1. Name Of The Medicinal Product
Daxas ®
2. Qualitative And Quantitative Composition
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. Pharmaceutical Form
Film-coated tablet (tablet).
Yellow, D-shaped film-coated tablet, 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
The recommended dose is one tablet of 500 micrograms roflumilast once daily.
Daxas may need to be taken for several weeks to achieve its effect (see section 5.1). Daxas 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 Daxas 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 should not take Daxas (see section 4.3).
Paediatric population
There is no relevant use of Daxas 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.
4.3 Contraindications
Hypersensitivity to roflumilast or to any of the excipients (see 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 and should be given a patient card before starting Daxas.
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 Daxas compared to placebo-treated patients. After discontinuation of Daxas, 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 Daxas should be stopped and body weight should be further followed-up.
Special clinical conditions
Due to lack of relevant experience, treatment with Daxas should not be initiated or existing treatment with Daxas 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
Daxas is associated with an increased risk of psychiatric disorders such as insomnia, anxiety, nervousness and depression. Rare instances of suicidal ideation and behaviour, including completed suicide, have been observed in clinical trials (see section 4.8). Therefore, the risks and benefits of starting or continuing treatment with Daxas 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. Patients should be instructed to notify their prescriber of any changes in behaviour or mood and of any suicidal ideation. Moreover, Daxas is not recommended in patients with a history of depression associated with suicidal ideation or behaviour.
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, Daxas 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
Daxas 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.
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. Clinical interaction studies with CYP3A4 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 Daxas with these active substances might lead to an increase of exposure and persistent intolerability. In this case, Daxas 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
4.6 Pregnancy And Lactation
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). Daxas is not recommended during pregnancy and in women of childbearing potential not using contraception.
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. Daxas 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
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
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 (
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions with roflumilast in clinical COPD studies
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In clinical studies, rare instances of suicidal thinking and behaviour (including completed suicide) were reported. Patients should be instructed to notify their prescriber of any suicidal ideation (see also section 4.4).
4.9 Overdose
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. 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 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
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.
Clinical efficacy
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 Daxas. 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)
In a pooled analysis of the one-year studies M2-124 and M2-125, Daxas 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 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 Daxas 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 (M21, 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 M21 was significantly improved by 49 ml (primary endpoint, p<0.0001) beyond the bronchodilator effect of concomitant treatment with salmeterol in study M2
No study has been conducted to compare Daxas 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 Daxas 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 Nmax) 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 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 Nin vivo.
In vitro studies and clinical interaction studies suggest that the metabolism of roflumilast to its Nin 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 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, Daxas 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 Daxas 250 micrograms once-daily was tested in 8 patients with mild to moderate hepatic impairment classified as Child
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 (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 And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Nycomed GmbH
Byk-Gulden-Straße 2
D-78467 Konstanz
Germany
8. Marketing Authorisation Number(S)
EU/1/10/636/001: 10 tablets pack
EU/1/10/636/002: 30 tablets pack
EU/1/10/636/003: 90 tablets pack
9. Date Of First Authorisation/Renewal Of The Authorisation
July 2010
10. Date Of Revision Of The Text
July 2010
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
© Merck Sharp & Dohme Limited, 2010. All rights reserved.
SPC.DAX.10.UK.3281
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