Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT

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
Daliresp 500 micrograms
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500 micrograms of roflumilast.
Excipient with known effect:
Each
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Yellow,
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Daliresp is indicated for maintenance treatment of severe chronic obstructive pulmonary disease (COPD) (FEV1
4.2Posology and method of administration
Posology
The recommended dose is 500 micrograms (one tablet) roflumilast once daily.
Daliresp may need to be taken for several weeks to achieve its effect (see section 5.1). Daliresp has been studied in clinical trials for up to one year.
Special populations
Elderly
No dose adjustment is necessary.
Renal impairment
No dose adjustment is necessary.
Hepatic impairment
The clinical data with Daliresp in patients with mild hepatic impairment classified as
Patients with moderate or severe hepatic impairment classified as
Paediatric population
There is no relevant use of Daliresp in the paediatric population (under 18 years) in the indication 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.
4.3Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Moderate or severe hepatic impairment
4.4Special warnings and precautions for use
All patients should be informed about the risks of Daliresp and the precautions for safe use and should be given a patient card before starting Daliresp.
Rescue medicinal products
Daliresp is not indicated as rescue medicinal product for the relief of acute bronchospasms.
Weight decrease
In
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
Special clinical conditions
Due to lack of relevant experience, treatment with roflumilast should not be initiated or existing treatment with roflumilast should be stopped in patients with severe immunological diseases (e.g. HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy), severe acute infectious diseases, cancers (except basal cell carcinoma), or patients being treated with immunosuppressive medicinal products (i.e.: methotrexate, azathioprine, infliximab, etanercept, or oral corticosteroids to be taken
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
- Libertek - roflumilast
- Daxas - roflumilast
Prescription drugs listed. Substance: "Roflumilast"
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,
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
Daliresp tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or
4.5Interaction 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
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.
No interactions were observed with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, warfarin, sildenafil and midazolam.
4.6Fertility, 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
Fertility
In a human spermatogenesis study, roflumilast 500 micrograms had no effects on semen parameters or reproductive hormones during the
4.7Effects on ability to drive and use machines
Daliresp has no influence on the ability to drive and use machines.
4.8Undesirable effects
Summary of the safety profile
In clinical COPD studies, approximately 16% of patients experienced adverse reactions with roflumilast (compared to 5% in placebo). The most commonly reported adverse reactions were diarrhoea (5.9%), weight decreased (3.4%), nausea (2.9%), abdominal pain (1.9%) and headache (1.7%). The majority of these adverse reactions were mild or moderate. These adverse reactions mainly occurred within the first weeks of therapy and mostly resolved on continued treatment.
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
Frequency | Common | Uncommon | Rare |
System |
|
|
|
Organ Class |
|
|
|
Immune system disorders |
| Hypersensitivity | Angioedema |
Endocrine disorders |
|
| Gynaecomastia |
Metabolism and nutrition | Weight decreased |
|
|
disorders | Decreased |
|
|
| appetite |
|
|
Psychiatric disorders | Insomnia | Anxiety | Suicidal ideation and |
|
|
| behaviour* |
|
|
| Depression |
|
|
| Nervousness |
|
|
| Panic attack |
Nervous system disorders | Headache | Tremor | Dysgeusia |
|
| Vertigo |
|
|
| Dizziness |
|
Cardiac disorders |
| Palpitations |
|
Respiratory, thoracic and |
|
| Respiratory tract |
mediastinal disorders |
|
| infections (excluding |
|
|
| Pneumonia) |
Gastrointestinal disorders | Diarrhoea | Gastritis | Haematochezia |
| Nausea | Vomiting | Constipation |
| Abdominal pain |
| |
|
| reflux disease |
|
|
| Dyspepsia |
|
Hepatobiliary disorders |
|
| |
|
|
| Aspartate |
|
|
| aminotransferase (AST) |
|
|
| increased |
Skin and subcutaneous |
| Rash | Urticaria |
tissue disorders |
|
|
|
Musculoskeletal and |
| Muscle spasms and | Blood creatine |
connective tissue disorders |
| weakness | phosphokinase (CPK) |
|
| Myalgia | increased |
|
| Back pain |
|
General disorders and |
| Malaise |
|
administration site |
| Asthenia |
|
conditions |
| Fatigue |
|
Description of selected adverse reactions
* In clinical studies and
Other special populations
A higher incidence of sleep disorders (mainly insomnia) in patients ≥75 years or older was observed in Study
A higher incidence of sleep disorders (mainly insomnia) in patients with a baseline body weight <60 kg was observed in Study

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
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.
4.9Overdose
- Komboglyze - AstraZeneca AB
- Brimica genuair - AstraZeneca AB
- Zavicefta - AstraZeneca AB
- Libertek - AstraZeneca AB
- Onglyza - AstraZeneca AB
- Lynparza - AstraZeneca AB
Prescription drugs listed. Manufacturer: "AstraZeneca AB"
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,
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
5.1Pharmacodynamic 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
Pharmacodynamic effects
Inhibition of PDE4 leads to elevated intracellular cAMP levels and mitigates
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
The
In a pooled analysis of the
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 randomized in two supportive
Two
concomitant treatment with salmeterol in study
Study
Table 2. Summary of COPD exacerbation endpoints in Study
|
| Roflumilast | Placebo | Ratio Roflumilast/Placebo |
| |||
Exacerbation | Analysis | (N=969) | (N=966) | Rate | Change |
| ||
Category | model | Rate (n) | Rate (n) | Ratio | (%) | 95% CI | ||
Moderate or | Poisson | 0.805 | 0.927 | 0.868 | 0.753, | 0.0529 | ||
severe | regression | (380) | (432) | 1.002 | ||||
|
|
| ||||||
Moderate | Poisson | 0.574 | 0.627 | 0.914 | 0.775, | 0.2875 | ||
| regression | (287) | (333) | 1.078 | ||||
|
|
|
| |||||
Severe | Negative | 0.239 | 0.315 |
|
| 0.601, |
| |
| binomial | (151) | (192) | 0.757 | 0.0175 | |||
| 0.952 | |||||||
| regression |
|
|
|
|
| ||
|
|
|
|
|
|
|
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
The
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).
Seventeen (1.8%) patients in the roflumilast group and 18 (1.9%) patients in the placebo group died during the
and placebo groups, respectively. The observed adverse reactions for roflumilast in Study
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.
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).
5.2Pharmacokinetic properties
Roflumilast is extensively metabolised in humans, with the formation of a major pharmacodynamically active metabolite, roflumilast
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
Distribution
Plasma protein binding of roflumilast and its
Biotransformation
Roflumilast is extensively metabolised via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The
In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to its
Elimination
The plasma clearance after
approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its
- Daxas - R03DX07
Prescription drugs listed. ATC Code: "R03DX07"
The pharmacokinetics of roflumilast and its
Special populations
In older people, females and in
In study
Renal impairment
Total PDE4 inhibitory activity decreased by 9% in patients with severe renal impairment (creatinine clearance
Hepatic impairment
The pharmacokinetics of roflumilast 250 micrograms
5.3Preclinical 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
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,
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
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Core
Lactose monohydrate
Maize starch
Povidone (K90)
Magnesium stearate
Coating
Hypromellose Macrogol 4000
Titanium dioxide (E171)
Iron oxide yellow (E172)
6.2Incompatibilities
Not applicable.
6.3Shelf life
3 years.
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5Nature and contents of container
PVC/PVDC aluminum blisters in packs of 10, 30, or 90
Not all pack sizes may be marketed.
6.6Special precautions for disposal
No special requirements.
7.MARKETING AUTHORISATION HOLDER
AstraZeneca AB
Sweden
8.MARKETING AUTHORISATION NUMBER(S)
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 28 February 2011
- Capecitabine medac
- Grastofil
- Lonquex
- Insuman
- Modigraf
- Integrilin
Prescription drugs listed:
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
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