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Drug Details
DAXAS 500 micrograms film-coated tablets
- Presentation
Film-coated tablet (tablet). Yellow, D-shaped film-coated tablet, embossed with “D” on one side. - Description
Each tablet contains 500 micrograms of roflumilast. Excipient: This product contains 199 mg lactose monohydrate per film-coated tablet. - Indications
Daxas is indicated for maintenance treatment 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 as add on to bronchodilator treatment.
- Adult Dosage
Posology
The recommended dose is one tablet of 500 micrograms roflumilast once daily.
Daxas may need to be taken for several weeks to achieve its effect. Daxas has been studied in clinical trials for up to one year.
Special populations
Elderly (65 years and older)
No dose adjustment is necessary.
Renal impairment
No dose adjustment is necessary.
Hepatic impairment
The clinical data with Daxas in patients with mild hepatic impairment classified as Child-Pugh A are insufficient to recommend a dose adjustment and therefore Daxas should be used with caution in these patients.
Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C should not take Daxas.
Paediatric population
There is no relevant use of Daxas in the paediatric population (under 18 years).
Method of administration
For oral use.
The tablet should be swallowed with water and taken at the same time every day. The tablet can be taken with or without food
- Contra Indications
Hypersensitivity to roflumilast or to any of the excipients.
Moderate or severe hepatic impairment (Child-Pugh B or C).
- Special Precautions
All patients should be informed about the risks of Daxas and the precautions for safe use and should be given a patient card before starting Daxas.
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.
Weight decrease
In 1-year studies (M2-124, M2-125), a decrease of body weight occurred more frequently in patients treated with Daxas compared to placebo-treated patients. After discontinuation of Daxas, 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 Daxas should be stopped and body weight should be further followed-up.
Special clinical conditions
Due to lack of relevant experience, treatment with Daxas should not be initiated or existing treatment with Daxas 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.
Patients with congestive heart failure (NYHA grades 3 and 4) have not been studied and therefore treatment of these patients is not recommended.
Psychiatric disorders
Daxas is associated with an increased risk of psychiatric disorders such as insomnia, anxiety, nervousness and depression. Rare instances of suicidal ideation and behaviour, including completed suicide, have been observed in clinical trials. Therefore, the risks and benefits of starting or continuing treatment with Daxas 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. Patients should be instructed to notify their prescriber of any changes in behaviour or mood and of any suicidal ideation. Moreover, Daxas is not recommended in patients with a history of depression associated with suicidal ideation or behaviour.
Persistent intolerability
While adverse reactions like diarrhoea, nausea, abdominal pain and headache mainly occur within the first weeks of therapy and mostly resolve on continued treatment, Daxas 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 the CYP1A2 inhibitor fluvoxamine or the dual CYP3A4/1A2 inhibitors enoxacin and cimetidine.
Theophylline
There are no clinical data to support the concomitant treatment with theophylline for maintenance therapy. Therefore, the concomitant treatment with theophylline is not recommended.
Lactose
Daxas tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
- Interactions
Interaction studies have only been performed 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 phosphodiesterase 4 (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. Clinical interaction studies with CYP3A4 inhibitors erythromycin and ketoconazole showed increases of 9% of the total PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast N-oxide). Interaction studies with CYP1A2 inhibitor fluvoxamine, and the dual CYP3A4/1A2 inhibitors enoxacin and cimetidine resulted in increases of the total PDE4 inhibitory activity of 59%, 25% and 47%, respectively. A combination of Daxas with these active substances might lead to an increase of exposure and persistent intolerability. In this case, Daxas 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 inducers (e.g. phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic efficacy of roflumilast.
Co-administration with theophylline resulted in an increase of 8% of the total PDE4 inhibitory activity. In an interaction study with an oral contraceptive containing gestodene and ethinyl oestradiol, the total PDE4 inhibitory activity was increased 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 Noxide.
- Adverse Drug Reactions
In clinical COPD studies, approximately 16% of patients experienced adverse reactions with roflumilast (compared to 5% in placebo). The most commonly reported adverse reactions were diarrhoea (5.9%), weight decreased (3.4%), nausea (2.9%), abdominal pain (1.9%) and headache (1.7%). 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.
Within the following table, adverse reactions are ranked under the MedDRA frequency classification:
Very common (
1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to <1/100); rare ( 1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions with roflumilast in clinical COPD studies
Frequency System Organ Class Common Uncommon Rare Immune system disorders Hypersensitivity Endocrine disorders Gynaecomastia Metabolism and nutrition disorders Weight decreased Decreased appetite Psychiatric disorders Insomnia Anxiety Depression Nervousness Nervous system disorders Headache Tremor Vertigo Dizziness Dysgeusia Cardiac disorders Palpitations Respiratory, thoracic and mediastinal disorders Respiratory tract infections (excluding Pneumonia) Gastrointestinal disorders Diarrhoea Nausea Abdominal pain Gastritis Vomiting Gastro-esophageal reflux disease Dyspepsia Haematochezia Constipation Hepatobiliary disorders Gamma-GT increased Aspartate aminotransferase (AST) increased Skin and subcutaneous tissue disorders Rash Urticaria Musculoskeletal and connective tissue disorders Muscle spasms and weakness Myalgia Back pain Blood creatine phosphokinase (CPK) increased General disorders and administration site conditions Malaise Asthenia Fatigue In clinical studies, rare instances of suicidal thinking and behaviour (including completed suicide) were reported. Patients should be instructed to notify their prescriber of any suicidal ideation.