Roflumilast
FDA Drug Information • Also known as: Daliresp, Roflumilast, Zoryve
- Brand Names
- Daliresp, Roflumilast, Zoryve
- Dosage Form
- POWDER
- Product Type
- BULK INGREDIENT
Description
11 DESCRIPTION The active ingredient in roflumilast tablets is roflumilast, USP. Roflumilast and its active metabolite (roflumilast N-oxide) 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 C 17 H 14 Cl 2 F 2 N 2 O 3 and the molecular weight is 403.22. The chemical structure is: The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is freely soluble in acetone, sparingly to slightly soluble in ethanol and practically insoluble in n-Hexane and in water. Roflumilast, USP is supplied as white to off-white, round tablets, flat faced beveled edge, debossed with “T” and “250” or “500” on one side and plain on the other side. Each tablet contains 250 mcg or 500 mcg of roflumilast, USP. Each tablet of roflumilast for oral administration contains the following inactive ingredients: corn starch, hypromellose, lactose monohydrate, magnesium stearate and poloxamer. Chemical Structure
What Is Roflumilast Used For?
1 INDICATIONS AND USAGE Roflumilast tablets are 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 Roflumilast tablets are not a bronchodilator and is not indicated for the relief of acute bronchospasm. Roflumilast tablets 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose. Roflumilast 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. ( 1 , 14 ) Limitations of Use: Roflumilast tablets are not a bronchodilator and is not indicated for the relief of acute bronchospasm. ( 1 , 14 ) Roflumilast tablets 250 mcg is a starting dose, for the first 4 weeks of treatment only and is not the effective (therapeutic) dose. ( 2 , 14 )
Dosage and Administration
2 DOSAGE AND ADMINISTRATION The maintenance dose of roflumilast tablet is one 500 micrograms (mcg) tablet per day, with or without food. Starting treatment with a dose of roflumilast tablets 250 mcg once daily for 4 weeks and increasing to roflumilast tablets 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients [see Clinical Studies (14.1) ]. However, 250 mcg per day is not the effective (therapeutic) dose. The maintenance dose for patients with COPD is one 500 mcg tablet per day, with or without food. Starting treatment with a dose of roflumilast tablets 250 mcg once daily for 4 weeks and increasing to roflumilast tablets 500 mcg once daily thereafter may reduce the rate of treatment discontinuation in some patients. ( 2 )
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Psychiatric Events Including Suicidality [see Warnings and Precautions (5.2) ] Weight Decrease [see Warnings and Precautions (5.3) ] Most common adverse reactions (≥2%) are diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness and decreased appetite. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adverse Reactions in Clinical Studies Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflect exposure of 4438 patients to roflumilast 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials [see Clinical Studies (14.1) ]. In these trials, 3136 and 1232 COPD patients were exposed to roflumilast 500 mcg once daily for 6 months and 1 year, respectively. The population had a median age of 64 years (range 40 to 91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV 1 ) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with roflumilast reported an adverse reaction compared with 65.3% treated with placebo. The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for roflumilast-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of roflumilast were diarrhea (2.4%) and nausea (1.6%). Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in roflumilast-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure. Table 1 summarizes the adverse reactions reported by ≥2% of patients in the roflumilast group in 8 controlled COPD clinical trials. Table 1: Adverse Reactions Reported by ≥2% of Patients Treated with Roflumilast 500 mcg daily and Greater Than Placebo Treatment Adverse Reactions (Preferred Term) Roflumilast Placebo (N=4438) (N=4192) n (%) n (%) Diarrhea 420 (9.5) 113 (2.7) Weight decreased 331 (7.5) 89 (2.1) Nausea 209 (4.7) 60 (1.4) Headache 195 (4.4) 87 (2.1) Back pain 142 (3.2) 92 (2.2) Influenza 124 (2.8) 112 (2.7) Insomnia 105 (2.4) 41 (1.0) Dizziness 92 (2.1) 45 (1.1) Decreased appetite 91 (2.1) 15 (0.4) Adverse reactions that occurred in the roflumilast group at a frequency of 1 to 2% where rates exceeded that in the placebo group include: Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting Infections and infestations - rhinitis, sinusitis, urinary tract infection Musculoskeletal and connective tissue disorders - muscle spasms Nervous system disorders - tremor Psychiatric disorders - anxiety, depression The safety profile of roflumilast reported during Trial 9 was consistent with the key pivotal studies. 6.2 Postmarketing Experience The following adverse reactions have been identified from spontaneous reports of roflumilast received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to roflumilast. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to roflumilast exposure: hypersensitivity reactions (including angioedema, urticaria, and rash), gynecomastia.
Drug Interactions
7 DRUG INTERACTIONS A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 [see Clinical Pharmacology (12.3) ] . Use with inhibitors of CYP3A4 or dual inhibitors of CYP3A4 and CYP1A2 (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) will increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit. ( 7.2 ) 7.1 Drugs that Induce Cytochrome P450 (CYP) Enzymes Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of roflumilast. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with roflumilast is not recommended [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ]. 7.2 Drugs that Inhibit Cytochrome P450 (CYP) Enzymes The co-administration of roflumilast (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 [see Clinical Pharmacology (12.3) ]. 7.3 Oral Contraceptives Containing Gestodene and Ethinyl Estradiol The co-administration of roflumilast (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 [see Clinical Pharmacology (12.3) ].
Contraindications
4 CONTRAINDICATIONS The use of roflumilast tablets are contraindicated in the following condition: Moderate to severe liver impairment (Child-Pugh B or C) [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6) ] . Moderate to severe liver impairment (Child-Pugh B or C) ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no randomized clinical studies of roflumilast in pregnant women. In animal reproductive toxicity studies, roflumilast administered to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities. The highest roflumilast dose in these studies was approximately 30 and 26 times, respectively, the maximum recommended human dose (MRHD). Roflumilast induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD. Roflumilast induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the MRHD. Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice at doses corresponding to 49 times the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Labor and delivery Roflumilast should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast on preterm labor or labor at term; however, animal studies showed that roflumilast disrupted the labor and delivery process in mice. Data Animal data In an embryo-fetal development study, pregnant rats were dosed orally during the period of organogenesis with up to 1.8 mg/kg/day roflumilast (approximately 30 times the MRHD on an AUC basis). No evidence of structural abnormalities or effects on survival rates were observed. Roflumilast did not affect embryo-fetal development at approximately 3 times the MRHD (on a mg/m 2 basis at a maternal oral dose of 0.2 mg/kg/day). In a fertility and embryo-fetal development study, male rats were dosed...
Overdosage
10 OVERDOSAGE 10.1 Human Experience No case of overdose has been reported in clinical studies with roflumilast. During the Phase I studies of roflumilast, 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. 10.2 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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Roflumilast tablets, 250 mcg are supplied as white to off-white, round tablets, flat faced beveled edge, debossed with “T” and “250” on one side and plain on the other side. Roflumilast 250 mcg tablets are available: Blister pack 28 NDC 59651-801-28 1X20 Unit Dose NDC 59651-801-20 Roflumilast tablets, 500 mcg are supplied as white to off-white, round tablets, flat faced beveled edge, debossed with “T” and “500” on one side and plain on the other side. Roflumilast 500 mcg tablets are available: Bottles of 30 NDC 59651-275-30 Bottles of 90 NDC 59651-275-90 16.2 Storage and Handling Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.