DAXAS Tablet Ref.[8547] Active ingredients: Roflumilast

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

Daxas 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 roflumilast compared to placebo-treated patients. 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

Due to lack of relevant experience, 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.

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

Roflumilast is associated with an increased risk of psychiatric disorders such as insomnia, anxiety, nervousness and depression. Rare instances of suicidal ideation and behaviour, including suicide, have been observed in patients with or without history of depression, usually within the first weeks of treatment (see section 4.8). 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 behaviour. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour 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 diarrhoea, 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 (see section 5.2) or in patients concomitantly treated with CYP1A2/2C19/3A4 inhibitors (such as fluvoxamine and cimetidine) or the CYP1A2/3A4 inhibitor enoxacin (see section 4.5).

Body weight <60 kg

Treatment with roflumilast may lead to a higher risk of sleep disorders (mainly insomnia) in patients with a baseline body weight of <60 kg, due to a higher total PDE4 inhibitory activity found in these patients (see section 4.8).

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.

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. Interaction studies 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. The tested dose of fluvoxamine was 50 mg. 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 (see section 4.4).

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 studies 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 (see section 4.4). In an interaction study with an oral contraceptive containing gestodene and ethinyl oestradiol, the total PDE4 inhibitory activity was increased by 17%. No dose adjustment is necessary in patients receiving these active substances.

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.

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

There are limited amount of data from the use of roflumilast in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3). Roflumilast is not recommended during pregnancy.

Roflumilast has been demonstrated to cross the placenta in pregnant rats.

Breastfeeding

Available pharmacokinetic data in animals have shown excretion of roflumilast or its metabolites in milk. A risk to the breastfed infant cannot be excluded. Roflumilast should not be used during breast-feeding.

Fertility

In a human spermatogenesis study, roflumilast 500 micrograms had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period.

Daxas has no influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reactions are diarrhoea (5.9%), weight decreased (3.4%), nausea (2.9%), abdominal pain (1.9%) and headache (1.7%). These adverse reactions mainly occurred within the first weeks of therapy and mostly resolved on continued treatment.

Tabulated list of adverse reactions

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 and post-marketing experience:

Description of selected adverse reactions

In clinical studies and post-marketing experience, rare instances of suicidal ideation and behaviour, including suicide, were reported. Patients and caregivers should be instructed to notify the prescriber of any suicidal ideation (see also section 4.4).

Other special populations

Elderly

A higher incidence of sleep disorders (mainly insomnia) in patients ≥75 years or older was observed in Study RO-2455-404-RD for patients treated with roflumilast when compared to those treated with placebo (3.9% vs 2.3%). The incidence observed was also higher in patients less than 75 years old, treated with roflumilast when compared to those treated with placebo (3.1% vs 2.0%).

Body weight <60 kg

A higher incidence of sleep disorders (mainly insomnia) in patients with a baseline body weight <60 kg was observed in Study RO-2455-404-RD for patients treated with roflumilast when compared to those treated with placebo (6.0% vs 1.7%). The incidence was 2.5% vs 2.2% in patients with a baseline body weight ≥60 kg, treated with roflumilast when compared to those treated with placebo.

Concomitant treatment with long acting muscarinic antagonists (LAMA)

A higher incidence of weight decrease, decreased appetite, headache and depression was observed during Study RO-2455-404-RD in patients receiving concomitant roflumilast and long-acting muscarinic antagonists (LAMA) plus concomitant inhaled corticosteroids (ICS) and long acting B2 agonists (LABA) compared to those treated only with concomitant roflumilast, ICS and LABA. Difference of incidence between roflumilast and placebo was quantitatively greater with concomitant LAMA for weight decreased (7.2% vs 4.2%), decreased appetite (3.7% vs 2.0%), headache (2.4% vs 1.1%) and depression (1.4% vs -0.3%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.