Daxas

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Daxas 250 micrograms tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250 micrograms of roflumilast.

Excipient with known effect:
Each tablet contains 49.7 mg lactose monohydrate.
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

White to off-white, round tablet, 5 mm in diameter, embossed with “D” on one side and “250” on the 
other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic 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.

4.2 Posology and method of administration

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.



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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.

4.3 Contraindications

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).

4.4 Special warnings and precautions for use

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 



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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.

4.5 Interaction with other medicinal products and other forms of interaction

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%



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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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects



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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



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Frequency

System
Organ Class

Common Uncommon Rare

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.

4.9 Overdose

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.



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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

5.1 Pharmacodynamic 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.

In a pooled analysis of the one-year studies M2-124 and M2-125, roflumilast 500 micrograms once 
daily significantly improved lung function compared to placebo, on average by 48 ml 
(pre-bronchodilator FEV1, primary endpoint, p<0.0001), and by 55 ml (post-bronchodilator FEV1, 
p<0.0001). The improvement in lung function was apparent at the first visit after 4 weeks and was 
maintained up to one year (end of treatment period). The rate (per patient per year) of moderate 



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exacerbations (requiring intervention with systemic glucocorticosteroids) or severe exacerbations 
(resulting in hospitalisation and/or leading to death) after 1 year was 1.142 with roflumilast and 1.374 
with placebo corresponding to a relative risk reduction of 16.9% (95% CI: 8.2% to 24.8%) (primary 
endpoint, p=0.0003). Effects were similar, independent of previous treatment with inhaled 
corticosteroids or underlying treatment with LABAs. In the subgroup of patients with history of 
frequent exacerbations (at least 2 exacerbations during the last year), the rate of exacerbations was 
1.526 with roflumilast and 1.941 with placebo corresponding to a relative risk reduction of 21.3% 
(95% CI: 7.5% to 33.1%). Roflumilast did not significantly reduce the rate of exacerbations compared 
with placebo in the subgroup of patients with moderate COPD.

The reduction of moderate or severe exacerbations with roflumilast and LABA compared to placebo 
and LABA was on average 21% (p=0.0011). The respective reduction in exacerbations seen in patients 
without concomitant LABAs was on average 15% (p=0.0387). The numbers of patients who died due 
to any reason were equal for those treated with placebo or roflumilast (42 deaths each group; 2.7% 
each group; pooled analysis).

A total of 2,690 patients were included and randomised in two supportive 1-year studies (M2-111 and 
M2-112). In contrast to the two confirmative studies, a history of chronic bronchitis and of COPD 
exacerbations was not requested for patients’ inclusion. Inhaled corticosteroids were used in 809 
(61%) of the roflumilast treated patients, whereas the use of LABAs and theophylline was prohibited. 
Roflumilast 500 micrograms once daily significantly improved lung function compared to placebo, on 
average by 51 ml (pre-bronchodilator FEV1, p<0.0001), and by 53 ml (post-bronchodilator FEV1, 
p<0.0001). The rate of exacerbations (as defined in the protocols) were not significantly reduced by 
roflumilast in the individual studies (relative risk reduction: 13.5% in Study M2-111 and 6.6% in 
Study M2-112; p= not significant). Adverse events rates were independent of concomitant treatment 
with inhaled corticosteroids.

Two six-month supportive studies (M2-127 and M2-128) included patients with a history of COPD for 
at least 12 months prior to baseline. Both studies included moderate to severe patients with a 
non-reversible airway obstruction and a FEV1 of 40% to 70% of predicted. Roflumilast or placebo 
treatment was added to continuous treatment with a long-acting bronchodilator, in particular 
salmeterol in Study M2-127 or tiotropium in Study M2-128. In the two six-month studies, 
pre-bronchodilator FEV1 was significantly improved by 49 ml (primary endpoint, p<0.0001) beyond 
the bronchodilator effect of concomitant treatment with salmeterol in Study M2-127 and by 80 ml 
(primary endpoint, p<0.0001) incremental to concomitant treatment with tiotropium in Study M2-128.

Study RO-2455-404-RD was a one-year study in COPD patients with a baseline (pre-bronchodilator) 
FEV1 <50% of predicted normal and a history of frequent exacerbations. The study assessed the effect 
of roflumilast on COPD exacerbation rate in patients treated with fixed combinations of LABA and 
inhaled corticosteroids, compared to placebo. A total of 1935 patients were randomised to double-
blind medication and approximately 70% were also using a long-acting muscarinic antagonist 
(LAMA) through the course of the trial. The primary endpoint was reduction in rate of moderate or 
severe COPD exacerbations per patient per year. The rate of severe COPD exacerbations and changes 
in FEV1 were evaluated as key secondary endpoints.



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Table 2. Summary of COPD exacerbation endpoints in Study RO-2455-404-RD

Exacerbation 
Category

Analysis 
model

Roflumilast

(N=969)
Rate (n)

Placebo
(N=966)
Rate (n)

Ratio Roflumilast/Placebo 2-Sided
p-

value
Rate 
Ratio

Change
(%) 95% CI

Moderate or 
severe

Poisson 
regression

0.805 
(380)

0.927 
(432)

0.868 -13.2
0.753, 
1.002

0.0529

Moderate Poisson 
regression

0.574 
(287)

0.627 
(333)

0.914 -8.6
0.775, 
1.078

0.2875

Severe Negative 
binomial 

regression

0.239 
(151)

0.315 
(192) 0.757 -24.3

0.601, 
0.952

0.0175

There was a trend towards a reduction in moderate or severe exacerbations in subjects treated with 
roflumilast compared with placebo over 52 weeks, which did not achieve statistical significance (Table 
2). A pre-specified sensitivity analysis using the negative binomial regression model treatment showed 
a statistically significant difference of -14.2% (rate ratio: 0.86; 95% CI: 0.74 to 0.99).

The per-protocol Poisson regression analysis and the non-significant sensitivity to drop-out Poisson 
regression intention-to-treat analysis rate ratios were 0.81 (95% CI: 0.69 to 0.94) and 0.89 (95% CI: 
0.77 to 1.02), respectively.

Reductions were achieved in the subgroup of patients concomitantly treated with LAMA (rate ratio: 
0.88; 95% CI: 0.75 to 1.04) and in the subgroup not treated with LAMA (rate ratio: 0.83; 95% CI: 0.62 
to 1.12).

The rate of severe exacerbations was reduced in the overall patient group (rate ratio: 0.76; 95% CI: 
0.60 to 0.95) with a rate of 0.24 per patient/year compared to a rate of 0.32 per patient/year in patients 
treated with placebo. A similar reduction was achieved in the subgroup of patients concomitantly 
treated with LAMA (rate ratio: 0.77; 95% CI: 0.60 to 0.99) and in the subgroup not treated with 
LAMA (rate ratio: 0.71; 95% CI: 0.42 to 1.20).

Roflumilast improved lung function after 4 weeks (sustained over 52 weeks). Post-bronchodilator 
FEV1 increased for the roflumilast group by 52 mL (95% CI: 40, 65 mL) and decreased for the placebo 
group by 4 mL (95% CI: -16, 9 mL). Post-bronchodilator FEV1 showed a clinically significant 
improvement in favour of roflumilast by 56 mL over placebo (95% CI: 38, 73 mL).

Seventeen (1.8%) patients in the roflumilast group and 18 (1.9%) patients in the placebo group died 
during the double-blind treatment period due to any reason and 7 (0.7%) patients in each group due to 
a COPD exacerbation. The proportion of patients who experienced at least 1 adverse event during the 
double-blind treatment period were 648 (66.9%) patients and 572 (59.2%) patients in the roflumilast 
and placebo groups, respectively. The observed adverse reactions for roflumilast in Study RO-2455-
404-RD were in line with those already included in section 4.8.

More patients in the roflumilast group (27.6%) than placebo (19.8%) withdrew study medication due 
to any reason (risk ratio: 1.40; 95% CI: 1.19 to 1.65). The major reasons for trial discontinuation were 
withdrawal of consent and reported adverse events.

Starting dose titration trial

The tolerability of roflumilast was evaluated in a 12-week randomised, double-blind, parallel group 
trial (RO-2455-302-RD) in patients with severe COPD associated with chronic bronchitis. At 
screening, patients were required to have had at least one exacerbation in the previous year and on 
standard of care COPD maintenance treatment for at least 12 weeks. A total of 1323 patients were 
randomised to receive roflumilast 500 micrograms once a day for 12 weeks (n=443), roflumilast 
500 micrograms every other day for 4 weeks followed by roflumilast 500 micrograms once a day for 



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8 weeks (n=439), or roflumilast 250 micrograms once a day for 4 weeks followed by roflumilast 
500 micrograms once a day for 8 weeks (n=441).

Over the entire study period of 12 weeks, the percentage of patients discontinuing treatment due to any 
reason was statistically significantly lower in patients initially receiving roflumilast 250 micrograms 
once a day for 4 weeks followed by roflumilast 500 micrograms once a day for 8 weeks (18.4%) 
compared to those receiving roflumilast 500 micrograms once a day for 12 weeks (24.6%; Odds Ratio 
0.66, 95% CI [0.47, 0.93], p=0.017). The discontinuation rate for those receiving 500 micrograms
every other day for 4 weeks followed by 500 micrograms once a day for 8 weeks was not statistically 
significantly different to those receiving 500 micrograms once a day for 12 weeks. The percentage of 
patients experiencing a Treatment Emergent Adverse Event (TEAE) of interest, defined as diarrhoea, 
nausea, headache, decreased appetite, insomnia, and abdominal pain (secondary endpoint), was 
nominally statistically significantly lower in patients initially receiving roflumilast 250 micrograms 
once a day for 4 weeks followed by roflumilast 500 micrograms once a day for 8 weeks (45.4%) 
compared to those receiving roflumilast 500 micrograms once a day for 12 weeks (54.2%, Odds Ratio 
0.63, 95% CI [0.47, 0.83], p=0.001). The rate of experiencing a TEAE of interest for those receiving 
500 micrograms every other day for 4 weeks followed by 500 micrograms once a day for 8 weeks was 
not statistically significantly different to those receiving 500 micrograms once a day for 12 weeks.

Patients receiving a 500 micrograms dose once a day had a median PDE4 inhibitory activity of 1.2
(0.35, 2.03) and those receiving a 250 micrograms dose once a day had a median PDE4 inhibitory 
activity of 0.6 (0.20, 1.24). Long-term administration at the 250 micrograms dose level may not induce 
sufficient PDE4 inhibition to exert clinical efficacy. 250 micrograms once a day is a sub-therapeutic 
dose, and should be used only as a starting dose for the first 28 days (see sections 4.2 and 5.2).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with 
roflumilast in all subsets of the paediatric population in chronic obstructive pulmonary disease (see 
section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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 



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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

Roflumilast is extensively metabolised via Phase I (cytochrome P450) and Phase II (conjugation) 
reactions. The N-oxide metabolite is the major metabolite observed in the plasma of humans. The 
plasma AUC of the N-oxide metabolite on average is about 10-fold greater than the plasma AUC of 
roflumilast. Thus, the N-oxide metabolite is considered to be the main contributor to the total PDE4 
inhibitory activity in vivo.

In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to its 
N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human 
hepatic microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not 
inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low 
probability of relevant interactions with substances metabolised by these P450 enzymes. In addition, in 
vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak 
induction of CYP2B6 by roflumilast.

Elimination

The plasma clearance after short-term intravenous infusion of roflumilast is about 9.6 l/h. Following 
an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are 
approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its 
N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast 
N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabelled 
roflumilast, about 20% of the radioactivity was recovered in the faeces and 70% in urine as inactive 
metabolites.

Linearity/non-linearity

The pharmacokinetics of roflumilast and its N-oxide metabolite are dose-proportional over a range of
doses from 250 micrograms to 1,000 micrograms.

Special populations

In older people, females and in non-Caucasians, total PDE4 inhibitory activity was increased. Total 
PDE4 inhibitory activity was slightly decreased in smokers. None of these changes were considered to 
be clinically meaningful. No dose adjustment is recommended in these patients. A combination of 
factors, such as in black, non-smoking females, might lead to an increase of exposure and persistent 
intolerability. In this case, roflumilast treatment should be reassessed (see section 4.4).

In Study RO-2455-404-RD when compared with the overall population, the total PDE4 inhibitory 
activity determined from ex vivo unbound fractions was found to be 15% higher in patients ≥75 years 
of age, and 11% higher in patients with baseline body weight <60 kg (refer to section 4.4).

Renal impairment
Total PDE4 inhibitory activity decreased by 9% in patients with severe renal impairment (creatinine 
clearance 10-30 ml/min). No dose adjustment is necessary.

Hepatic impairment
The pharmacokinetics of roflumilast 250 micrograms once-daily was tested in 16 patients with mild to 
moderate hepatic impairment classified as Child-Pugh A and B. In these patients, the total PDE4 
inhibitory activity was increased by about 20% in patients with Child-Pugh A and about 90% in 
patients with Child-Pugh B. Simulations suggest dose proportionality between roflumilast 250 and 
500 micrograms in patients with mild and moderate hepatic impairment. Caution is necessary in 



13

Child-Pugh A patients (see section 4.2). Patients with moderate or severe hepatic impairment classified 
as Child-Pugh B or C should not take roflumilast (see section 4.3).

5.3 Preclinical safety data

There is no evidence for an immunotoxic, skin sensitising or phototoxic potential.

A slight reduction in male fertility was seen in conjunction with epididymal toxicity in rats. No 
epididymal toxicity or changes in semen parameters were present in any other rodent or non-rodent 
species including monkeys in spite of higher exposures.

In one of two rat embryofetal development studies, a higher incidence of incomplete skull bone 
ossification was seen at a dose producing maternal toxicity. In one of three rat studies on fertility and 
embryofetal development, post-implantation losses were observed. Post-implantation losses were not 
seen in rabbits. Prolongation of gestation was seen in mice.

The relevance of these findings to humans is unknown.

Most relevant findings in safety pharmacology and toxicology studies occurred at higher doses and 
exposure than that intended for clinical use. These findings consisted mainly of gastrointestinal 
findings (i.e. vomiting, increased gastric secretion, gastric erosions, intestine inflammation) and 
cardiac findings (i.e. focal haemorrhages, haemosiderin deposits and lympho-histiocytic cell 
infiltration in the right atria in dogs, and decreased blood pressure and increased heart rate in rats, 
guinea pigs and dogs).

Rodent-specific toxicity in the nasal mucosa was observed in repeat-dose toxicity and carcinogenicity 
studies. This effect seems to be due to an ADCP (4-Amino-3,5-dichloro-pyridine) N-oxide 
intermediate specifically formed in rodent olfactory mucosa, with special binding affinity in these 
species (i.e. mouse, rat and hamster).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate
Maize starch
Povidone
Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC aluminium blisters in packs of 28 tablets.

6.6 Special precautions for disposal



14

No special requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/10/636/008 28 tablets

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 July 2010
Date of latest renewal: 24 April 2015

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



15

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICINAL PRODUCT

Daxas 500 micrograms film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 500 micrograms of roflumilast.

Excipient with known effect:
Each film-coated tablet contains 198.64 mg lactose monohydrate.
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Yellow, D-shaped film-coated tablet of 9 mm, embossed with “D” on one side.

4. CLINICAL PARTICULARS

4.1 Therapeutic 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.

4.2 Posology and method of administration

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.



16

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.

4.3 Contraindications

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).

4.4 Special warnings and precautions for use

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 



17

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.

4.5 Interaction with other medicinal products and other forms of interaction

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%



18

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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects



19

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



20

Frequency

System
Organ Class

Common Uncommon Rare

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.

4.9 Overdose

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.



21

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

5.1 Pharmacodynamic 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.

In a pooled analysis of the one-year studies M2-124 and M2-125, roflumilast 500 micrograms once 
daily significantly improved lung function compared to placebo, on average by 48 ml 
(pre-bronchodilator FEV1, primary endpoint, p<0.0001), and by 55 ml (post-bronchodilator FEV1, 
p<0.0001). The improvement in lung function was apparent at the first visit after 4 weeks and was 
maintained up to one year (end of treatment period). The rate (per patient per year) of moderate 



22

exacerbations (requiring intervention with systemic glucocorticosteroids) or severe exacerbations 
(resulting in hospitalisation and/or leading to death) after 1 year was 1.142 with roflumilast and 1.374 
with placebo corresponding to a relative risk reduction of 16.9% (95% CI: 8.2% to 24.8%) (primary 
endpoint, p=0.0003). Effects were similar, independent of previous treatment with inhaled 
corticosteroids or underlying treatment with LABAs. In the subgroup of patients with history of 
frequent exacerbations (at least 2 exacerbations during the last year), the rate of exacerbations was 
1.526 with roflumilast and 1.941 with placebo corresponding to a relative risk reduction of 21.3% 
(95% CI: 7.5% to 33.1%). Roflumilast did not significantly reduce the rate of exacerbations compared 
with placebo in the subgroup of patients with moderate COPD.
The reduction of moderate or severe exacerbations with roflumilast and LABA compared to placebo 
and LABA was on average 21% (p=0.0011). The respective reduction in exacerbations seen in patients 
without concomitant LABAs was on average 15% (p=0.0387). The numbers of patients who died due 
to any reason were equal for those treated with placebo or roflumilast (42 deaths each group; 2.7% 
each group; pooled analysis).

A total of 2,690 patients were included and randomised in two supportive 1-year studies (M2-111 and 
M2-112). In contrast to the two confirmative studies, a history of chronic bronchitis and of COPD 
exacerbations was not requested for patients’ inclusion. Inhaled corticosteroids were used in 809 
(61%) of the roflumilast treated patients, whereas the use of LABAs and theophylline was prohibited. 
Roflumilast 500 micrograms once daily significantly improved lung function compared to placebo, on 
average by 51 ml (pre-bronchodilator FEV1, p<0.0001), and by 53 ml (post-bronchodilator FEV1, 
p<0.0001). The rate of exacerbations (as defined in the protocols) were not significantly reduced by 
roflumilast in the individual studies (relative risk reduction: 13.5% in Study M2-111 and 6.6% in 
Study M2-112; p= not significant). Adverse events rates were independent of concomitant treatment 
with inhaled corticosteroids.

Two six-month supportive studies (M2-127 and M2-128) included patients with a history of COPD for 
at least 12 months prior to baseline. Both studies included moderate to severe patients with a 
non-reversible airway obstruction and a FEV1 of 40% to 70% of predicted. Roflumilast or placebo 
treatment was added to continuous treatment with a long-acting bronchodilator, in particular 
salmeterol in Study M2-127 or tiotropium in Study M2-128. In the two six-month studies, 
pre-bronchodilator FEV1 was significantly improved by 49 ml (primary endpoint, p<0.0001) beyond 
the bronchodilator effect of concomitant treatment with salmeterol in Study M2-127 and by 80 ml 
(primary endpoint, p<0.0001) incremental to concomitant treatment with tiotropium in Study M2-128.

Study RO-2455-404-RD was a one-year study in COPD patients with a baseline (pre-bronchodilator) 
FEV1 <50% of predicted normal and a history of frequent exacerbations. The study assessed the effect 
of roflumilast on COPD exacerbation rate in patients treated with fixed combinations of LABA and 
inhaled corticosteroids, compared to placebo. A total of 1935 patients were randomised to double-
blind medication and approximately 70% were also using a long-acting muscarinic antagonist 
(LAMA) through the course of the trial. The primary endpoint was reduction in rate of moderate or 
severe COPD exacerbations per patient per year. The rate of severe COPD exacerbations and changes 
in FEV1 were evaluated as key secondary endpoints.



23

Table 2. Summary of COPD exacerbation endpoints in Study RO-2455-404-RD

Exacerbation 
Category

Analysis 
model

Roflumilast

(N=969)
Rate (n)

Placebo
(N=966)
Rate (n)

Ratio Roflumilast/Placebo 2-Sided
p-

value
Rate 
Ratio

Change
(%) 95% CI

Moderate or 
severe

Poisson 
regression

0.805 
(380)

0.927 
(432)

0.868 -13.2
0.753, 
1.002

0.0529

Moderate Poisson 
regression

0.574 
(287)

0.627 
(333)

0.914 -8.6
0.775, 
1.078

0.2875

Severe Negative 
binomial 

regression

0.239 
(151)

0.315 
(192) 0.757 -24.3

0.601, 
0.952

0.0175

There was a trend towards a reduction in moderate or severe exacerbations in subjects treated with 
roflumilast compared with placebo over 52 weeks, which did not achieve statistical significance (Table 
2). A pre-specified sensitivity analysis using the negative binomial regression model treatment showed 
a statistically significant difference of -14.2% (rate ratio: 0.86; 95% CI: 0.74 to 0.99).

The per-protocol Poisson regression analysis and the non-significant sensitivity to drop-out Poisson 
regression intention-to-treat analysis rate ratios were 0.81 (95% CI: 0.69 to 0.94) and 0.89 (95% CI: 
0.77 to 1.02), respectively.

Reductions were achieved in the subgroup of patients concomitantly treated with LAMA (rate ratio: 
0.88; 95% CI: 0.75 to 1.04) and in the subgroup not treated with LAMA (rate ratio: 0.83; 95% CI: 0.62 
to 1.12).

The rate of severe exacerbations was reduced in the overall patient group (rate ratio: 0.76; 95% CI: 
0.60 to 0.95) with a rate of 0.24 per patient/year compared to a rate of 0.32 per patient/year in patients 
treated with placebo. A similar reduction was achieved in the subgroup of patients concomitantly 
treated with LAMA (rate ratio: 0.77; 95% CI: 0.60 to 0.99) and in the subgroup not treated with 
LAMA (rate ratio: 0.71; 95% CI: 0.42 to 1.20).

Roflumilast improved lung function after 4 weeks (sustained over 52 weeks). Post-bronchodilator 
FEV1 increased for the roflumilast group by 52 mL (95% CI: 40, 65 mL) and decreased for the placebo 
group by 4 mL (95% CI: -16, 9 mL). Post-bronchodilator FEV1 showed a clinically significant 
improvement in favour of roflumilast by 56 mL over placebo (95% CI: 38, 73 mL).

Seventeen (1.8%) patients in the roflumilast group and 18 (1.9%) patients in the placebo group died 
during the double-blind treatment period due to any reason and 7 (0.7%) patients in each group due to 
a COPD exacerbation. The proportion of patients who experienced at least 1 adverse event during the 
double-blind treatment period were 648 (66.9%) patients and 572 (59.2%) patients in the roflumilast 
and placebo groups, respectively. The observed adverse reactions for roflumilast in Study RO-2455-
404-RD were in line with those already included in section 4.8.

More patients in the roflumilast group (27.6%) than placebo (19.8%) withdrew study medication due 
to any reason (risk ratio: 1.40; 95% CI: 1.19 to 1.65). The major reasons for trial discontinuation were 
withdrawal of consent and reported adverse events.

Starting dose titration trial

The tolerability of roflumilast was evaluated in a 12-week randomised, double-blind, parallel group 
trial (RO-2455-302-RD) in patients with severe COPD associated with chronic bronchitis. At 
screening, patients were required to have had at least one exacerbation in the previous year and on 
standard of care COPD maintenance treatment for at least 12 weeks. A total of 1323 patients were 
randomised to receive roflumilast 500 micrograms once a day for 12 weeks (n=443), roflumilast 
500 micrograms every other day for 4 weeks followed by roflumilast 500 micrograms once a day for 



24

8 weeks (n=439), or roflumilast 250 micrograms once a day for 4 weeks followed by roflumilast 
500 micrograms once a day for 8 weeks (n=441).

Over the entire study period of 12 weeks, the percentage of patients discontinuing treatment due to any 
reason was statistically significantly lower in patients initially receiving roflumilast 250 micrograms 
once a day for 4 weeks followed by roflumilast 500 micrograms once a day for 8 weeks (18.4%) 
compared to those receiving roflumilast 500 micrograms once a day for 12 weeks (24.6%; Odds Ratio 
0.66, 95% CI [0.47, 0.93], p=0.017). The discontinuation rate for those receiving 500 micrograms
every other day for 4 weeks followed by 500 micrograms once a day for 8 weeks was not statistically 
significantly different to those receiving 500 micrograms once a day for 12 weeks. The percentage of 
patients experiencing a Treatment Emergent Adverse Event (TEAE) of interest, defined as diarrhoea, 
nausea, headache, decreased appetite, insomnia, and abdominal pain (secondary endpoint), was
nominally statistically significantly lower in patients initially receiving roflumilast 250 micrograms 
once a day for 4 weeks followed by roflumilast 500 micrograms once a day for 8 weeks (45.4%) 
compared to those receiving roflumilast 500 micrograms once a day for 12 weeks (54.2%, Odds Ratio 
0.63, 95% CI [0.47, 0.83], p=0.001). The rate of experiencing a TEAE of interest for those receiving 
500 micrograms every other day for 4 weeks followed by 500 micrograms once a day for 8 weeks was 
not statistically significantly different to those receiving 500 micrograms once a day for 12 weeks.

Patients receiving a 500 micrograms dose once a day had a median PDE4 inhibitory activity of 1.2
(0.35, 2.03) and those receiving a 250 micrograms dose once a day had a median PDE4 inhibitory 
activity of 0.6 (0.20, 1.24). Long-term administration at the 250 micrograms dose level may not induce 
sufficient PDE4 inhibition to exert clinical efficacy. 250 micrograms once a day is a sub-therapeutic 
dose, and should be used only as a starting dose for the first 28 days (see sections 4.2 and 5.2).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with 
roflumilast in all subsets of the paediatric population in chronic obstructive pulmonary disease (see 
section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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 



25

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

Roflumilast is extensively metabolised via Phase I (cytochrome P450) and Phase II (conjugation) 
reactions. The N-oxide metabolite is the major metabolite observed in the plasma of humans. The 
plasma AUC of the N-oxide metabolite on average is about 10-fold greater than the plasma AUC of 
roflumilast. Thus, the N-oxide metabolite is considered to be the main contributor to the total PDE4 
inhibitory activity in vivo.

In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to its 
N-oxide metabolite is mediated by CYP1A2 and 3A4. Based on further in vitro results in human 
hepatic microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not 
inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low 
probability of relevant interactions with substances metabolised by these P450 enzymes. In addition, in 
vitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak 
induction of CYP2B6 by roflumilast.

Elimination

The plasma clearance after short-term intravenous infusion of roflumilast is about 9.6 l/h. Following 
an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are 
approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its 
N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast 
N-oxide following once-daily dosing. Following intravenous or oral administration of radiolabelled 
roflumilast, about 20% of the radioactivity was recovered in the faeces and 70% in urine as inactive 
metabolites.

Linearity/non-linearity

The pharmacokinetics of roflumilast and its N-oxide metabolite are dose-proportional over a range of 
doses from 250 micrograms to 1,000 micrograms.

Special populations

In older people, females and in non-Caucasians, total PDE4 inhibitory activity was increased. Total 
PDE4 inhibitory activity was slightly decreased in smokers. None of these changes were considered to 
be clinically meaningful. No dose adjustment is recommended in these patients. A combination of 
factors, such as in black, non-smoking females, might lead to an increase of exposure and persistent 
intolerability. In this case, roflumilast treatment should be reassessed (see section 4.4).

In Study RO-2455-404-RD when compared with the overall population, the total PDE4 inhibitory 
activity determined from ex vivo unbound fractions was found to be 15% higher in patients ≥75 years 
of age, and 11% higher in patients with baseline body weight <60 kg (refer to section 4.4).

Renal impairment
Total PDE4 inhibitory activity decreased by 9% in patients with severe renal impairment (creatinine 
clearance 10-30 ml/min). No dose adjustment is necessary.

Hepatic impairment
The pharmacokinetics of roflumilast 250 micrograms once-daily was tested in 16 patients with mild to 
moderate hepatic impairment classified as Child-Pugh A and B. In these patients, the total PDE4 
inhibitory activity was increased by about 20% in patients with Child-Pugh A and about 90% in 
patients with Child-Pugh B. Simulations suggest dose proportionality between roflumilast 250 and 
500 micrograms in patients with mild and moderate hepatic impairment. Caution is necessary in 



26

Child-Pugh A patients (see section 4.2). Patients with moderate or severe hepatic impairment classified 
as Child-Pugh B or C should not take roflumilast (see section 4.3).

5.3 Preclinical safety data

There is no evidence for an immunotoxic, skin sensitising or phototoxic potential.

A slight reduction in male fertility was seen in conjunction with epididymal toxicity in rats. No 
epididymal toxicity or changes in semen parameters were present in any other rodent or non-rodent 
species including monkeys in spite of higher exposures.

In one of two rat embryofetal development studies, a higher incidence of incomplete skull bone 
ossification was seen at a dose producing maternal toxicity. In one of three rat studies on fertility and 
embryofetal development, post-implantation losses were observed. Post-implantation losses were not 
seen in rabbits. Prolongation of gestation was seen in mice.

The relevance of these findings to humans is unknown.

Most relevant findings in safety pharmacology and toxicology studies occurred at higher doses and 
exposure than that intended for clinical use. These findings consisted mainly of gastrointestinal 
findings (i.e. vomiting, increased gastric secretion, gastric erosions, intestine inflammation) and 
cardiac findings (i.e. focal haemorrhages, haemosiderin deposits and lympho-histiocytic cell 
infiltration in the right atria in dogs, and decreased blood pressure and increased heart rate in rats, 
guinea pigs and dogs).

Rodent-specific toxicity in the nasal mucosa was observed in repeat-dose toxicity and carcinogenicity 
studies. This effect seems to be due to an ADCP (4-Amino-3,5-dichloro-pyridine) N-oxide 
intermediate specifically formed in rodent olfactory mucosa, with special binding affinity in these 
species (i.e. mouse, rat and hamster).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core
Lactose monohydrate
Maize starch
Povidone 
Magnesium stearate

Coating
Hypromellose
Macrogol (4000)
Titanium dioxide (E171)
Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage



27

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PVDC aluminium blisters in packs of 10, 14, 28, 30, 84, 90 or 98 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/10/636/001 10 film-coated tablets
EU/1/10/636/002 30 film-coated tablets
EU/1/10/636/003 90 film-coated tablets
EU/1/10/636/004 14 film-coated tablets
EU/1/10/636/005 28 film-coated tablets
EU/1/10/636/006 84 film-coated tablets
EU/1/10/636/007 98 film-coated tablets

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 05 July 2010
Date of latest renewal: 24 April 2015

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



28

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



29

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Takeda GmbH
Production Site Oranienburg
Lehnitzstrasse 70-98
D-16515 Oranienburg
Germany

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING
AUTHORISATION

 Periodic safety update reports (PSURs)

The marketing authorisation holder shall submit PSURs for this product in accordance with the 
requirements set out in the list of Union reference dates (EURD list) provided for under Article 
107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted 
at the same time.

 Obligation to conduct post-authorisation measures

The MAH shall complete, within the stated timeframe, the below measures:

Description Due date

ANX 2.1 - The MAH commits to conduct a long-term comparative 

observational safety study. This study should be appropriate to compare 

the incidences of all-cause mortality, major cardiovascular events, new 

diagnosis of cancer, all-cause hospitalisation, hospitalisation related to 

respiratory disease, suicide or hospitalisation for suicide attempt, and new 

diagnosis of depression, tuberculosis or viral hepatitis B or C in 

Final study report 

by 31/03/2021.



30

roflumilast treated COPD patients compared with COPD patients not 

treated with roflumilast.



31

ANNEX III

LABELLING AND PACKAGE LEAFLET



32

A. LABELLING



33

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON FOR BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Daxas 250 micrograms tablets
roflumilast

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 250 micrograms roflumilast.

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 tablets – 28-day starter pack.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE



34

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/10/636/008 28 tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

daxas 250 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



35

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Daxas 250 micrograms tablets
roflumilast

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca (AstraZeneca logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



36

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON FOR BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Daxas 500 micrograms film-coated tablets
roflumilast

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 500 micrograms roflumilast.

3. LIST OF EXCIPIENTS

Contains lactose. See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

10 film-coated tablets
14 film-coated tablets
28 film-coated tablets
30 film-coated tablets
84 film-coated tablets
90 film-coated tablets
98 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS



37

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/10/636/001 10 film-coated tablets
EU/1/10/636/002 30 film-coated tablets
EU/1/10/636/003 90 film-coated tablets
EU/1/10/636/004 14 film-coated tablets
EU/1/10/636/005 28 film-coated tablets
EU/1/10/636/006 84 film-coated tablets
EU/1/10/636/007 98 film-coated tablets

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

daxas 500 mcg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC
SN
NN



38

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Daxas 500 micrograms tablets
roflumilast

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca (AstraZeneca logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



39

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

CALENDAR BLISTERS

1. NAME OF THE MEDICINAL PRODUCT

Daxas 500 micrograms tablets
roflumilast

2. NAME OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca (AstraZeneca logo)

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

Monday Tuesday Wednesday Thursday Friday Saturday Sunday



40

B. PACKAGE LEAFLET



41

Package leaflet: Information for the patient

Daxas 250 micrograms tablets
roflumilast

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet:
1. What Daxas is and what it is used for
2. What you need to know before you take Daxas
3. How to take Daxas
4. Possible side effects
5. How to store Daxas
6. Contents of the pack and other information

1. What Daxas is and what it is used for

Daxas contains the active substance roflumilast, which is an anti-inflammatory medicine called 
phosphodiesterase-4 inhibitor. Roflumilast reduces the activity of phosphodiesterase-4, a protein 
occurring naturally in body cells. When the activity of this protein is reduced, there is less 
inflammation in the lungs. This helps to stop narrowing of airways occurring in chronic obstructive 
pulmonary disease (COPD). Thus Daxas eases breathing problems.

Daxas is used for maintenance treatment of severe COPD in adults who in the past had frequent 
worsening of their COPD symptoms (so-called exacerbations) and who have chronic bronchitis. 
COPD is a chronic disease of the lungs that results in tightening of the airways (obstruction) and 
swelling and irritation of the walls of the small air passages (inflammation). This leads to symptoms 
such as coughing, wheezing, chest tightness or difficulty in breathing. Daxas is to be used in addition 
to bronchodilators.

2. What you need to know before you take Daxas

Do not take Daxas
- if you are allergic to roflumilast or any of the other ingredients of this medicine (listed in section 

6)
- if you have moderate or severe liver problems.

Warnings and precautions
Talk to your doctor or pharmacist before taking Daxas.

Sudden attack of breathlessness
Daxas is not intended for the treatment of a sudden attack of breathlessness (acute bronchospasms). In 
order to relieve a sudden attack of breathlessness it is very important that your doctor provides you 



42

with another medicine to be available to you at all times that can cope with such an attack. Daxas will 
not help you in this situation.

Body weight
You should check your body weight on a regular basis. Talk to your doctor if, while taking this 
medicine, you observe an unintentional loss of body weight (not related to a diet or exercise 
programme).

Other diseases
Daxas is not recommended if you have one or more of the following diseases:
- severe immunological diseases such as HIV infection, multiple sclerosis (MS), lupus 

erythematosus (LE) or progressive multifocal leukoencephalopathy (PML)
- severe acute infectious diseases such as acute hepatitis
- cancer (except basal-cell carcinoma, a slow-growing type of skin cancer)
- or severe impairment of the heart function
There is a lack of relevant experience with Daxas under these conditions. You should talk to your 
doctor, if you are diagnosed with any of these diseases.

Experience is also limited in patients with a previous diagnosis of tuberculosis, viral hepatitis, herpes 
viral infection or herpes zoster. Please talk to your doctor if you have one of these diseases.

Symptoms you should be aware of
You may experience diarrhoea, nausea, abdominal pain or headache during the first weeks of 
treatment with Daxas. Talk to your doctor if these side effects do not resolve within the first weeks of 
treatment.

Daxas is not recommended in patients with a history of depression associated with suicidal thinking or 
behaviour. You may also experience sleeplessness, anxiety, nervousness, or depressive mood. Before 
starting treatment with Daxas, inform your doctor if you are suffering from any symptoms of this kind 
and of any additional medicines you may take since some of those could increase the probability of 
these side effects. You or your caregiver should also immediately inform your doctor of any changes 
in behaviour or mood and of any suicidal thoughts you may have.

Children and adolescents
Do not give this medicine to children and adolescents under 18 years of age.

Other medicines and Daxas
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, especially the following:
- a medicine containing theophylline (a medicine to treat respiratory diseases), or
- a medicine used for treatment of immunological diseases, such as methotrexate, azathioprine, 

infliximab, etanercept, or oral corticosteroids to be taken long-term.
- a medicine containing fluvoxamine (a medicine to treat anxiety disorders and depression), 

enoxacin (a medicine to treat bacterial infections) or cimetidine (a medicine to treat stomach 
ulcers or heartburn).

The effect of Daxas may be reduced if taken together with rifampicin (an antibiotic medicine) or with 
phenobarbital, carbamazepine or phenytoin (medicines usually prescribed for the treatment of 
epilepsy). Ask your doctor for advice.

Daxas may be taken with other medicines used in the treatment of COPD such as inhaled or oral 
corticosteroids or bronchodilators. Do not stop taking these medicines or reduce their dose unless 
advised by your doctor.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.



43

You should not become pregnant during treatment with this medicine and should use an effective 
method of contraception during therapy, because Daxas may be harmful for the unborn baby.

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

Daxas contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.

3. How to take Daxas

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

 For the first 28 days - the recommended starting dose is one 250 micrograms tablet once daily. 

- The starting dose is a low dose used to help your body get used to the medicine before you 

start taking the full dose. At this low dose you will not get the full effect from the medicine –

therefore it is important that you move on to the full dose (called a ‘maintenance dose’) after 

28 days.

 After 28 days - the recommended maintenance dose is one 500 micrograms tablet once daily.

Swallow the tablet with some water. You may take this medicine with or without food. Take the tablet
at the same time every day.

You may need to take Daxas for several weeks to achieve its beneficial effect.

If you take more Daxas than you should
If you have taken more tablets than you should, you may experience the following symptoms: 
headache, nausea, diarrhoea, dizziness, throbbing of your heart, light-headedness, clamminess and low 
blood pressure. Tell your doctor or pharmacist straight away. If possible take your medicine and this 
leaflet with you.

If you forget to take Daxas
If you forget to take a tablet at the usual time, take the tablet as soon as you remember on the same 
day. If on one day you have forgotten to take a tablet of Daxas, just carry on the next day with the next 
tablet as usual. Continue taking your medicine at the usual times. Do not take a double dose to make 
up for a forgotten dose.

If you stop taking Daxas
It is important to continue taking Daxas for as long as prescribed by your doctor, even when you have 
no symptoms, in order to maintain control of your lung function.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You may experience diarrhoea, nausea, stomach ache or headache during the first weeks of treatment 
with Daxas. Talk to your doctor if these side effects do not resolve within the first weeks of treatment.

Some side effects could be serious. In clinical studies and post-marketing experience, rare instances of 
suicidal thinking and behaviour (including suicide) were reported. Please notify your doctor 



44

immediately of any suicidal thoughts you may have. You may also experience sleeplessness 
(common), anxiety (uncommon), nervousness (rare), panic attack (rare) or depressive mood (rare).

In uncommon cases allergic reactions may occur. Allergic reactions may affect the skin and in rare 
cases cause swelling of the eyelids, face, lips and tongue, possibly leading to difficulties in breathing
and/or a drop in blood pressure and accelerated heartbeat. In case of an allergic reaction, stop taking 
Daxas and contact your doctor immediately, or go immediately to the emergency department in the 
nearest hospital. Take all your medicines and this leaflet with you and provide full information of your 
current medications.

Other side effects include the following:

Common side effects (may affect up to 1 in 10 people)
- diarrhoea, nausea, stomach ache
- weight decrease, decreased appetite
- headache

Uncommon side effects (may affect up to 1 in 100 people)
- trembling, sensation of spinning head (vertigo), dizziness
- sensation of rapid or irregular heartbeat (palpitations)
- gastritis, vomiting
- reflux of stomach acid to the gullet (acid regurgitations), indigestion
- rash
- muscle pain, muscle weakness or cramps
- back pain
- feeling of weakness or tiredness, feeling unwell.

Rare side effects (may affect up to 1 in 1,000 people)
- male breast enlargement
- decreased sense of taste
- respiratory tract infections (excluding pneumonia)
- bloody stools, constipation
- elevation of liver or muscle enzymes (seen in blood tests)
- wheals (urticaria).

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Daxas

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.



45

6. Contents of the pack and other information

What Daxas contains
The active substance is roflumilast.

Each Daxas 250 micrograms tablet contains 250 micrograms roflumilast. The other ingredients are
lactose monohydrate (see section 2 under “Daxas contains lactose”), maize starch, povidone, 
magnesium stearate.

What Daxas looks like and contents of the pack
Daxas 250 micrograms tablets are white to off-white, embossed with ‘D’ on one side and ‘250’ on the 
other side.
Each pack contains 28 tablets.

Marketing Authorisation Holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
Takeda GmbH
Production site Oranienburg
Lehnitzstraße 70-98
16515 Oranienburg
Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 24455000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00

Ελλάδα
AstraZeneca A.E.
Τηλ: +30 210 6871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0



46

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.
Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777

Italia
Simesa S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last approved in

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu



47

Package leaflet: Information for the patient

Daxas 500 micrograms film-coated tablets 
roflumilast

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects.

Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet:
1. What Daxas is and what it is used for
2. What you need to know before you take Daxas
3. How to take Daxas
4. Possible side effects
5. How to store Daxas
6. Contents of the pack and other information

1. What Daxas is and what it is used for

Daxas contains the active substance roflumilast, which is an anti-inflammatory medicine called 
phosphodiesterase-4 inhibitor. Roflumilast reduces the activity of phosphodiesterase-4, a protein 
occurring naturally in body cells. When the activity of this protein is reduced, there is less 
inflammation in the lungs. This helps to stop narrowing of airways occurring in chronic obstructive 
pulmonary disease (COPD). Thus Daxas eases breathing problems.

Daxas is used for maintenance treatment of severe COPD in adults who in the past had frequent 
worsening of their COPD symptoms (so-called exacerbations) and who have chronic bronchitis. 
COPD is a chronic disease of the lungs that results in tightening of the airways (obstruction) and 
swelling and irritation of the walls of the small air passages (inflammation). This leads to symptoms 
such as coughing, wheezing, chest tightness or difficulty in breathing. Daxas is to be used in addition 
to bronchodilators.

2. What you need to know before you take Daxas

Do not take Daxas
- if you are allergic to roflumilast or any of the other ingredients of this medicine (listed in section 

6)
- if you have moderate or severe liver problems.

Warnings and precautions
Talk to your doctor or pharmacist before taking Daxas.

Sudden attack of breathlessness
Daxas is not intended for the treatment of a sudden attack of breathlessness (acute bronchospasms). In 
order to relieve a sudden attack of breathlessness it is very important that your doctor provides you 



48

with another medicine to be available to you at all times that can cope with such an attack. Daxas will 
not help you in this situation.

Body weight
You should check your body weight on a regular basis. Talk to your doctor if, while taking this 
medicine, you observe an unintentional loss of body weight (not related to a diet or exercise 
programme).

Other diseases
Daxas is not recommended if you have one or more of the following diseases:
- severe immunological diseases such as HIV infection, multiple sclerosis (MS), lupus 

erythematosus (LE) or progressive multifocal leukoencephalopathy (PML)
- severe acute infectious diseases such as acute hepatitis
- cancer (except basal-cell carcinoma, a slow-growing type of skin cancer)
- or severe impairment of the heart function
There is a lack of relevant experience with Daxas under these conditions. You should talk to your 
doctor, if you are diagnosed with any of these diseases.

Experience is also limited in patients with a previous diagnosis of tuberculosis, viral hepatitis, herpes 
viral infection or herpes zoster. Please talk to your doctor if you have one of these diseases.

Symptoms you should be aware of
You may experience diarrhoea, nausea, abdominal pain or headache during the first weeks of 
treatment with Daxas. Talk to your doctor if these side effects do not resolve within the first weeks of 
treatment.

Daxas is not recommended in patients with a history of depression associated with suicidal thinking or 
behaviour. You may also experience sleeplessness, anxiety, nervousness, or depressive mood. Before 
starting treatment with Daxas, inform your doctor if you are suffering from any symptoms of this kind 
and of any additional medicines you may take since some of those could increase the probability of 
these side effects. You or your caregiver should also immediately inform your doctor of any changes 
in behaviour or mood and of any suicidal thoughts you may have.

Children and adolescents
Do not give this medicine to children and adolescents under 18 years of age.

Other medicines and Daxas
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, especially the following:
- a medicine containing theophylline (a medicine to treat respiratory diseases), or 
- a medicine used for treatment of immunological diseases, such as methotrexate, azathioprine, 

infliximab, etanercept, or oral corticosteroids to be taken long-term.
- a medicine containing fluvoxamine (a medicine to treat anxiety disorders and depression), 

enoxacin (a medicine to treat bacterial infections) or cimetidine (a medicine to treat stomach 
ulcers or heartburn).

The effect of Daxas may be reduced if taken together with rifampicin (an antibiotic medicine) or with 
phenobarbital, carbamazepine or phenytoin (medicines usually prescribed for the treatment of 
epilepsy). Ask your doctor for advice.

Daxas may be taken with other medicines used in the treatment of COPD such as inhaled or oral 
corticosteroids or bronchodilators. Do not stop taking these medicines or reduce their dose unless 
advised by your doctor.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.



49

You should not become pregnant during treatment with this medicine and should use an effective 
method of contraception during therapy, because Daxas may be harmful for the unborn baby.

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

Daxas contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.

3. How to take Daxas

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.

 For the first 28 days - the recommended starting dose is one 250 micrograms tablet once daily. 

- The starting dose is a low dose used to help your body get used to the medicine before you 

start taking the full dose. At this low dose you will not get the full effect from the medicine –

therefore it is important that you move on to the full dose (called a ‘maintenance dose’) after 

28 days.

 After 28 days - the recommended maintenance dose is one 500 micrograms tablet once daily.

Swallow the tablet with some water. You may take this medicine with or without food. Take the tablet
at the same time every day.

You may need to take Daxas for several weeks to achieve its beneficial effect.

If you take more Daxas than you should
If you have taken more tablets than you should, you may experience the following symptoms: 
headache, nausea, diarrhoea, dizziness, throbbing of your heart, light-headedness, clamminess and low 
blood pressure. Tell your doctor or pharmacist straight away. If possible take your medicine and this 
leaflet with you.

If you forget to take Daxas
If you forget to take a tablet at the usual time, take the tablet as soon as you remember on the same 
day. If on one day you have forgotten to take a tablet of Daxas, just carry on the next day with the next 
tablet as usual. Continue taking your medicine at the usual times. Do not take a double dose to make 
up for a forgotten dose.

If you stop taking Daxas
It is important to continue taking Daxas for as long as prescribed by your doctor, even when you have 
no symptoms, in order to maintain control of your lung function.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You may experience diarrhoea, nausea, stomach ache or headache during the first weeks of treatment 
with Daxas. Talk to your doctor if these side effects do not resolve within the first weeks of treatment.

Some side effects could be serious. In clinical studies and post-marketing experience, rare instances of 
suicidal thinking and behaviour (including suicide) were reported. Please notify your doctor 



50

immediately of any suicidal thoughts you may have. You may also experience sleeplessness
(common), anxiety (uncommon), nervousness (rare), panic attack (rare) or depressive mood (rare).

In uncommon cases allergic reactions may occur. Allergic reactions may affect the skin and in rare 
cases cause swelling of the eyelids, face, lips and tongue, possibly leading to difficulties in breathing
and/or a drop in blood pressure and accelerated heartbeat. In case of an allergic reaction, stop taking 
Daxas and contact your doctor immediately, or go immediately to the emergency department in the 
nearest hospital. Take all your medicines and this leaflet with you and provide full information of your 
current medications.

Other side effects include the following:

Common side effects (may affect up to 1 in 10 people)
- diarrhoea, nausea, stomach ache
- weight decrease, decreased appetite
- headache

Uncommon side effects (may affect up to 1 in 100 people)
- trembling, sensation of spinning head (vertigo), dizziness
- sensation of rapid or irregular heartbeat (palpitations)
- gastritis, vomiting
- reflux of stomach acid to the gullet (acid regurgitations), indigestion
- rash
- muscle pain, muscle weakness or cramps
- back pain
- feeling of weakness or tiredness, feeling unwell.

Rare side effects (may affect up to 1 in 1,000 people)
- male breast enlargement
- decreased sense of taste
- respiratory tract infections (excluding pneumonia)
- bloody stools, constipation
- elevation of liver or muscle enzymes (seen in blood tests)
- wheals (urticaria).

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Daxas

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.



51

6. Contents of the pack and other information

What Daxas contains
The active substance is roflumilast.

Each film-coated tablet (tablet) contains 500 micrograms roflumilast.
- The other ingredients are:

- Core: lactose monohydrate (see section 2 under “Daxas contains lactose”), maize starch, 
povidone, magnesium stearate,

- Coating: hypromellose, macrogol (4000), titanium dioxide (E171), and iron oxide yellow 
(E172).

What Daxas looks like and contents of the pack
Daxas 500 micrograms film-coated tablets are yellow, D-shaped film-coated tablets, embossed with 'D' 
on one side.
Each pack contains 10, 14, 28, 30, 84 , 90 or 98 film-coated tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
Takeda GmbH
Production site Oranienburg
Lehnitzstraße 70-98
16515 Oranienburg
Germany

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 24455000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca 
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00



52

Ελλάδα
AstraZeneca A.E.
Τηλ: +30 210 6871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.
Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777 

Italia
Simesa S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last approved in

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET