ROFLUMILAST

Posology Starting dose The recommended starting dose is 250 micrograms roflumilast to be taken once daily, for 28 days. This starting dose is intended to reduce adverse reactions and patient discontinuation when initiating therapy, but it is a sub-therapeutic dose.

2). Maintenance dose After 28 days of treatment with the 250-micrograms starting dose, patients must be up-titrated to 500 micrograms roflumilast, to be taken once daily. 2). Roflumilast 500 microgram has been studied in clinical trials for up to one year, and is intended for maintenance treatment.

Special populations Elderly No dose adjustment is necessary. Renal impairment No dose adjustment is necessary. 2) and therefore Roflumilast tablets should be used with caution in these patients. 3). Paediatric population There is no relevant use of Roflumilast in the paediatric population (under 18 years) for the indication of COPD.

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.

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 Frequency System Organ Class Common Uncommon Rare Immune system disorders Hypersensitivity Angioedema Endocrine disorders Gynaecomastia Metabolism and nutrition disorders Weight decreased Decreased appetite Psychiatric disorders Insomnia Anxiety Suicidal ideation and behaviour Depression Nervousness Panic attack 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 creatinine phosphokinase (CPK) increased General disorders and administration site conditions Malaise Asthenia Fatigue Description of selected adverse reactions In clinical studies and post-marketing experience, rare instances of suicidal ideation and behaviour, including suicide, were reported.

4). 3 %). 0 %). 7 %). 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.

All patients should be informed about the risks of Roflumilast tablets and the precautions for safe use before starting treatment. Rescue medicinal products Roflumilast tablets 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.

g. 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.

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.

1. Moderate or severe hepatic impairment (Child-Pugh B or C).