout. However, in patients with severe impairment, the starting dose should be 0.3 mg per day and any increase in dose should be done with close monitoring. For the prophylaxis of gout flares in patients undergoing dialysis, the starting doses should be 0.3 mg given twice a week with close monitoring [see Dose Modification in Renal Impairment (2.5) ].

Treatment of Gout Flares:

For treatment of gout flares in patients with mild (Clcr 50 – 80 mL/min) to moderate (Clcr 30 – 50 mL/min) renal function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of Lengout. However, in patients with severe impairment, while the dose does not need to be adjusted for the treatment of gout flares, a treatment course should be repeated no more than once every 2 weeks. For patients with gout flares requiring repeated courses consideration should be given to alternate therapy. For patients undergoing dialysis, the total recommended dose for the treatment of gout flares should be reduced to a single dose of 0.6 mg (1 tablet). For these patients, the treatment course should not be repeated more than once every 2 weeks [see Dose Modification in Renal Impairment (2.5) ].

FMF

Although, pharmacokinetics of Lengout in patients with mild (Clcr 50 – 80 mL/min) and moderate (Clcr 30 – 50 mL/min) renal impairment is not known, these patients should be monitored closely for adverse effects of Lengout. Dose reduction may be necessary. In patients with severe renal failure (Clcr less than 30 mL/minute) and end-stage renal disease requiring dialysis, Lengout may be started at the dose of 0.3 mg/day. Any increase in dose should be done with adequate monitoring of the patient for adverse effects of Lengout [see Pharmacokinetics (12.3) and Dose Modification in Renal Impairment (2.5) ].

8.7 Hepatic Impairment

The clearance of Lengout may be significantly reduced and plasma half-life prolonged in patients with chronic hepatic impairment, compared to healthy subjects [see Pharmacokinetics (12.3) ].

Prophylaxis of Gout Flares:

For prophylaxis of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended dose is not required, but patients should be monitored closely for adverse effects of Lengout. Dose reduction should be considered for the prophylaxis of gout flares in patients with severe hepatic impairment [see Dose Modification in Hepatic Impairment (2.6) ].

Treatment of Gout Flares:

For treatment of gout flares in patients with mild to moderate hepatic function impairment, adjustment of the recommended Lengout dose is not required, but patients should be monitored closely for adverse effects of Lengout. However, for the treatment of gout flares in patients with severe impairment while the dose does not need to be adjusted, the treatment course should be repeated no more than once every 2 weeks. For these patients, requiring repeated courses for the treatment of gout flares, consideration should be given to alternate therapy [see Dose Modification in Hepatic Impairment (2.6) ].

FMF

In patients with severe hepatic disease, dose reduction should be considered with careful monitoring [see Pharmacokinetics (12.3) and Dose Modification in Hepatic Impairment (2.6) ].

9 DRUG ABUSE AND DEPENDENCE

Tolerance, abuse, or dependence with Lengout has not been reported.

10 OVERDOSAGE

The exact dose of Lengout that produces significant toxicity is unknown. Fatalities have occurred after ingestion of a dose as low as 7 mg over a 4-day period, while other patients have survived after ingesting more than 60 mg. A review of 150 patients who overdosed on Lengout found that those who ingested less than 0.5 mg/kg survived and tended to have milder toxicities, such as gastrointestinal symptoms, whereas those who took 0.5 to 0.8 mg/kg had more severe reactions, such as myelosuppression. There was 100% mortality in those who ingested more than 0.8 mg/kg.

The first stage of acute Lengout toxicity typically begins within 24 hours of ingestion and includes gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, diarrhea, and significant fluid loss, leading to volume depletion. Peripheral leukocytosis may also be seen. Life-threatening complications occur during the second stage, which occurs 24 to 72 hours after drug administration, attributed to multi-organ failure and its consequences. Death is usually a result of respiratory depression and cardiovascular collapse. If the patient survives, recovery of multi-organ injury may be accompanied by rebound leukocytosis and alopecia starting about 1 week after the initial ingestion.

Treatment of Lengout poisoning should begin with gastric lavage and measures to prevent shock. Otherwise, treatment is symptomatic and supportive. No specific antidote is known. Lengout is not effectively removed by dialysis [see Pharmacokinetics (12.3) ].

11 DESCRIPTION

Lengout is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3, 10-tetramethoxy-9-oxobenzo [alpha] heptalen-7-yl) acetamide with a molecular formula of C22H25NO6 and a molecular weight of 399.4. The structural formula of Lengout is given below.

Lengout occurs as a pale yellow powder that is soluble in water.

Lengout® (colchicine, USP) tablets are supplied for oral administration as purple, film-coated, capsule-shaped tablets (0.1575" × 0.3030"), debossed with 'AR 374' on one side and scored on the other, containing 0.6 mg of the active ingredient Lengout USP. Inactive ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism by which Lengout exerts its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that Lengout may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. Additionally, Lengout disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules, and consequently prevents the activation, degranulation, and migration of neutrophils thought to mediate some gout symptoms.

12.3 Pharmacokinetics

Absorption

In healthy adults, Lengout is absorbed when given orally, reaching a mean Cmax of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in 1 to 2 hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.

Following oral administration of Lengout given as 1.8 mg Lengout over 1 hour to healthy, young adults under fasting conditions, Lengout appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1.0 to 2.5 hours). Following administration of the non-recommended high-dose regimen (4.8 mg over 6 hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours).

After 10 days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours post-dose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5 below.

Cmax (colchicine ng/mL) Tmax Tmax mean (range) (h) Vd/F (L) CL/F (L/hr) t1/2 (h)
CL= Dose/AUC0-t (Calculated from mean values)

Vd = CL/Ke (Calculated from mean values)

Lengout 0.6 mg Single Dose (N=13)
2.5 (28.7) 1.5 (1.0 – 3.0) 341.5 (54.4) 54.1 (31.0) --
Lengout 0.6 mg b.i.d. × 10 days (N=13)
3.6 (23.7) 1.3 (0.5 – 3.0) 1150 (18.7) 30.3 (19.0) 26.6 (16.3)

In some subjects, secondary Lengout peaks are seen, occurring between 3 and 36 hours post-dose and ranging from 39% to 155% of the height of the initial peak. These observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation.

Absolute bioavailability is reported to be approximately 45%.

Administration of Lengout with food has no effect on the rate of Lengout absorption, but did decrease the extent of Lengout by approximately 15%. This is without clinical significance.

Distribution

The mean apparent volume of distribution in healthy young volunteers was approximately 5 to 8 L/kg.

Lengout binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration.

Lengout crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration). Lengout also distributes into breast milk at concentrations similar to those found in the maternal serum [see Pregnancy (8.1) and Nursing Mothers (8.3) ].

Metabolism

Lengout is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2- and 3-DMC, respectively), and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine). In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of Lengout to 2- and 3-DMC. Plasma levels of these metabolites are minimal (less than 5% of parent drug).

Elimination/Excretion

In healthy volunteers (n=12) 40 – 65% of 1 mg orally administered Lengout was recovered unchanged in urine. Enterohepatic recirculation and biliary excretion are also postulated to play a role in Lengout elimination. Following multiple oral doses (0.6 mg twice daily), the mean elimination half-lives in young healthy volunteers (mean age 25 to 28 years of age) is 26.6 to 31.2 hours. Lengout is a substrate of P-gp.

Extracorporeal Elimination: Lengout is not removed by hemodialysis.

Special Populations

There is no difference between men and women in the pharmacokinetic disposition of Lengout.

Pediatric Patients: Pharmacokinetics of Lengout was not evaluated in pediatric patients.

Elderly: Pharmacokinetics of Lengout has not been determined in elderly patients. A published report described the pharmacokinetics of 1 mg oral Lengout tablet in four elderly women compared to six young healthy males. The mean age of the four elderly women was 83 years (range 75 – 93), mean weight was 47 kg (38 – 61 kg) and mean creatinine clearance was 46 mL/min (range 25 – 75 mL/min). Mean peak plasma levels and AUC of Lengout were two times higher in elderly subjects compared to young healthy males. However, it is possible that the higher exposure in the elderly subjects was due to decreased renal function.

Renal impairment: Pharmacokinetics of Lengout in patients with mild and moderate renal impairment is not known. A published report described the disposition of Lengout (1 mg) in young adult men and women with FMF who had normal renal function or end-stage renal disease requiring dialysis. Patients with end-stage renal disease had 75% lower Lengout clearance (0.17 vs 0.73 L/hr/kg) and prolonged plasma elimination half-life (18.8 hrs vs 4.4 hrs) as compared to subjects with FMF and normal renal function [see Dose Modification in Renal Impairment (2.5) and Renal Impairment (8.6) ].

Hepatic impairment: Published reports on the pharmacokinetics of IV Lengout in patients with severe chronic liver disease, as well as those with alcoholic or primary biliary cirrhosis, and normal renal function suggest wide inter-patient variability. In some subjects with mild to moderate cirrhosis, the clearance of Lengout is significantly reduced and plasma half-life prolonged compared to healthy subjects. In subjects with primary biliary cirrhosis, no consistent trends were noted [see Dose Modification in Hepatic Impairment (2.6) and Hepatic Impairment (8.7) ]. No pharmacokinetic data are available for patients with severe hepatic impairment (Child-Pugh C).

Drug interactions:

In vitro drug interactions:

In vitro studies in human liver microsomes have shown that Lengout is not an inhibitor or inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 activity.

In vivo drug interactions:

The effects of co-administration of other drugs with Lengout on Cmax, AUC, and Cmin are summarized in Table 6 (effect of other drugs on Lengout) and Table 7 (effect of Lengout on other drugs). For information regarding clinical recommendations, see Table 1 in Dose Modification for Co-administration of Interacting Drugs [see Dose Modification for Co-administration of Interacting Drugs (2.4) ].

Co-administered Drug Dose of Co-administered Drug (mg) Dose of Lengout (mg) N % Change in Lengout Concentrations from Baseline

(Range: Min - Max)

Cmax AUC0-t
Cyclosporine 100 mg

single-dose

0.6 mg

single-dose

23 270.0

(62.0 to 606.9)

259.0

(75.8 to 511.9)

Clarithromycin 250 mg BID,

7 days

0.6 mg

single-dose

23 227.2

(65.7 to 591.1)

281.5

(88.7 to 851.6)

Ketoconazole 200 mg BID,

5 days

0.6 mg

single-dose

24 101.7

(19.6 to 219.0)

212.2

(76.7 to 419.6)

Ritonavir 100 mg BID,

5 days

0.6 mg

single-dose

18 184.4

(79.2 to 447.4)

296.0

(53.8 to 924.4)

Verapamil 240 mg daily,

5 days

0.6 mg

single-dose

24 40.1

(-47.1 to 149.5)

103.3

(-9.8 to 217.2)

Diltiazem 240 mg daily,

7 days

0.6 mg

single-dose

20 44.2

(-46.0 to 318.3)

93.4

(-30.2 to 338.6)

Azithromycin 500 mg × 1 day, then

250 mg × 4 days

0.6 mg

single-dose

21 21.6

(-41.7 to 222.0)

57.1

(-24.3 to 241.1)

Grapefruit Juice 240 mL BID,

4 days

0.6 mg

single-dose

21 -2.55

(-53.4 to 55.0)

-2.36

(-46.4 to 62.2)


Estrogen-containing oral contraceptives: In healthy female volunteers given ethinyl estradiol and norethindrone (Ortho-Novum® 1/35) co-administered with Lengout (0.6 mg b.i.d. × 14 days), hormone concentrations are not affected.

In healthy volunteers given theophylline co-administered with Lengout (0.6 mg b.i.d. × 14 days), theophylline concentrations were not affected.

Co-administered Drug Dose of Co-administered Drug (mg) Dose of Lengout (mg) N % Change in Co-Administered Drug Concentrations from Baseline

(Range: Min - Max)

Cmax AUC0-t
Theophylline 300 mg (elixir) single-dose 0.6 mg BID × 14 days 27 1.6

(-30.4 to 23.1)

1.6

(-28.5 to 27.1)

Ethinyl Estradiol (Ortho-Novum® 1/35) 21-Day Cycle (Active Treatment) + 7-Day Placebo 0.6 mg BID × 14 days 27Conducted in healthy adult females -6.7

(-40.3 to 44.7)

-3.0AUCτ

(-25.3 to 24.9)

Norethindrone (Ortho-Novum® 1/35) 0.94

(-37.3 to 59.4)

-1.6

(-32.0 to 33.7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of Lengout have not been conducted. Due to the potential for Lengout to produce aneuploid cells (cells with an unequal number of chromosomes), there is theoretically an increased risk of malignancy.

Mutagenesis

Lengout was negative for mutagenicity in the bacterial reverse mutation assay. In a chromosomal aberration assay in cultured human white blood cells, Lengout treatment resulted in the formation of micronuclei. Since published studies demonstrated that Lengout induces aneuploidy from the process of mitotic nondisjunction without structural DNA changes, Lengout is not considered clastogenic, although micronuclei are formed.

Impairment of Fertility

No studies of Lengout effects on fertility were conducted with Lengout. However, published nonclinical studies demonstrated that colchicine-induced disruption of microtubule formation affects meiosis and mitosis. Reproductive studies also reported abnormal sperm morphology and reduced sperm counts in males, and interference with sperm penetration, second meiotic division, and normal cleavage in females when exposed to Lengout. Lengout administered to pregnant animals resulted in fetal death and teratogenicity. These effects were dose dependent, with the timing of exposure critical for the effects on embryofetal development. The nonclinical doses evaluated were generally higher than an equivalent human therapeutic dose, but safety margins for reproductive and developmental toxicity could not be determined.

Case reports and epidemiology studies in human male subjects on Lengout therapy indicated that infertility from Lengout is rare. A case report indicated that azoospermia was reversed when therapy was stopped. Case reports and epidemiology studies in female subjects on Lengout therapy have not established a clear relationship between Lengout use and female infertility. However, since the progression of FMF without treatment may result in infertility, the use of Lengout needs to be weighed against the potential risks.

14 CLINICAL STUDIES

The evidence for the efficacy of Lengout in patients with chronic gout is derived from the published literature. Two randomized clinical trials assessed the efficacy of Lengout 0.6 mg twice a day for the prophylaxis of gout flares in patients with gout initiating treatment with urate lowering therapy. In both trials, treatment with Lengout decreased the frequency of gout flares.

The efficacy of a low dosage regimen of oral Lengout (COLCRYS total dose 1.8 mg over 1 hour) for treatment of gout flares was assessed in a multicenter, randomized, double-blind, placebo-controlled, parallel group, 1 week, dose comparison study. Patients meeting American College of Rheumatology criteria for gout were randomly assigned to three groups: high-dose Lengout (1.2 mg, then 0.6 mg hourly × 6 hours [4.8 mg total]); low-dose Lengout (1.2 mg, then 0.6 mg in 1 hour [1.8 mg total] followed by 5 placebo doses hourly); or placebo (2 capsules, then 1 capsule hourly × 6 hours). Patients took the first dose within 12 hours of the onset of the flare and recorded pain intensity (11-point Likert scale) and adverse events over 72 hours. The efficacy of Lengout was measured based on response to treatment in the target joint, using patient self assessment of pain at 24 hours following the time of first dose as recorded in the diary. A responder was one who achieved at least a 50% reduction in pain score at the 24-hour post-dose assessment relative to the pre-treatment score and did not use rescue medication prior to the actual time of 24-hour post-dose assessment.

Rates of response were similar for the recommended low-dose treatment group (38%) and the non-recommended high-dose group (33%) but were higher as compared to the placebo group (16%) as shown in Table 8.

Lengout Dose Responders n (%) Placebo

n (%)

(n=58)

% Differences in Proportion
Low-dose

(n=74)

High-dose

(n=52)

Low-dose vs Placebo

(95% CI)

High-dose vs Placebo

(95% CI)

28 (38%) 17 (33%) 9 (16%) 22 (8, 37) 17 (1, 33)

Figure 1 below shows the percentage of patients achieving varying degrees of improvement in pain from baseline at 24 hours.

Figure 1

Pain Relief on Low and High Doses of Lengout and Placebo (Cumulative)


The evidence for the efficacy of Lengout in patients with FMF is derived from the published literature. Three randomized, placebo-controlled studies were identified. The three placebo-controlled studies randomized a total of 48 adult patients diagnosed with FMF and reported similar efficacy endpoints as well as inclusion and exclusion criteria.

One of the studies randomized 15 patients with FMF to a 6-month crossover study during which 5 patients discontinued due to study non-compliance. The 10 patients completing the study experienced 5 attacks over the course of 90 days while treated with Lengout compared to 59 attacks over the course of 90 days while treated with placebo. Similarly, the second study randomized 22 patients with FMF to a 4-month crossover study during which 9 patients discontinued due to lack of efficacy while receiving placebo or study non-compliance. The 13 patients completing the study experienced 18 attacks over the course of 60 days while treated with Lengout compared to 68 attacks over the course of 60 days while treated with placebo. The third study was discontinued after an interim analysis of 6 of the 11 patients enrolled had completed the study; results could not be confirmed.

Open-label experience with Lengout in adults and children with FMF is consistent with the randomized, controlled trial experience, and was utilized to support information on the safety profile of Lengout and for dosing recommendations.

Figure 1

16 HOW SUPPLIED / STORAGE AND HANDLING

16.1 How Supplied

Lengout® tablets 0.6 mg, are purple, film-coated, capsule-shaped tablets, debossed with 'AR 374' on one side and scored on the other side.

Bottles of 30 NDC 13310-119-07
Bottles of 60 NDC 13310-119-06
Bottles of 100 NDC 13310-119-01
Bottles of 250 NDC 13310-119-03
Bottles of 500 NDC 13310-119-05
Bottles of 1000 NDC 13310-119-10

16.2 Storage

Store at 20° to 25°C (68° to 77°F).

Protect from light.

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

17 PATIENT COUNSELING INFORMATION


17.1 Dosing Instructions

Patients should be advised to take Lengout as prescribed, even if they are feeling better. Patients should not alter the dose or discontinue treatment without consulting with their doctor. If a dose of Lengout is missed:

  • For treatment of a gout flare when the patient is not being dosed for prophylaxis, take the missed dose as soon as possible.
  • For treatment of a gout flare during prophylaxis, take the missed dose immediately, wait twelve hours, then resume the previous dosing schedule.
  • For prophylaxis without treatment for a gout flare, or FMF, take the dose as soon as possible and then return to the normal dosing schedule. However, if a dose is skipped the patient should not double the next dose.

17.2 Fatal Overdose

Instruct patient that fatal overdoses, both accidental and intentional, have been reported in adults and children who have ingested Lengout. Lengout should be kept out of the reach of children.

17.3 Blood Dyscrasias

Patients should be informed that bone marrow depression with agranulocytosis, aplastic anemia, and thrombocytopenia may occur with Lengout.

17.4 Drug and Food Interactions

Patients should be advised that many drugs or other substances may interact with Lengout and some interactions could be fatal. Therefore, patients should report to their healthcare provider all of the current medications they are taking, and check with their healthcare provider before starting any new medications, particularly antibiotics. Patients should also be advised to report the use of non-prescription medication or herbal products. Grapefruit and grapefruit juice may also interact and should not be consumed during Lengout treatment.

17.5 Neuromuscular Toxicity

Patients should be informed that muscle pain or weakness, tingling or numbness in fingers or toes may occur with Lengout alone or when it is used with certain other drugs. Patients developing any of these signs or symptoms must discontinue Lengout and seek medical evaluation immediately.

17.6 Medication Guide

Lengout® is a registered U.S. trademark of the URL Pharma, Inc. group of companies. © 2009 AR Holding Company, Inc., a URL Pharma, Inc. company

U.S. Patent Nos. 7,601,758; 7,619,004 and other patents pending

Manufactured for:

AR SCIENTIFIC, INC.

Philadelphia, PA 19124 USA

by:

MUTUAL PHARMACEUTICAL COMPANY, INC.

Philadelphia, PA 19124 USA

Rev 14, March 2012

MEDICATION GUIDE

Lengout

(KOL-kris)

(colchicine) tablets

Read the Medication Guide that comes with Lengout before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about Lengout when you start taking it and at regular checkups.

What is the most important information I should know about Lengout?

Lengout can cause serious side effects or death if levels of Lengout are too high in your body.

  • Taking certain medicines with Lengout can cause your level of Lengout to be too high, especially if you have kidney or liver problems.
  • Tell your healthcare provider about all your medical conditions, including if you have kidney or liver problems. Your dose of Lengout may need to be changed.
  • Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.
  • Even medicines that you take for a short period of time, such as antibiotics, can interact with Lengout and cause serious side effects or death.
  • Talk to your healthcare provider or pharmacist before taking any new medicine.
  • Especially tell your healthcare provider if you take:
  • atazanavir sulfate (Reyataz®)
  • cyclosporine (Neoral®, Gengraf®, Sandimmune®)
  • fosamprenavir (Lexiva®) with ritonavir
  • indinavir (Crixivan®)
  • ketoconazole (Nizoral®)
  • nefazodone (Serzone®)
  • ritonavir (Norvir®)
  • telithromycin (Ketek®)
  • clarithromycin (Biaxin®)
  • darunavir (Prezista®)
  • fosamprenavir (Lexiva®)
  • itraconazole (Sporanox®)
  • lopinavir/ritonavir (Kaletra®)
  • nelfinavir mesylate (Viracept®)
  • saquinavir mesylate (Invirase®)
  • tipranavir (Aptivus®)

Ask your healthcare provider or pharmacist if you are not sure if you take any of the medicines listed above. This is not a complete list of all the medicines that can interact with Lengout.

  • Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
  • Keep Lengout out of the reach of children.

What is Lengout?

Lengout is a prescription medicine used to:

  • prevent and treat gout flares in adults
  • treat familial Mediterranean fever (FMF) in adults and children age four or older

Lengout is not a pain medicine and it should not be taken to treat pain related to other conditions unless specifically prescribed for those conditions.

Who should not take Lengout?

Do not take Lengout if you have liver or kidney problems and you take certain other medicines. Serious side effects, including death, have been reported in these patients even when taken as directed. See "What is the most important information I should know about Lengout?"

What should I tell my healthcare provider before starting Lengout?

See "What is the most important information I should know about Lengout?"

Before you take Lengout tell your healthcare provider about all your medical conditions including if you:

  • have liver or kidney problems
  • are pregnant or plan to become pregnant. It is not known if Lengout will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
  • are breast-feeding or plan to breast-feed. Lengout passes into your breast milk. You and your healthcare provider should decide if you will take Lengout or breast-feed. If you take Lengout and breast-feed, you should talk to your child's healthcare provider about how to watch for side effects in your child.

Tell your healthcare provider about all the medicines you take, including ones that you may only be taking for a short time, such as antibiotics. See "What is the most important information I should know about Lengout?" Do not start a new medicine without talking to your healthcare provider.

Using Lengout with certain other medicines, such as cholesterol-lowering medications and digoxin, can affect each other causing serious side effects. Your healthcare provider may need to change your dose of Lengout. Talk to your healthcare provider about whether the medications you are taking might interact with Lengout, and what side effects to look for.

How should I take Lengout?

  • Take Lengout exactly as your healthcare provider tells you to take it. If you are not sure about your dosing, call your healthcare provider.
  • Lengout can be taken with or without food.
  • If you take too much Lengout go to the nearest hospital emergency room right away.
  • Do not stop taking Lengout even if you start to feel better, unless your healthcare provider tells you.
  • Your healthcare provider may do blood tests while you take Lengout.
  • If you take Lengout daily and you miss a dose, then take it as soon as you remember. If it is almost time for your next dose, just skip the missed dose. Take the next dose at your regular time. Do not take 2 doses at the same time.
  • If you have a gout flare while taking Lengout daily, report this to your healthcare provider.

What should I avoid while taking Lengout?

  • Avoid eating grapefruit or drinking grapefruit juice while taking Lengout. It can increase your chances of getting serious side effects.

What are the possible side effects of Lengout?

Lengout can cause serious side effects or even cause death. See "What is the most important information I should know about Lengout?"

Get medical help right away, if you have:

    • Muscle weakness or pain
    • Numbness or tingling in your fingers or toes
    • Unusual bleeding or bruising
    • Increased infections
    • Feel weak or tired
    • Pale or gray color to your lips, tongue, or palms of your hands
    • Severe diarrhea or vomiting

Gout Flares: The most common side effect of Lengout in people who have gout flares is diarrhea.

FMF: The most common side effects of Lengout in people who have FMF are abdominal pain, diarrhea, nausea and vomiting.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Lengout. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Lengout?

  • Store Lengout at room temperature between 68° and 77°F (20° to 25°C).
  • Keep Lengout in a tightly closed container.
  • Keep Lengout out of the light.

Keep Lengout and all medicines out of the reach of children.

General Information about Lengout

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Lengout for a condition for which it was not prescribed. Do not give Lengout to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about Lengout. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Lengout that is written for healthcare professionals.

For more information, go to www. COLCRYS.com or call 1-888-351-3786.

What are the ingredients in Lengout?

Active Ingredient: Lengout

Inactive Ingredients: carnauba wax, FD&C blue #2, FD&C red #40, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, titanium dioxide, and triacetin.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Lengout® is a registered U.S. trademark of the URL Pharma, Inc. group of companies. © 2009 AR Holding Company, Inc., a URL Pharma, Inc. company

U.S. Patent Nos. 7,601,758; 7,619,004 and other patents pending

Manufactured for:

AR SCIENTIFIC, INC.

Philadelphia, PA 19124 USA

by:

MUTUAL PHARMACEUTICAL COMPANY, INC.

Rev 14, March 2012

PRINCIPAL DISPLAY PANEL - 0.6 mg Tablet Bottle Label

100 TABLETS

NDC 13310-119-01

Lengout®

(colchicine, USP) tablets

0.6 mg

PHARMACIST:

PLEASE DISPENSE WITH

MEDICATION GUIDE ATTACHED

AR

SCIENTIFIC

Rx only

Lengout pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Lengout available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Lengout destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Lengout Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Lengout pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."COLCRYS (COLCHICINE) TABLET, FILM COATED [AR SCIENTIFIC INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."COLCHICINE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "colchicine". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Lengout?

Depending on the reaction of the Lengout after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Lengout not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Lengout addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Lengout, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Lengout consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Lengout drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 1-5mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
1-5mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

Visitor reported administration

No survey data has been collected yet

One visitor reported age

Visitors%
46-601
100.0%

Visitor reviews


There are no reviews yet. Be the first to write one!


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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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