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brand daliresp 500 mcg tablet

In stock Manufacturer ASTRAZENECA 00310009530
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Uses

Bronchospasm

Chronic Obstructive Pulmonary Disease

Roflumilast is used to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm. The effects of roflumilast on COPD exacerbations when added to a fixed-combination preparation containing a long-acting β2-adrenergic agonist and orally inhaled corticosteroid have not been established.

Safety and efficacy of roflumilast have been evaluated in 8 randomized, double-blind, placebo- and active-controlled studies in adults 40 years of age or older with COPD. Data from two 6-month, placebo-controlled, dose-selection studies in patients with COPD of varying severity (forced expiratory volume in 1 second [FEV1] 30-80% of predicted) resulted in a roflumilast dosage of 500 mcg once daily being selected, based mainly based on improvements in lung function (e.g., FEV1) observed with this dosage compared with roflumilast 250 mcg once daily.

The effect of roflumilast 500 mcg once daily on COPD exacerbations has been evaluated in four 1-year, placebo-controlled studies in patients with severe COPD (FEV1 50% of predicted or less). In the first 2 studies, roflumilast did not substantially reduce the rate of moderate (defined as requiring systemic corticosteroids and/or antibiotics) or severe (defined as resulting in hospitalization and/or death) COPD exacerbations compared with placebo. However, based on results of exploratory analyses of these studies, some patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year appeared to have a greater reduction in the incidence of COPD exacerbations compared with the overall study population. In 2 subsequent studies in patients with severe COPD associated with chronic bronchitis who had at least one COPD exacerbation in the previous year and a history of smoking (20 pack-years or more), roflumilast reduced the incidence of moderate (defined as requiring systemic corticosteroids) or severe (defined as resulting in hospitalization and/or death) exacerbations compared with placebo. In addition, in patients receiving concomitant long-acting β2-adrenergic agonists or short-acting antimuscarinics in these studies, the reduction in moderate or severe COPD exacerbations with roflumilast was similar to that observed in the overall study populations.

While roflumilast is not a bronchodilator, the previous four 1-year studies also evaluated the effect of roflumilast on lung function (as determined by change in pre- or post-bronchodilator FEV1). In these studies, roflumilast 500 mcg once daily improved lung function compared with placebo. In addition, in two 6-month comparative studies in patients with moderate or severe COPD (FEV1 40-70% of predicted) receiving either roflumilast (500 mcg once daily) or placebo as add-on therapy to treatment with salmeterol or tiotropium, roflumilast improved lung function (as determined by mean change in prebronchodilator FEV1) compared with placebo.

For additional information on the treatment of COPD,

Dosage and Administration

Administration

Roflumilast is administered orally once daily without regard to meals.

Dosage

The recommended adult dosage of roflumilast to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations is 500 mcg once daily.

Special Populations

Clinicians should consider the risks and benefits of using roflumilast in patients with mild hepatic impairment (Child-Pugh class A). Roflumilast is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).(See Cautions: Contraindications and also see Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not necessary in geriatric patients or patients with renal impairment. In addition, dosage adjustment is not necessary based on gender or race.

Cautions

Contraindications

Moderate or severe hepatic impairment (Child-Pugh class B or C).(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Warnings/Precautions

Acute Bronchospasm

Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.

Psychiatric Events and Suicidality

Roflumilast therapy is associated with an increase in adverse psychiatric effects. Adverse psychiatric effects were reported in 5.9% of patients receiving roflumilast (500 mcg once daily) compared with 3.3% of those receiving placebo in clinical studies. The most frequently reported adverse psychiatric effects were insomnia, anxiety, and depression, which were reported at an increased incidence in patients receiving roflumilast compared with placebo (2.4, 1.4, and 1.2% versus 1, 0.9, and 0.9%, respectively). Suicidal ideation or behavior, including completed suicide, has been observed in clinical studies. Three patients experienced suicide-related adverse effects while receiving roflumilast (one completed suicide and two suicide attempts) compared with one patient who received placebo (suicidal ideation).

Clinicians should carefully weigh the risks and benefits of roflumilast therapy before using the drug in patients with a history of depression and/or suicidal thoughts or behavior. In addition, clinicians should carefully evaluate the risks and benefits of continuing therapy with roflumilast if such effects occur. Some clinicians state that roflumilast should be avoided in patients with depression.(See Advice to Patients.)

Weight Loss

Weight loss was reported in clinical studies in 7.5% of patients receiving roflumilast (500 mcg once daily) compared with 2.1% of those receiving placebo. In addition to being reported as an adverse effect, weight loss was prospectively evaluated in 2 placebo-controlled studies of 1 year's duration. In these studies, moderate (5-10% of body weight) or severe (greater than 10% of body weight) weight loss was reported in 20 or 7%, respectively, of patients receiving roflumilast compared with 7 or 2%, respectively, of those receiving placebo. Most patients with decreased body weight during roflumilast therapy regained some of the lost weight after treatment discontinuance.

Weight should be regularly monitored in patients receiving roflumilast. If unexplained or clinically important weight loss occurs, decreased body weight should be evaluated and discontinuance of roflumilast should be considered. Some clinicians advise that roflumilast therapy be avoided in underweight patients.

Interactions

Concomitant use of roflumilast with potent cytochrome P-450 (CYP) isoenzyme 3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) is not recommended.(See Drug Interactions.)

Specific Populations

Pregnancy

Category C.

Roflumilast should not be used during labor and delivery. The effect of roflumilast on preterm labor or labor at term in humans is unknown; however, disruption of labor and delivery has occurred in animals receiving the drug.

Lactation

Roflumilast and/or its metabolites are distributed into milk in rats. Roflumilast and/or its metabolites are likely distributed into human milk. The effects of roflumilast on breast-fed infants have not been established. Roflumilast should not be used in nursing women.

Pediatric Use

Safety and efficacy of roflumilast have not been established in pediatric patients; chronic obstructive pulmonary disease (COPD) does not occur in children.

Geriatric Use

Approximately 46% of patients with COPD who received roflumilast in clinical studies have been older than 65 years of age and about 11% have been older than 75 years of age. Although no substantial differences in safety and efficacy relative to younger adults have been observed, and other clinical experience revealed no evidence of age-related differences, the possibility of increased sensitivity in some older patients cannot be ruled out. Dosage adjustment is not necessary in geriatric patients.

Hepatic Impairment

In a pharmacokinetic study evaluating a roflumilast dosage of 250 mcg once daily for 14 days, areas under the plasma concentration-time curve (AUCs) of roflumilast and roflumilast N-oxide were 51 and 24% higher, respectively, in individuals with mild hepatic impairment (Child-Pugh class A) and 92 and 41% higher, respectively, in individuals with moderate hepatic impairment (Child-Pugh class B) compared with values in healthy individuals matched for age, weight, and gender. Peak plasma concentrations of roflumilast and roflumilast N-oxide were 3 and 26% higher, respectively, in individuals with mild hepatic impairment and 26 and 40% higher, respectively, in individuals with moderate hepatic impairment compared with values for healthy individuals matched for age, weight, and gender. A roflumilast dosage of 500 mcg once daily has not been studied in patients with hepatic impairment.

Clinicians should consider the risks and benefits of using roflumilast in patients with mild hepatic impairment (Child-Pugh class A). Roflumilast is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

After administration of a single 500-mcg dose of roflumilast to individuals with severe renal impairment, AUCs of roflumilast and roflumilast N-oxide were reduced by 21 and 7%, respectively, and peak plasma concentrations were reduced by 16 and 12%, respectively. Dosage adjustment is not necessary in patients with renal impairment.

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving roflumilast include diarrhea, weight loss, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite.

Drug Interactions

In vitro, roflumilast and roflumilast N-oxide do not inhibit the P-glycoprotein transport system.

Drugs Affecting Hepatic Microsomal Enzymes

A major pathway for roflumilast metabolism is pyridine N-oxidation of roflumilast to roflumilast N-oxide by cytochrome P-450 (CYP) isoenzymes 3A4 and 1A2. Roflumilast N-oxide is O-dealkylated mainly by CYP3A4, and to a lesser extent by CYP2C19 and extrahepatic CYP1A, and glucuronidated.

Potent CYP3A4 inducers decrease systemic exposure to roflumilast and may reduce the therapeutic efficacy of the drug. Therefore, concomitant use of potent CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin) with roflumilast is not recommended.

Concomitant administration of agents that inhibit CYP3A4 or inhibit both CYP3A4 and CYP1A2 (e.g., cimetidine, enoxacin [no longer commercially available in the US], erythromycin, fluvoxamine, ketoconazole) may increase systemic exposure to roflumilast and may result in increased adverse effects. The risk of such concurrent use should be weighed carefully against the benefit.

Drugs Metabolized by Hepatic Microsomal Enzymes

In vitro, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11; clinically important pharmacokinetic interactions with drugs metabolized by these isoenzymes are unlikely. In vitro, roflumilast does not induce CYP isoenzymes 1A2, 2A6, 2C9, 2C19, or 3A4/5 and is a weak inducer of CYP2B6.

Albuterol

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with orally inhaled albuterol; no dosage adjustment is recommended.

Antacids

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with an aluminum and magnesium hydroxides antacid; no dosage adjustment is recommended.

Budesonide

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with orally inhaled budesonide; no dosage adjustment is recommended.

Cimetidine

Concomitant administration of cimetidine (400 mg twice daily for 7 days), a dual CYP3A4 and CYP1A2 inhibitor, and roflumilast (single 500-mcg dose) increased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of roflumilast by 46 and 85%, respectively, and decreased peak plasma concentrations and increased AUC of roflumilast N-oxide by 4 and 27%, respectively. Roflumilast and cimetidine should be used concomitantly with caution; the risk of such concurrent use should be weighed carefully against the benefit.

Digoxin

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with oral digoxin; no dosage adjustment is recommended.

Enoxacin

Concomitant administration of enoxacin (400 mg twice daily for 12 days; no longer commercially available in the US), a dual CYP3A4 and CYP1A2 inhibitor, and roflumilast (single 500-mcg dose) increased peak plasma concentrations and AUC of roflumilast by 20 and 56%, respectively, and decreased peak plasma concentrations and increased AUC of roflumilast N-oxide by 14 and 23%, respectively. Roflumilast and enoxacin should be used concomitantly with caution; the risk of such concurrent use should be weighed carefully against the benefit.

Erythromycin

Concomitant administration of erythromycin (500 mg three times daily for 13 days), a CYP3A4 inhibitor, and roflumilast (single 500-mcg dose) increased peak plasma concentrations and AUC of roflumilast by 40 and 70%, respectively, and decreased peak plasma concentrations and increased AUC of roflumilast N-oxide by 34 and 4%, respectively. Roflumilast and erythromycin should be used concomitantly with caution; the risk of such concurrent use should be weighed carefully against the benefit.

Fluvoxamine

Concomitant administration of fluvoxamine (50 mg daily for 14 days), a dual CYP3A4 and CYP1A2 inhibitor, and roflumilast (single 500-mcg dose) increased peak plasma concentrations and AUC of roflumilast by 12 and 156%, respectively, and decreased peak plasma concentrations and increased AUC of roflumilast N-oxide by 210 and 52%, respectively. Roflumilast and fluvoxamine should be used concomitantly with caution; the risk of such concurrent use should be weighed carefully against the benefit.

Formoterol

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with orally inhaled formoterol; no dosage adjustment is recommended.

Ketoconazole

Concomitant administration of ketoconazole (200 mg twice daily for 13 days), a potent CYP3A4 inhibitor, and roflumilast (single 500-mcg dose) increased peak plasma concentrations and AUC of roflumilast by 23 and 99%, respectively, and decreased peak plasma concentrations and increased AUC of roflumilast N-oxide by 38 and 3%, respectively. Roflumilast and ketoconazole should be used concomitantly with caution; the risk of such concurrent use should be weighed carefully against the benefit.

Midazolam

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with oral midazolam; no dosage adjustment is recommended.

Montelukast

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with oral montelukast; no dosage adjustment is recommended.

Oral Contraceptives

Concomitant administration of roflumilast and oral contraceptives containing gestodene (not commercially available in the US) and ethinyl estradiol may increase systemic exposure to roflumilast and may increase the risk of adverse effects. Concomitant administration of the fixed-combination preparation containing 0.075 mg of gestodene and 0.03 mg of ethinyl estradiol daily and roflumilast (single 500-mcg dose) increased peak plasma concentrations and AUC of roflumilast by 38 and 51%, respectively, and decreased peak plasma concentrations and increased AUC of roflumilast N-oxide by 12 and 14%, respectively. Roflumilast and contraceptives containing gestodene and ethinyl estradiol should be used concomitantly with caution; the risk of such concurrent use should be weighed carefully against the benefit.

Rifampin

Potent CYP inducers decrease systemic exposure to roflumilast and may reduce the therapeutic efficacy of roflumilast. Concomitant administration of rifampin (600 mg daily for 11 days), a potent CYP3A4 inducer, and roflumilast (single 500-mcg dose) decreased peak plasma concentrations and AUC of roflumilast by 68 and 79%, respectively, and increased peak plasma concentrations and decreased AUC of roflumilast N-oxide by 30 and 56%, respectively. Concomitant use is not recommended.

Sildenafil

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with oral sildenafil; no dosage adjustment is recommended.

Theophylline

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with oral theophylline; no dosage adjustment is recommended. However, some clinicians do not recommend concomitant administration of roflumilast with theophylline.

Warfarin

No clinically important pharmacokinetic interactions were observed when roflumilast was administered concomitantly with oral warfarin; no dosage adjustment is recommended.

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