roflumilast: prescribing information – dosing, contraindications, interactions, side effects

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.

Posology

Starting dose
The recommended starting dose is one tablet of 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. Therefore, the 250 micrograms dose should be used only as a starting dose (see sections 5.1 and 5.2).

Maintenance dose
After 28 days of treatment with the 250 micrograms starting dose, patients must be up-titrated to one tablet of 500 micrograms roflumilast, to be taken once daily.

Roflumilast 500 micrograms may need to be taken for several weeks to achieve its full effect (see sections 5.1 and 5.2). Roflumilast 500 micrograms 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.

Hepatic impairment
The clinical data with roflumilast in patients with mild hepatic impairment classified as Child-Pugh A are insufficient to recommend a dose adjustment (see section 5.2) 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 must not take Daxas (see section 4.3).

Paediatric population
There is no relevant use of Daxas 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.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Moderate or severe hepatic impairment (Child-Pugh B or C).

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

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 creatine 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. 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.

All patients should be informed about the risks of Daxas and the precautions for safe use before starting treatment.

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 content

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total 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.

Symptoms

In Phase I studies, the following symptoms were observed at an increased rate after single oral doses of 2,500 micrograms and one single dose of 5,000 micrograms (ten times the recommended dose):
headache, gastrointestinal disorders, dizziness, palpitations, light-headedness, clamminess and arterial hypotension.

Management

In case of overdose, it is recommended that the appropriate supportive medical care is provided. Since roflumilast is highly protein bound, haemodialysis is not likely to be an efficient method of its removal. It is not known whether roflumilast is dialysable by peritoneal dialysis.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: R03DX07

Mechanism of action

Roflumilast is a PDE4 inhibitor, a non-steroid, anti-inflammatory active substance designed to target both the systemic and pulmonary inflammation associated with 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.

Pharmacodynamic effects

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 in experimental models. Upon in vitro stimulation of human neutrophils, monocytes, macrophages or lymphocytes, roflumilast and roflumilast N-oxide suppress the release of inflammatory mediators e.g. leukotriene B4, reactive oxygen species, tumour 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 of endotoxin challenged healthy volunteers.

Clinical efficacy and safety

In two confirmative replicate one-year studies (M2-124 and M2-125) and two supplementary six-month studies (M2-127 and M2-128), a total number of 4,768 patients were randomised and treated, of whom 2,374 were treated with roflumilast. The design of the studies was parallel-group, double-blind and placebo-controlled.

The one-year studies included patients with a history of severe to very severe COPD [FEV1 (forced expiratory volume in one second) ≤50% of predicted] associated with chronic bronchitis, with at least one documented exacerbation in the previous year and with symptoms at baseline as determined by cough and sputum score. Long-acting beta-agonists (LABAs) were allowed in the studies and were used in approximately 50% of the study population. Short-acting anticholinergics (SAMAs) were allowed for those patients not taking LABAs. Rescue medicinal products (salbutamol or albuterol) were allowed on an as-needed basis. The use of inhaled corticosteroids and theophylline was prohibited during the studies. Patients with no history of exacerbations were excluded.

Pharmacotherapeutic group: Drugs for obstructive airway diseases, other systemic drugs for obstructive airway diseases, ATC code: R03DX07

Mechanism of action

Roflumilast is a PDE4 inhibitor, a non-steroid, anti-inflammatory active substance designed to target both the systemic and pulmonary inflammation associated with 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.

Pharmacodynamic effects

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 in experimental models. Upon in vitro stimulation of human neutrophils, monocytes, macrophages or lymphocytes, roflumilast and roflumilast N-oxide suppress the release of inflammatory mediators e.g. leukotriene B4, reactive oxygen species, tumour 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 of endotoxin challenged healthy volunteers.

Clinical efficacy and safety

In two confirmative replicate one-year studies (M2-124 and M2-125) and two supplementary six-month studies (M2-127 and M2-128), a total number of 4,768 patients were randomised and treated of whom 2,374 were treated with roflumilast. The design of the studies was parallel-group, double-blind and placebo-controlled.

The one-year studies included patients with a history of severe to very severe COPD [FEV1 (forced expiratory volume in one second) ≤50% of predicted] associated with chronic bronchitis, with at least one documented exacerbation in the previous year and with symptoms at baseline as determined by cough and sputum score. Long-acting beta-agonists (LABAs) were allowed in the studies and were used in approximately 50% of the study population. Short-acting anticholinergics (SAMAs) were allowed for those patients not taking LABAs. Rescue medicinal products (salbutamol or albuterol) were allowed on an as-needed basis. The use of inhaled corticosteroids and theophylline was prohibited during the studies. Patients with no history of exacerbations were excluded.

Roflumilast is extensively metabolised in humans, with the formation of a major pharmacodynamically active metabolite, roflumilast N-oxide. Since both roflumilast and roflumilast N-oxide contribute to PDE4 inhibitory activity in vivo, pharmacokinetic considerations are based on total PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast N-oxide).

Absorption

The absolute bioavailability of roflumilast following a 500 micrograms oral dose is approximately 80%. Maximum plasma concentrations of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state. Maximum concentrations of the N-oxide metabolite are reached after about eight hours (ranging from 4 to 13 hours). Food intake does not affect the total PDE4 inhibitory activity, but delays time to maximum concentration (tmax) of roflumilast by one hour and reduces Cmax by approximately 40%. However, Cmax and tmax of roflumilast N-oxide are unaffected.

Distribution

Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single dose of 500 micrograms roflumilast is about 2.9 l/kg.
Due to the physico-chemical properties, roflumilast is readily distributed to organs and tissues including fatty tissue of mice, hamster and rat. An early distribution phase with marked penetration into tissues is followed by a marked elimination phase out of fatty tissue most probably due to pronounced break-down of parent compound to roflumilast N-oxide. These studies in rats with radiolabelled roflumilast also indicate low penetration across the blood-brain barrier. There is no evidence for a specific accumulation or retention of roflumilast or its metabolites in organs and fatty tissue.

Biotransformation