DALIRESP® (roflumilast) tablets

DALIRESP® (roflumilast) tablets

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DALIRESP® (roflumilast) tablets

The active ingredient in DALIRESP tablets is roflumilast. Roflumilast and its active metabolite (roflumilast Noxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its empirical formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22.

Indications and usage

DALIRESP is a selective phosphodiesterase 4 inhibitor indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.

Limitations of Use:

  • DALIRESP is not a bronchodilator and is not indicated for the relief of acute bronchospasm.
  • DALIRESP 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose

Mechanism of Action

Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which DALIRESP exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.

Dosage and administration

The maintenance dose of DALIRESP is one 500 micrograms (mcg) tablet per day, with or without food.

Starting treatment with a dose of DALIRESP 250 mcg once daily for 4 weeks and increasing to DALIRESP 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients. However, 250 mcg per day is not the effective (therapeutic) dose.

Contraindications

The use of DALIRESP is contraindicated in the following condition: Moderate to severe liver impairment (Child-Pugh B or C)

Warnings and precautions

Treatment of Acute Bronchospasm: DALIRESP is not a bronchodilator and should not be used for the relief of acute bronchospasm.

Psychiatric Events including Suicidality: Before using DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with DALIRESP in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with DALIRESP if such events occur.

Weight Decrease: Patients treated with DALIRESP should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of DALIRESP should be considered.

Drug Interactions: A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease in the therapeutic effectiveness of DALIRESP. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with DALIRESP is not recommended

Drug interactions

Drugs that Induce Cytochrome P450 (CYP) Enzymes: Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of DALIRESP. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with DALIRESP is not recommended

Drugs that Inhibit Cytochrome P450 (CYP) Enzymes: The co-administration of DALIRESP (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit

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Oral Contraceptives Containing Gestodene and Ethinyl Estradiol: The co-administration of DALIRESP (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit

Use in specific populations

Pregnancy: There are no randomized clinical studies of DALIRESP in pregnant women.

DALIRESP should not be used during labor and delivery. There are no human studies that have investigated effects of DALIRESP on preterm labor or labor at term; however, animal studies showed that DALIRESP disrupted the labor and delivery process in mice.

Lactation: There is no information regarding the presence of DALIRESP in human milk, the effects on the breastfed infant, or the effects on milk production.

Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. DALIRESP should not be used by women who are nursing.

Pediatric Use: COPD does not normally occur in children. The safety and effectiveness of DALIRESP in pediatric patients have not been established.

Hepatic Impairment: Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively, in Child-Pugh A subjects and by 92% and 41%, respectively, in Child-Pugh B subjects, as compared to age-, weight-, and gender-matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. DALIRESP 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering DALIRESP to patients who have mild liver impairment (Child-Pugh A). DALIRESP is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C)

Renal Impairment: In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment

Overdosage

No case of overdose has been reported in clinical studies with DALIRESP. During the Phase I studies of DALIRESP, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess, and arterial hypotension.

Management of Overdose

In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis.

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