Roflumilast

ROFLUMILAST — roflumilast tablet
Novadoz Pharmaceuticals LLC

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.

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 Tablet 250 mcg once daily for 4 weeks and increasing to Roflumilast Tablet 500 mcg once daily thereaftermay 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.

3 DOSAGE FORMS AND STRENGTHS


  • Roflumilast 250 mcg tablets are white to off-white, round, flat face bevel edged, uncoated tablets, debossed with “R” on one side and “0.25” on the other side
  • Roflumilast 500 mcg tablets are white to off-white, round, flat face bevel edged, uncoated tablets, debossed with “R” on one side and “0.5” on the other side

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Treatment of Acute Bronchospasm

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

5.2 Psychiatric Events including Suicidality


Treatment with Roflumilast Tablets are associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with Roflumilast Tablets 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with Roflumilast Tablets 500 mcg daily (2.4%, 1.4%, and 1.2% for Roflumilast Tablets versus 1.0%, 0.9%, and 0.9% for placebo, respectively) [see Adverse Reactions (6.1)]. Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving Roflumilast Tablets compared to one patient (suicidal ideation) who received placebo.
One patient completed suicide while receiving Roflumilast Tablets in Trial 9 [see Clinical Studies (14.1)] , which assessed the effect of adding roflumilast to a fixed-dose combination (FDC) of ICS/LABA on rates of exacerbations in COPD patients over 1 year of treatment. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression.
Before using Roflumilast Tablets in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with Roflumilast Tablets 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 Roflumilast Tablets if such events occur.

5.3 Weight Decrease

Weight loss was a common adverse reaction in Roflumilast Tablets clinical trials and was reported in 7.5% (331) of patients treated with Roflumilast Tablets 500 mcg once daily compared to 2.1% (89) treated with placebo [see Adverse Reactions ( 6.1)]. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving Roflumilast Tablets. Patients treated with Roflumilast Tablets should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of Roflumilast Tablets should be considered.

5.4 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 Roflumilast Tablets. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) with Roflumilast Tablets are not recommended [see Drug interactions (7.1)and Clinical Pharmacology (12.3)].

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)]

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 Tablets 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 Tablets 500 mcg once daily for 6 months and 1 year, respectively.

The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1 ) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with Roflumilast Tablets 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 Tablets-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of Roflumilast Tablets 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 Tablets -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 Tablets group in 8 controlled COPD clinical trials.

Table 1: Adverse Reactions Reported by ≥ 2% of Patients Treated with Roflumilast Tablets 500 mcg daily and Greater Than Placebo

Adverse Reactions (Preferred Term) Treatment
Roflumilast Tablets 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 Tablets 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.

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