Phosphodiesterase 4 Inhibitor

Roflumilast

Approved 23 Nov 2018OralTablet

The FDA lists this product in 20 strengths and forms.

Indications

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

Roflumilast tablet 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 tablet is not a bronchodilator and is not indicated for the relief of acute bronchospasm. (1 , 14)
Roﬂumilast tablet 250 mcg is a starting dose, for the ﬁrst 4 weeks of treatment only and is not the effective (therapeutic) dose. ( 2 , 14 )

Contraindications

The use of roflumilast tablet is 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)

Warnings and precautions

Acute Bronchospasm: Do not use for the relief of acute bronchospasm. (5.1)
Psychiatric Events including Suicidality: Advise patients, their caregivers, and families 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. Carefully weigh the risks and benefits of treatment with roflumilast in patients with a history of depression and/or suicidal thoughts or behavior. (5.2)
Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of roflumilast. (5.3)

Indications

Roflumilast tablet is not a bronchodilator and is not indicated for the relief of acute bronchospasm. (1 , 14)
Roﬂumilast tablet 250 mcg is a starting dose, for the ﬁrst 4 weeks of treatment only and is not the effective (therapeutic) dose. ( 2 , 14 )

Warnings and precautions

Acute Bronchospasm: Do not use for the relief of acute bronchospasm. (5.1)
Psychiatric Events including Suicidality: Advise patients, their caregivers, and families 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. Carefully weigh the risks and benefits of treatment with roflumilast in patients with a history of depression and/or suicidal thoughts or behavior. (5.2)
Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of roflumilast. (5.3)

Pregnancy and breastfeeding

8.1Pregnancy 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 orally with up to 1.8 mg/kg/day roflumilast for 10 weeks and females for two weeks prior to pairing and throughout the organogenesis period. Roflumilast induced pre- and post-implantation loss at doses greater than or equal to approximately 10 times the MRHD (on a mg/m 2 basis at maternal oral doses greater than or equal to 0.6 mg/kg/day). Roflumilast did not cause fetal structural abnormalities at exposures up to approximately 29 times the MRHD (on an AUC basis at maternal oral doses up to 1.8 mg/kg/day).

In an embryo-fetal development study in rabbits, pregnant does were dosed orally with 0.8 mg/kg/day roflumilast during the period of organogenesis. Roflumilast did not cause fetal structural abnormalities at exposures approximately 26 times the MRHD (on a mg/m 2 basis at maternal oral doses of 0.8 mg/kg/day). In pre- and post-natal developmental studies in mice, dams were dosed orally with up to 12 mg/kg/day roflumilast during the period of organogenesis and lactation.

Roflumilast induced stillbirth and decreased pup viability at doses corresponding to approximately 16 and 49 times, respectively, the MRHD (on a mg/m 2 basis at maternal doses >2 mg/kg/day and 6 mg/kg/day, respectively). Roflumilast induced delivery retardation in pregnant mice at doses greater or equal to approximately 16 times the MRHD (on a mg/m 2 basis at maternal doses >2 mg/kg/day). Roflumilast decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/m 2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation.

Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m 2 basis at a maternal dose of 12 mg/kg/day).

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 Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Adverse 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) Decreasedappetite 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.

6.2Postmarketing 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.

Roflumilast

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Roflumilast

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

5.1Treatment of Acute Bronchospasm

5.2Psychiatric

5.3Weight Decrease

5.4Drug Interactions

Interactions

7.3Oral Contraceptives Containing Gestodene and Ethinyl Estradiol

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Adverse Reactions in Clinical Studies

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information

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