Each film coated tablet contains: Roflumilast 500 mcg.
Pharmacology: Pharmacodynamics: Roflumilast is a phosphodiesterase-4 (PDE4) inhibitor, a nonsteroid, anti-inflammatory agent
designed to target both the systemic and pulmonary inflammation associated with chronic obstructive pulmonary disease (COPD). The mechanism of action is the inhibition of PDE4, a major cyclic adenosine monophosphate (cAMP) − metabolizing enzyme found in structural and inflammatory cells important to the pathogenesis of COPD. Roflumilast targets the PDE4A, 4B, and 4D, splicing variants with similar potency in the nanomolar range. The affinity to the PDE4C splicing variants is 5 to 10-fold lower. This mechanism of action and the selectivity also apply to roflumilast N-oxide, which is the major active metabolite of roflumilast.
Inhibition of PDE4 leads to elevated intracellular cAMP levels and mitigates COPD-related malfunctions of leukocytes, airway and pulmonary vascular smooth muscle cells, endothelial and airway epithelial cells and fibroblasts. Upon stimulation of neutrophils, monocytes, macrophages or lymphocytes, roflumilast and roflumilast N-oxide suppress the release of inflammatory mediators, e.g. leukotriene B4, reactive oxygen species, tumor necrosis factor α, interferon γ, and granzyme B. In patients with COPD, roflumilast reduced sputum neutrophils. Furthermore, roflumilast attenuated influx of neutrophils and eosinophils into the airways.
Pharmacokinetics: The arithmetic means of AUC0-t for the test drug and reference product were 42.61 ng·hour/ml and 47.77 ng·hour/ml, respectively. The arithmetic means of AUC0-inf for the test drug and reference product were 47.03 ng·hour/ml and 51.85 ng·hour/ml, respectively. The arithmetic means of Cmax for the test drug and reference product were 10.38 ng/ml and 9.47 ng/ml, respectively.
The mean ratios (90% confidence intervals) of the test drug/reference product for roflumilast were 89.86% (85.71-94.22%) for AUC0-t, 91.29% (87.18-95.59%) for AUC0-inf and 107.68% (98.61-117.60%) for Cmax. The 90% confidence interval of the test/reference ratios for AUC and Cmax of roflumilast were within the acceptance range for bioequivalence.
The mean elimination half-life (t1/2) of roflumilast for the test drug was 17.20 hours and for the reference product was 17.47 hours. The median of the time to reach maximum plasma concentration (tmax) of the test drug was 0.75 (0.33-2) hours and 0.75 (0.50-1) hours for the reference drug.
Roflumilast is indicated as add-on therapy to long-acting bronchodilator(s) treatment for the maintenance of severe chronic obstructive pulmonary disease (COPD) (FEV1 post-bronchodilator less than 50% predicted) associated with chronic bronchitis in adult patients with a history of frequent exacerbations.
For oral use.
The recommended dose is one tablet of 500 mcg roflumilast once daily.
The tablet should be swallowed with water and taken at the same time every day. The tablet can be taken with or without food. FORESPI film coated tablet may need to be taken for several weeks to achieve its effect.
Special populations: No dosage adjustment is necessary for elderly patients (65 years and older).
Pediatric population: There is no relevant use of FORESPI film coated tablet in the pediatric population (under 18 years) in the indication of COPD.
Renal impairment: No dosage adjustment is necessary for patients with renal impairment.
Hepatic impairment: FORESPI film coated tablet should be used with caution in patients with mild hepatic impairment classified as Child-Pugh A. Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C must not take FORESPI film coated tablet.
The following symptoms were observed at an increased rate after single oral doses of 2,500 mcg and one single dose of 5,000 mcg (ten times the recommended dose): headache, gastrointestinal disorders, dizziness, palpitations, light-headedness, clamminess and arterial hypotension.
In case of overdose, it is recommended that the appropriate supportive medical care is provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of its removal. It is not known whether roflumilast is dialysable by peritoneal dialysis.
Hypersensitivity to roflumilast or to any of the excipients.
Moderate or severe hepatic impairment (Child-Pugh B or C).
Rescue medicinal products: Roflumilast is an anti-inflammatory substance indicated for maintenance treatment of severe COPD associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on to bronchodilator treatment. It is not indicated as rescue medicinal product for the relief of acute bronchospasms.
All patients should be informed about the risk of roflumilast and the precautions for safe use.
Weight decrease: A decrease of body weight occurs more frequently in patients treated with roflumilast. After discontinuation of roflumilast, the majority of patients had regained body weight after 3 months. Body weight of underweight patients should be checked at each visit. Patients should be advised to check their body weight on a regular basis. In the event of an unexplained and clinically concerning weight decrease, the intake of roflumilast should be stopped and body weight should be further followed-up.
Special clinical conditions: Treatment with roflumilast should not be initiated or existing treatment with roflumilast should be stopped in patients with severe immunological diseases (e.g. HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy), severe acute infectious diseases, cancers (except basal cell carcinoma), or patients being treated with immunosuppressive medicinal products (i.e. methotrexate, azathioprine, infliximab, etanercept, or oral corticosteroids to be taken long-term; except short-term systemic corticosteroids). Experience in patients with latent infections such as tuberculosis, viral hepatitis, herpes viral infection and herpes zoster is limited.
Roflumilast treatment is not recommended in patients with congestive heart failure (NYHA grades 3 and 4).
Psychiatric disorders: Roflumilast is associated with an increased risk of psychiatric disorders such as insomnia, anxiety, nervousness and depression. Rare instances of suicidal ideation and behavior, including completed suicide, have been observed in patients with or without history of depression, usually within the first weeks of treatment.
The risks and benefits of starting or continuing treatment with roflumilast should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Roflumilast is not recommended in patients with a history of depression associated with suicidal ideation or behavior. Patients and caregivers should be instructed to notify the prescriber of any changes in behavior or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with roflumilast.
Persistent intolerability: While adverse reactions like diarrhea, nausea, abdominal pain and headache mainly occur within the first weeks of therapy and mostly resolve on continued treatment, roflumilast treatment should be reassessed in case of persistent intolerability. This might be the case in special populations that may have higher exposure, such as in black, non-smoking females or in patients concomitantly treated with CYP1A2/ 2C19/3A4 inhibitors (such as fluvoxamine and cimetidine) or the CYP1A2/3A4 inhibitor enoxacin.
Theophylline: The concomitant treatment with theophylline is not recommended.
Lactose: FORESPI film coated tablet contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: Roflumilast has no influence on the ability to drive and use machines.
Use in Women of childbearing potential: Women of childbearing age should be advised to use an effective method of contraception during treatment. Roflumilast is not recommended in women of childbearing potential not using contraception.
Use in Pregnancy: Roflumilast is not recommended during pregnancy.
Use in Lactation: Roflumilast should not be used during breast-feeding.
Women of childbearing potential: Women of childbearing age should be advised to use an effective method of contraception during treatment. Roflumilast is not recommended in women of childbearing potential not using contraception.
Pregnancy: Roflumilast is not recommended during pregnancy.
Lactation: Roflumilast should not be used during breast-feeding.
The most commonly reported adverse reactions were diarrhea, weight decreased, nausea, abdominal pain and headache. The majority of these adverse reactions were mild or moderate.
These adverse reactions mainly occurred within the first weeks of therapy and mostly resolved on continued treatment. (See table.)
Click on icon to see table/diagram/image
Interactions have only been observed in adults.
A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. Both roflumilast and roflumilast N-oxide have intrinsic PDE4 inhibitory activity. Therefore, following administration of roflumilast, the total PDE4 inhibition is considered to be the combined effect of both roflumilast and roflumilast N-oxide.
Interaction with CYP1A2/3A4 inhibitor enoxacin and the CYP1A2/2C19/3A4 inhibitors cimetidine and fluvoxamine, resulted in increases of the total PDE4 inhibitory activity of 25%, 47% and 59%, respectively. A combination of roflumilast with these active substances might lead to an increase of exposure and persistent intolerability. In this case, roflumilast treatment should be reassessed. Administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in total PDE4 inhibitory activity by about 60%. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic efficacy of roflumilast. Thus, roflumilast treatment is not recommended in patients receiving strong cytochrome P450 enzyme inducers.
Clinical interaction with CYP3A4 inhibitors erythromycin and ketoconazole showed increases of 9% of the total PDE4 inhibitory activity. Co-administration with theophylline resulted in an increase of 8% of the total PDE4 inhibitory activity. Interaction between oral contraceptive containing gestodene and ethinyl oestradiol with roflumilast resulted in increased total PDE4 inhibitory activity by 17%. No interactions were observed with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, warfarin, sildenafil and midazolam.
Co-administration with an antacid (combination of aluminium hydroxide and magnesium hydroxide) did not alter the absorption or pharmacokinetics of roflumilast or its N-oxide.
Store at temperature below 30°C.
R03DX07 - roflumilast ; Belongs to the class of other systemic drugs used in the treatment of obstructive airway diseases.
FC tab 500 mcg x 3 x 10's.