ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Daliresp 500 micrograms film-coated tablets
2.
Each tablet contains 500 micrograms of roflumilast.
Excipient: This product contains 199 mg lactose monohydrate per film-coated tablet.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Yellow, D-shaped film-coated tablet, embossed with “D” on one side.
4.
Daliresp 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.
The recommended dose is one tablet of 500 micrograms 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 (65 years and older)
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 Child-Pugh A
are insufficient to recommend a dose adjustment (see section 5.2) and therefore Daliresp should be
used with caution in these patients.
Patients with moderate or severe hepatic impairment classified as Child-Pugh B or C should not take
Daliresp (see section 4.3).
2
Posology
Paediatric population
There is no relevant use of Daliresp in the paediatric population (under 18 years).
Method of administration
For oral use.
The tablet should be swallowed with water and taken at the same time every day. The tablet can be
taken with or without food.
Hypersensitivity to roflumilast or to any of the excipients (see section 6.1).
Moderate or severe hepatic impairment (Child-Pugh B or C).
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
Roflumilast is an anti-inflammatory substance indicated for maintenance treatment of severe
COPD
associated with chronic bronchitis in adult patients with a history of frequent exacerbations as add on
to bronchodilator treatment. It 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 Daliresp compared to placebo-treated patients. After discontinuation of Daliresp, 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 Daliresp should be stopped and body weight should be further
followed-up.
Special clinical conditions
Due to lack of relevant experience, treatment with Daliresp should not be initiated or existing
treatment with Daliresp should be stopped in patients with severe immunological diseases (e.g. HIV
infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy),
severe acute infectious diseases, cancers (except basal cell carcinoma), or patients being treated with
immunosuppressive medicinal products (i.e.: methotrexate, azathioprine, infliximab, etanercept, or
oral corticosteroids to be taken long-term; except short-term systemic corticosteroids). Experience in
patients with latent infections such as tuberculosis, viral hepatitis, herpes viral infection and herpes
zoster is limited.
Patients with congestive heart failure (NYHA grades 3 and 4) have not been studied and therefore
treatment of these patients is not recommended.
Psychiatric disorders
Daliresp is associated with an increased risk of psychiatric disorders such as insomnia, anxiety,
nervousness and depression. Rare instances of suicidal ideation and behavior, including completed
suicide, have been observed in clinical trials (see section 4.8). Therefore, the risks and benefits of
starting or continuing treatment with Daliresp 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.
Pati ents shoul d be i nstructed to noti f y thei r prescri ber of any
changes i n behavi or or mood and of any sui ci dal i deati on. M oreover, D al i r esp i s not recommended i n
pat i ent s w i t h a hi story of depressi on associ ated wi th sui ci dal i deati on or behavi or.
3
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, Daliresp 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 the CYP1A2 inhibitor fluvoxamine or the dual CYP3A4/1A2 inhibitors
enoxacin and cimetidine (see section 4.5).
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 glucose-galactose malabsorption should not take this medicinal product.
Interaction studies have only been performed in adults.
A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by
CYP3A4 and CYP1A2. Both roflumilast and roflumilast N-oxide have intrinsic phosphodiesterase 4
(PDE4) inhibitory activity. Therefore, following administration of roflumilast, the total PDE4
inhibition is considered to be the combined effect of both roflumilast and roflumilast N-oxide.
Clinical interaction studies with CYP 3A4 inhibitors erythromycin and ketoconazole showed
increases of 9% of the total PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast
N-oxide). Interaction studies with CYP1A2 inhibitor fluvoxamine, and the dual CYP3A4/1A2
inhibitors enoxacin and cimetidine resulted in increases of the total PDE4 inhibitory activity of 59%,
25% and 47%, respectively. A combination of Daliresp with these active substances might lead to an
increase of exposure and persistent intolerability. In this case, Daliresp 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 inducers (e.g.
phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic efficacy of roflumilast.
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 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.
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). Daliresp is not recommended
during pregnancy and in women of childbearing potential not using contraception.
4
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 suckling child cannot be excluded. Daliresp 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.
Daliresp has no influence on the ability to drive and use machines.
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.
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
Frequency
Common
Uncommon
Rare
System
Organ Class
Immune system disorders
Hypersensitivity
Endocrine disorders
Gynaecomastia
Metabolism and nutrition
disorders
Weight decreased
Decreased
appetite
Psychiatric disorders
Insomnia
Anxiety
Depression
Nervousness
Nervous system disorders Headache
Tremor
Vertigo
Dizziness
Dysgeusia
Cardiac disorders
Palpitations
Respiratory, thoracic and
mediastinal disorders
Respiratory tract
infections (excluding
Pneumonia)
Gastrointestinal disorders Diarrhoea
Gastritis
Haematochezia
5
Frequency
Common
Uncommon
Rare
System
Organ Class
Nausea
Abdominal pain
Vomiting
Gastro-esophageal
reflux disease
Dyspepsia
Constipation
Hepatobiliary disorders
Gamma-GT increased
Aspartate
aminotransferase (AST)
increased
Skin and subcutaneous
tissue disorders
Rash
Urticaria
Musculoskeletal and
connective tissue
disorders
Muscle spasms and
weakness
Myalgia
Back pain
Blood creatine
phosphokinase (CPK)
increased
General disorders and
administration site
conditions
Malaise
Asthenia
Fatigue
In clinical studies, rare instances of suicidal thinking and behavior (including completed suicide) were
reported. Patients should be instructed to notify their prescriber of any suicidal ideation (see also
section 4.4).
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.
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.
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 agent 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.
6
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, tumor 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.
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 randomized and treated of
whom 2,374 were treated with Daliresp. 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 [FEV
1
(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, Daliresp 500 micrograms once daily
significantly improved lung function compared to placebo, on average by 48 ml (pre-bronchodilator
FEV
1
, primary endpoint, p<0.0001), and by 55 ml (post-bronchodilator FEV
1
, 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 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 Daliresp 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 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.
Daliresp 500 micrograms once daily significantly improved lung function compared to placebo, on
average by 51 ml (pre-bronchodilator FEV
1
, p<0.0001), and by 53 ml (post-bronchodilator FEV
1
,
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.
7
Clinical efficacy
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 FEV
1
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 FEV
1
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.
No study has been conducted to compare Daliresp to the combination of LABA plus inhaled
corticosteroids or on top of the combination of LABA plus inhaled corticosteroids.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with
Daliresp 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 (t
max
) of
roflumilast by one hour and reduces C
max
by approximately 40%. However, C
max
and t
max
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
radiolabeled 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
8
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 radiolabeled
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 elderly, 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, Daliresp treatment should be reassessed (see 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 Daliresp 250 micrograms once-daily was tested in 8 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 Daliresp 250 and
500 micrograms in patients with mild and moderate hepatic impairment. Caution is necessary in
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 Daliresp (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
9
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.
6.1 List of excipients
Core
Lactose monohydrate
Maize starch
Povidone (K90)
Magnesium stearate
Coating
Hypromellose 2910
Macrogol 4000
Titanium dioxide (E171)
Iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 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 10, 30, or 90 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Nycomed GmbH
Byk-Gulden-Straße 2
D-78467 Konstanz
Germany
10
8.
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
11
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR
BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
12
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Nycomed GmbH
Production Site Oranienburg
Lehnitzstrasse 70-98
D-16515 Oranienburg
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Prior to launch of the product in each Member State, the Marketing Authorisation Holder shall agree
the content and format of the educational material with the national competent authority.
The Marketing Authorisation Holder (MAH) should ensure that, at launch, all Healthcare
Professionals who are expected to prescribe Daliresp are provided with an Educational pack.
The educational pack should contain the following:
•
Summary of Product Characteristics and Patient Information Leaflet for Daliresp
•
Educational material for the physician.
•
Copies of the patient card to be given to patients before they receive Daliresp
The educational material for the prescriber should include information on the following key elements:
The specific indication approved. The fact that Daliresp is not indicated for the treatment of
COPD patients other than those covered by the approved indication, nor for use in patients
with asthma or alpha 1 anti trypsine deficiency.
The need to inform patients about the risks of Daliresp and the precautions for safe use
The risk of weight decrease in underweight patients and the need to monitor the body weight
at each visit and to stop the treatment in the event of an unexplained and clinically concerning
weight decrease. Patients should be advised to weigh themselves at regular intervals and
record the weight in the patient card.
The risk of psychiatric disorders such as insomnia, anxiety, depression in patients receiving
Daliresp and the potential risk of suicide. Hence, the need to carefully assess the benefit risk
balance of this treatment in patients with existing psychiatric symptoms or with history of
depression and to inform patients to report any changes in behaviour, mood and any suicidal
ideation. Daliresp is not recommended in patients with a history of depression associated with
suicidal ideation or behaviour.
13
The potential risk of malignant tumours and the lack of experience in patients with past
history of cancer. Daliresp should not be initiated or should be stopped in patients with
cancers (except basal cell carcinoma).
That increased exposure might occur in certain populations and increase the risk of persistent
intolerability:
o
Special populations who have increased PDE4 inhibition such as black non smoking
females
o
Patients concomitantly treated with CYP1A2 inhibitors (such as fluvoxamine) or dual
CYP3A4/1A2 inhibitors (such as enoxacin and cimetidine)
The potential risk of infections: Daliresp should not be initiated, or treatment should be
stopped, in patients with severe acute infectious diseases. The limited experience in patients
with latent infections such as tuberculosis, viral hepatitis or herpes infections.
The lack of experience in patients with HIV infection or active hepatitis, with severe
immunological diseases (e.g.multiple sclerosis, lupus erythematous, multifocal
leukoencephalopathy) or treated with immunosuppressive therapy (other than short-term
systemic corticosteroids) and that Daliresp should not be initiated or should be stopped in
these patients.
The potential cardiac risk: Daliresp has not been studied in patients in congestive heart failure
(NYHA grade 3 and 4); hence, it is not recommended in this population.
The limited or missing information in patients with liver impairment. Daliresp is
contraindicated in patients with moderate or severe liver impairment (Child Pugh B or C).
Clinical data are considered insufficient to recommend dose adjustment and caution should be
observed in patients with mild liver impairment (child Pugh A).
The lack of clinical data to support the combination with theophylline and that such
combination is not recommended.
Patient Card
The patient card should contain the following key elements:
That they should tell their doctor if they have a history of any of the following conditions
•
cancer
•
insomnia, anxiety, depression, suicidal ideation or behaviour
•
multiple sclerosis or SLE
•
infection with tuberculosis, herpes, hepatitis, HIV
That patients should tell their doctor if they develop symptoms indicative of:
•
insomnia, anxiety, depression, suicidal ideation or behaviour
•
severe infection
That patients should tell their doctor if they are taking any other medicines.
That Daliresp may cause weight loss and patients should weigh themselves regularly and record their
weight on the patient card.
The patient card should include an area where patients can record their weight and the date they
weighed themselves and they should be asked to bring the patient card with them at each visit.
14
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.0 dated 11 October 2010 of the Risk Management
Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of
the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
15
ANNEX III
LABELLING AND PACKAGE LEAFLET
16
A. LABELLING
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON FOR BLISTER
1.
Daliresp 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.
10 film-coated tablets
30 film-coated tablets
90 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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
18
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Nycomed GmbH
Byk-Gulden-Straße 2
D-78467 Konstanz
Germany
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Daliresp 500
19
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTERS
1.
Daliresp 500 micrograms tablets
roflumilast
2.
Nycomed
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
Daliresp 500 micrograms film-coated tablets
Roflumilast
Read all of this leaflet carefully before you start taking this medicine.
-
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. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Daliresp is and what it is used for
2.
Before you take Daliresp
3.
How to take Daliresp
4.
Possible side effects
5.
How to store Daliresp
1
WHAT DALIRESP IS AND WHAT IT IS USED FOR
Daliresp 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 Daliresp eases breathing problems.
Daliresp is used to treat severe COPD in adults. 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) leading to symptoms such as coughing, wheezing, chest tightness or
difficulty in breathing. Daliresp is to be used in addition to bronchodilators.
2
BEFORE YOU TAKE DALIRESP
Do not take Daliresp
-
if you are allergic (hypersensitive) to roflumilast or any of the other ingredients of Daliresp
(listed in section 6 ‘What Daliresp contains’)
-
if you have moderate or severe liver disease.
Take special care with Daliresp
Daliresp 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
with another medicine to be available to you at all times that can cope with such an attack. Daliresp
will not help you in this situation.
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).
Daliresp is not recommended for patients having severe immunological diseases (such as HIV
infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy, and
others), severe acute infectious diseases (such as tuberculosis, or acute hepatitis), cancer (except
22
6.
Further information
basal-cell carcinoma, a slow-growing type of skin cancer), or severe impairment of the heart function,
due to lack of relevant experience with Daliresp 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.
You may experience diarrhoea, nausea, abdominal pain or headache during the first weeks of
treatment with Daliresp. Talk to your doctor if these side effects do not resolve within the first weeks
of treatment.
You may also experience sleeplessness, anxiety, nervousness, or depressive mood. Before starting
treatment with Daliresp, inform your doctor if you are suffering from any symptoms of this kind and
of any additional medicinal products you may take since some of those could increase the probability
of these side effects. You should also immediately inform your doctor of any suicidal thoughts you
may have.
Children
Daliresp should not be used by children and adolescents under 18 years of age.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Daliresp 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.
Please let your doctor know before you start to take Daliresp, if you already take:
- 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, enoxacin or cimetidine.
The effect of Daliresp 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.
Taking Daliresp with food and drink
You may take this medicine with or without food.
Pregnancy and breast-feeding
Do not take Daliresp if you are or plan to become pregnant, think you may be pregnant, or are
breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Daliresp has no influence on the ability to drive and use machines.
Important information about some of the ingredients of Daliresp
Daliresp tablets contain lactose. If you have been told by your doctor that you have an intolerance to
some sugars, contact your doctor before taking this medicine.
23
3
HOW TO TAKE DALIRESP
Always take Daliresp exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose is one 500 micrograms tablet once daily. Do not take more tablets than your doctor has
recommended.
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 Daliresp for several weeks to achieve its beneficial effect.
If you take more Daliresp than you should
Tell your doctor or pharmacist straight away. If possible take your medicine and this leaflet with you.
If you forget to take Daliresp
If you forget to take a tablet at the usual time, take the tablet as soon as you remember. If on one day
you have forgotten to take a tablet of Daliresp, 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 Daliresp
It is important to continue taking Daliresp 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, Daliresp can cause side effects, although not everybody gets them.
Side effects may occur with certain frequencies, which are defined as follows:
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.
Common side effects
Weight decrease, decreased appetite; sleeplessness; headache; diarrhoea, nausea, stomach ache.
Uncommon side effects
Hypersensitivity (a generalised allergic reaction that may affect the skin, mouth and tongue, possibly
leading to difficulties in breathing and/or a drop in blood pressure and accelerated heartbeat); feeling
anxious; 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 or cramps; back pain; feeling of weakness or tiredness; feeling unwell.
Rare side effects
Male breast enlargement; feeling nervous or depressed; decreased sense of taste; respiratory tract
infections (excluding pneumonia); bloody stools, constipation; elevation of liver or muscle enzymes
(seen in blood tests); wheals (urticaria).
24
In the rare case of a severe allergic reaction, stop taking Daliresp and contact your doctor
immediately, or go immediately to the emergency department in the nearest hospital. Take your
medicine and this leaflet with you to provide full information of your proper treatment. Typical
symptoms of a severe allergic reaction are: swelling of the face, lips, mouth, tongue and/or throat,
which may cause difficulty in swallowing or breathing, hives (nettle rash), severe dizziness with very
fast heartbeat and heavy sweating.
In clinical studies, some instances of suicidal thinking and behavior (including suicide) were reported.
Please notify your doctor immediately of any suicidal thoughts you may have.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE DALIRESP
Keep out of the reach and sight of children.
Do not use Daliresp 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.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Daliresp contains
-
The active substance is roflumilast. Each film-coated tablet (tablet) contains 500 micrograms
roflumilast.
-
The other ingredients are:
-
Core: lactose monohydrate, maize starch, povidone (K90), magnesium stearate,
-
Coating: hypromellose 2910, Macrogol 4000, titanium dioxide (E171), and iron oxide
yellow (E172).
What Daliresp looks like and contents of the pack
Daliresp 500 micrograms film-coated tablets are yellow, D-shaped film-coated tablets, embossed with
'D' on one side.
Each PVC/PVDC aluminium blister pack contains 10, 30, or 90 film-coated tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Nycomed GmbH
Byk-Gulden-Straße 2
78467 Konstanz
Germany
Manufacturer
Nycomed GmbH
Production site Oranienburg
Lehnitzstraße 70-98
16515 Oranienburg
Germany
25
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Nycomed Belgium
Chaussée de Gand 615 Gentsesteenweg
B-1080 Brussel / Bruxelles / Brüssel
Tél/Tel: + 32 2 464 06 11
Lietuva
”Nycomed”, UAB
Gynėjų 16
LT-01109 Vilnius
Tel: +370 521 09 070
България
ТП „Никомед” ГМБХ
бул. България № 58, вх. С, етаж 6, офис 21
София 1404
Тел.: + 3592 958 27 36; + 3592 958 15 29
Luxembourg/Luxemburg
Nycomed Belgium
Chaussée de Gand 615 Gentsesteenweg
B-1080 Bruxelles / Brüssel
Belgique/Belgien
Tél/Tel: + 32 2 464 06 11
Česká republika
Nycomed s.r.o.
Novodvorská 994/138
142 21 Praha 4
Tel: + 420 239 044 244
Magyarország
Nycomed Pharma Kft.
Népfürdő u. 22.
H-1138 Budapest
Tel.: + 36 1 270 7030
Danmark
Nycomed Danmark ApS
Langebjerg 1
DK-4000 Roskilde
Tlf: + 45 46 77 11 11
Nederland
Nycomed bv
Jupiterstraat 250
NL-2132 HK Hoofddorp
Tel: + 31 23 566 8777
Deutschland
Nycomed Deutschland GmbH
Moltkestr. 4
D-78467 Konstanz
Tel: + 49 7531-36660
Norge
Nycomed Pharma AS
Postboks 205
Drammensveien 852
N-1372 Asker
Tlf: + 47 6676 3030
Eesti
Nycomed SEFA AS
Pirita tee 20T
EE-10127 Tallinn
Tel: + 372 6177 669
Österreich
Nycomed Pharma GmbH
EURO PLAZA, Gebäude F
Technologiestraße 5
A-1120 Wien
Tel: + 43 (0)1 815 0202-0
Ελλάδα
Nycomed Hellas S.A.
Λεωφ. Κηφισίας 196
GR-152 31 Χαλάνδρι, Αθήνα
Tηλ: + 30 210 672 9570
Polska
Nycomed Pharma Sp. z o.o.
Al. Jerozolimskie 146 A
PL – 02-305 Warszawa
Tel.: +48 22 608 13 00
España
Nycomed Pharma, S.A.
Calle Alsasua 20
E-28023 Madrid
Tlf: + 34 91 714 99 00
Portugal
Nycomed Portugal – Produtos Farmacêuticos,
Lda.
Quinta da Fonte – Edifício Gil Eanes
P – 2770-192 Paço de Arcos
Tel: + 351 214 460 200
26
France
Nycomed France SAS
13 rue Watt
F-75013 Paris
Tél: + 33 1 56 61 48 48
România
Nycomed Pharma SRL
Str. Episcop Chesarie nr.15, City Center, Corp C,
Sector 4
Bucureşti, Cod 020656-RO
Tel: + 40213350391
Ireland
Nycomed Products Limited
2051 Castledrive
Citywest Business Campus
Dublin 24, Ireland
Tel: + 353 1 642 0021
Slovenija
Nycomed GmbH
Podružnica Ljubljana
Dalmatinova ulica 2
SI-1000 Ljubljana
Tel: + 386 1 23 96 110
Ísland / Malta
Nycomed GmbH
Byk-Gulden-Straße 2
D-78467 Konstanz
Þýskalandi / Il-Ġermanja / Γερμανία
Sími / Tel / Τηλ: +49 7531 84 0
corporatecommunications@nycomed.com
Slovenská republika
Nycomed s.r.o.
Plynárenská 7B
SK-821 02 Bratislava
Tel: + 421 22060 2600
Italia
Nycomed S.p.A.
Via Libero Temolo 4
I-20126 Milano
Tel: + 39 02 641601
Suomi/Finland
Oy Leiras Finland Ab
PL/PB 1406
FIN-00101 Helsinki
Puh/Tel: + 358 20 746 5000
info@leiras.fi
Κύπρος
Mundipharma Pharmaceuticals Limited
13, Othellos Str.
Dhali Industrial Zone
CY- 1685 Nikosia
Τηλ: + 357 2281 5656
e-mail: Thekla.M.Petrou@Mundipharma.com.cy
Sverige
Nycomed AB
Box 27264
SE-102 53 Stockholm
Tel: + 46 8 731 28 00
infosweden@nycomed.com
Latvija
SIA Nycomed Latvija
Duntes iela 6
LV-1013 Riga
Tel: + 371 6784 0082
United Kingdom
Nycomed UK Ltd.
Three Globeside Business Park
Fieldhouse Lane
Marlow
Bucks, SL7 1HZ, UK
Tel: +44 1628 646400
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
27
Source: European Medicines Agency
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