DAXAS 500mcg tablets medication leaflet

Daxas 500 micrograms film-coated tablets

Each tablet contains 500 micrograms of roflumilast.

Each film-coated tablet contains 198.64 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

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

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 adultpatients with a history of frequent exacerbations as add on to bronchodilator treatment.

The recommended starting dose is one tablet of 250 micrograms roflumilast to be taken once daily, for28 days.

This starting dose is intended to reduce adverse reactions and patient discontinuation when initiatingtherapy, but it is a sub-therapeutic dose. Therefore, the 250 micrograms dose should be used only as astarting dose (see sections 5.1 and 5.2).

After 28 days of treatment with the 250 micrograms starting dose, patients must be up-titrated to onetablet 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 (seesections 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.

No dose adjustment is necessary.

No dose adjustment is necessary.

The clinical data with roflumilast in patients with mild hepatic impairment classified as Child-Pugh Aare insufficient to recommend a dose adjustment (see section 5.2) and therefore Daxas should be usedwith 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).

There is no relevant use of Daxas in the paediatric population (under 18 years) for the indication of

COPD.

For oral use.

The tablet should be swallowed with water and taken at the same time every day. The tablet can betaken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Moderate or severe hepatic impairment (Child-Pugh B or C).

All patients should be informed about the risks of Daxas and the precautions for safe use beforestarting 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 patientstreated with roflumilast compared to placebo-treated patients. After discontinuation of roflumilast, themajority of patients had regained body weight after 3 months.

Body weight of underweight patients should be checked at each visit. Patients should be advised tocheck their body weight on a regular basis. In the event of an unexplained and clinically concerningweight decrease, the intake of roflumilast should be stopped and body weight should be furtherfollowed-up.

Special clinical conditions

Due to lack of relevant experience, treatment with roflumilast should not be initiated or existingtreatment with roflumilast should be stopped in patients with severe immunological diseases (e.g. HIVinfection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy),severe acute infectious diseases, cancers (except basal cell carcinoma), or patients being treated withimmunosuppressive medicinal products (i.e. methotrexate, azathioprine, infliximab, etanercept, or oralcorticosteroids to be taken long-term; except short-term systemic corticosteroids). Experience inpatients with latent infections such as tuberculosis, viral hepatitis, herpes viral infection and herpeszoster is limited.

Patients with congestive heart failure (NYHA grades 3 and 4) have not been studied and thereforetreatment of these patients is not recommended.

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, havebeen observed in patients with or without history of depression, usually within the first weeks oftreatment (see section 4.8). The risks and benefits of starting or continuing treatment with roflumilastshould be carefully assessed if patients report previous or existing psychiatric symptoms or ifconcomitant 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 suicidalideation or behaviour. Patients and caregivers should be instructed to notify the prescriber of anychanges in behaviour or mood and of any suicidal ideation. If patients suffered from new or worseningpsychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended todiscontinue treatment with roflumilast.

Persistent intolerability

While adverse reactions like diarrhoea, nausea, abdominal pain and headache mainly occur within thefirst weeks of therapy and mostly resolve on continued treatment, roflumilast treatment should bereassessed in case of persistent intolerability. This might be the case in special populations that mayhave higher exposure, such as in black, non-smoking females (see section 5.2) or in patientsconcomitantly 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 patientswith a baseline body weight of <60 kg, due to a higher total PDE4 inhibitory activity found in thesepatients (see section 4.8).

Theophylline

There are no clinical data to support the concomitant treatment with theophylline for maintenancetherapy. Therefore, the concomitant treatment with theophylline is not recommended.

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

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 PDE4inhibition 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 inhibitorscimetidine and fluvoxamine, resulted in increases of the total PDE4 inhibitory activity of 25%, 47%and 59%, respectively. The tested dose of fluvoxamine was 50 mg. A combination of roflumilast withthese 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 enzymeinducers (e.g. phenobarbital, carbamazepine, phenytoin) may reduce the therapeutic efficacy ofroflumilast. Thus, roflumilast treatment is not recommended in patients receiving strong cytochrome

P450 enzyme inducers.

Clinical interaction studies with CYP3A4 inhibitors erythromycin and ketoconazole showed increasesof 9% of the total PDE4 inhibitory activity. Co-administration with theophylline resulted in anincrease of 8% of the total PDE4 inhibitory activity (see section 4.4). In an interaction study with anoral contraceptive containing gestodene and ethinyl oestradiol, the total PDE4 inhibitory activity wasincreased by 17%. No dose adjustment is necessary in patients receiving these active substances.

No interactions were observed with inhaled salbutamol, formoterol, budesonide and oral montelukast,digoxin, warfarin, sildenafil and midazolam.

Co-administration with an antacid (combination of aluminium hydroxide and magnesium hydroxide)did not alter the absorption or pharmacokinetics of roflumilast or its N-oxide.

Women of childbearing age should be advised to use an effective method of contraception duringtreatment. Roflumilast is not recommended in women of childbearing potential not usingcontraception.

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 notrecommended during pregnancy.

Roflumilast has been demonstrated to cross the placenta in pregnant rats.

Available pharmacokinetic data in animals have shown excretion of roflumilast or its metabolites inmilk. A risk to the breastfed infant cannot be excluded. Roflumilast should not be used duringbreast-feeding.

In a human spermatogenesis study, roflumilast 500 micrograms had no effects on semen parameters orreproductive hormones during the 3-month treatment period and the following 3-month off-treatmentperiod.

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

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 withinthe 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 availabledata).

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 Common Uncommon Rare

System

Organ Class

Immune system Hypersensitivity Angioedemadisorders

Endocrine disorders Gynaecomastia

Metabolism and Weight decreasednutrition disorders Decreasedappetite

Psychiatric disorders Insomnia Anxiety Suicidal ideation andbehaviour

Depression

Nervousness

Panic attack

Nervous system Headache Tremor Dysgeusiadisorders Vertigo

Dizziness

Cardiac disorders Palpitations

Respiratory, thoracic Respiratory tractand mediastinal infections (excludingdisorders Pneumonia)

Gastrointestinal Diarrhoea Gastritis Haematocheziadisorders Nausea Vomiting Constipation

Abdominal pain Gastro-esophagealreflux disease

Dyspepsia

Hepatobiliary disorders Gamma-GT increased

Aspartateaminotransferase (AST)increased

Skin and subcutaneous Rash Urticariatissue disorders

Musculoskeletal and Muscle spasms and Blood creatineconnective tissue weakness phosphokinase (CPK)disorders Myalgia increased

Back pain

Frequency Common Uncommon Rare

System

Organ Class

General disorders and Malaiseadministration site Astheniaconditions Fatigue

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 prescriberof any suicidal ideation (see also section 4.4).

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 withplacebo (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 comparedto those treated with placebo (6.0% vs 1.7%). The incidence was 2.5% vs 2.2% in patients with abaseline 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 observedduring Study RO-2455-404-RD in patients receiving concomitant roflumilast and long-actingmuscarinic antagonists (LAMA) plus concomitant inhaled corticosteroids (ICS) and long acting B2agonists (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% vs1.1%) and depression (1.4% vs -0.3%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In Phase I studies, the following symptoms were observed at an increased rate after single oral dosesof 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 arterialhypotension.

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

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

Roflumilast is a PDE4 inhibitor, a non-steroid, anti-inflammatory active substance designed to targetboth the systemic and pulmonary inflammation associated with COPD. The mechanism of action is theinhibition of PDE4, a major cyclic adenosine monophosphate (cAMP)-metabolizing enzyme found instructural 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 applyto roflumilast N-oxide, which is the major active metabolite of roflumilast.

Inhibition of PDE4 leads to elevated intracellular cAMP levels and mitigates COPD-relatedmalfunctions of leukocytes, airway and pulmonary vascular smooth muscle cells, endothelial andairway epithelial cells and fibroblasts in experimental models. Upon in vitro stimulation of humanneutrophils, monocytes, macrophages or lymphocytes, roflumilast and roflumilast N-oxide suppressthe release of inflammatory mediators e.g. leukotriene B4, reactive oxygen species, tumour necrosisfactor α, interferon γ and granzyme B.

In patients with COPD, roflumilast reduced sputum neutrophils. Furthermore, roflumilast attenuatedinflux 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 supplementarysix-month studies (M2-127 and M2-128), a total number of 4,768 patients were randomised andtreated 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 (forcedexpiratory volume in one second) ≤50% of predicted] associated with chronic bronchitis, with at leastone documented exacerbation in the previous year and with symptoms at baseline as determined bycough and sputum score. Long-acting beta-agonists (LABAs) were allowed in the studies and wereused in approximately 50% of the study population. Short-acting anticholinergics (SAMAs) wereallowed 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 wasprohibited 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 oncedaily 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 wasmaintained up to one year (end of treatment period). The rate (per patient per year) of moderateexacerbations (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 1.374with placebo corresponding to a relative risk reduction of 16.9% (95% CI: 8.2% to 24.8%) (primaryendpoint, p=0.0003). Effects were similar, independent of previous treatment with inhaledcorticosteroids or underlying treatment with LABAs. In the subgroup of patients with history offrequent exacerbations (at least 2 exacerbations during the last year), the rate of exacerbations was1.526 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 comparedwith placebo in the subgroup of patients with moderate COPD.

The reduction of moderate or severe exacerbations with roflumilast and LABA compared to placeboand LABA was on average 21% (p=0.0011). The respective reduction in exacerbations seen in patientswithout concomitant LABAs was on average 15% (p=0.0387). The numbers of patients who died dueto 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 COPDexacerbations 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, onaverage 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 byroflumilast 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 treatmentwith inhaled corticosteroids.

Two six-month supportive studies (M2-127 and M2-128) included patients with a history of COPD forat least 12 months prior to baseline. Both studies included moderate to severe patients with anon-reversible airway obstruction and a FEV1 of 40% to 70% of predicted. Roflumilast or placebotreatment was added to continuous treatment with a long-acting bronchodilator, in particularsalmeterol 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) beyondthe 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 effectof roflumilast on COPD exacerbation rate in patients treated with fixed combinations of LABA andinhaled 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 orsevere COPD exacerbations per patient per year. The rate of severe COPD exacerbations and changesin FEV1 were evaluated as key secondary endpoints.

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

Roflumilast Placebo Ratio Roflumilast/Placebo 2-Sided

Exacerbation Analysis (N=969) (N=966) Rate Change p-

Category model Rate (n) Rate (n) Ratio (%) 95% CI value

Moderate or Poisson 0.805 (380) 0.927 0.753,0.868 -13.2 0.0529severe regression (432) 1.002

Moderate Poisson 0.574 (287) 0.627 0.775,0.914 -8.6 0.2875regression (333) 1.078

Severe Negative 0.239 (151) 0.3150.601,binomial (192) 0.757 -24.3 0.01750.952regression

There was a trend towards a reduction in moderate or severe exacerbations in subjects treated withroflumilast compared with placebo over 52 weeks, which did not achieve statistical significance (Table2). A pre-specified sensitivity analysis using the negative binomial regression model treatment showeda 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 Poissonregression 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: 0.62to 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 patientstreated with placebo. A similar reduction was achieved in the subgroup of patients concomitantlytreated 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 placebogroup by 4 mL (95% CI: -16, 9 mL). Post-bronchodilator FEV1 showed a clinically significantimprovement 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 diedduring the double-blind treatment period due to any reason and 7 (0.7%) patients in each group due toa COPD exacerbation. The proportion of patients who experienced at least 1 adverse event during thedouble-blind treatment period were 648 (66.9%) patients and 572 (59.2%) patients in the roflumilastand 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 dueto any reason (risk ratio: 1.40; 95% CI: 1.19 to 1.65). The major reasons for trial discontinuation werewithdrawal of consent and reported adverse events.

Starting dose titration trial

The tolerability of roflumilast was evaluated in a 12-week randomised, double-blind, parallel grouptrial (RO-2455-302-RD) in patients with severe COPD associated with chronic bronchitis. Atscreening, patients were required to have had at least one exacerbation in the previous year and onstandard of care COPD maintenance treatment for at least 12 weeks. A total of 1323 patients wererandomised to receive roflumilast 500 micrograms once a day for 12 weeks (n=443), roflumilast500 micrograms every other day for 4 weeks followed by roflumilast 500 micrograms once a day for8 weeks (n=439), or roflumilast 250 micrograms once a day for 4 weeks followed by roflumilast500 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 anyreason was statistically significantly lower in patients initially receiving roflumilast 250 microgramsonce 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 Ratio0.66, 95% CI [0.47, 0.93], p=0.017). The discontinuation rate for those receiving 500 microgramsevery other day for 4 weeks followed by 500 micrograms once a day for 8 weeks was not statisticallysignificantly different to those receiving 500 micrograms once a day for 12 weeks. The percentage ofpatients experiencing a Treatment Emergent Adverse Event (TEAE) of interest, defined as diarrhoea,nausea, headache, decreased appetite, insomnia, and abdominal pain (secondary endpoint), wasnominally statistically significantly lower in patients initially receiving roflumilast 250 microgramsonce 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 Ratio0.63, 95% CI [0.47, 0.83], p=0.001). The rate of experiencing a TEAE of interest for those receiving500 micrograms every other day for 4 weeks followed by 500 micrograms once a day for 8 weeks wasnot 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 inhibitoryactivity of 0.6 (0.20, 1.24). Long-term administration at the 250 micrograms dose level may not inducesufficient PDE4 inhibition to exert clinical efficacy. 250 micrograms once a day is a sub-therapeuticdose, and should be used only as a starting dose for the first 28 days (see sections 4.2 and 5.2).

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

Roflumilast is extensively metabolised in humans, with the formation of a majorpharmacodynamically active metabolite, roflumilast N-oxide. Since both roflumilast and roflumilast

N-oxide contribute to PDE4 inhibitory activity in vivo, pharmacokinetic considerations are based ontotal PDE4 inhibitory activity (i.e. total exposure to roflumilast and roflumilast N-oxide).

The absolute bioavailability of roflumilast following a 500 micrograms oral dose is approximately80%. Maximum plasma concentrations of roflumilast typically occur approximately one hour afterdosing (ranging from 0.5 to 2 hours) in the fasted state. Maximum concentrations of the N-oxidemetabolite are reached after about eight hours (ranging from 4 to 13 hours). Food intake does notaffect the total PDE4 inhibitory activity, but delays time to maximum concentration (tmax) ofroflumilast by one hour and reduces Cmax by approximately 40%. However, Cmax and tmax of roflumilast

N-oxide are unaffected.

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 tissuesincluding fatty tissue of mice, hamster and rat. An early distribution phase with marked penetrationinto tissues is followed by a marked elimination phase out of fatty tissue most probably due topronounced break-down of parent compound to roflumilast N-oxide. These studies in rats withradiolabelled roflumilast also indicate low penetration across the blood-brain barrier. There is noevidence for a specific accumulation or retention of roflumilast or its metabolites in organs and fattytissue.

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. Theplasma AUC of the N-oxide metabolite on average is about 10-fold greater than the plasma AUC ofroflumilast. Thus, the N-oxide metabolite is considered to be the main contributor to the total PDE4inhibitory 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 humanhepatic microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do notinhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a lowprobability of relevant interactions with substances metabolised by these P450 enzymes. In addition, invitro studies demonstrated no induction of the CYP1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weakinduction of CYP2B6 by roflumilast.

The plasma clearance after short-term intravenous infusion of roflumilast is about 9.6 l/h. Followingan oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite areapproximately 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 radiolabelledroflumilast, about 20% of the radioactivity was recovered in the faeces and 70% in urine as inactivemetabolites.

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

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 tobe clinically meaningful. No dose adjustment is recommended in these patients. A combination offactors, such as in black, non-smoking females, might lead to an increase of exposure and persistentintolerability. 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 inhibitoryactivity determined from ex vivo unbound fractions was found to be 15% higher in patients ≥75 yearsof age, and 11% higher in patients with baseline body weight <60 kg (refer to section 4.4).

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

The pharmacokinetics of roflumilast 250 micrograms once-daily was tested in 16 patients with mild tomoderate hepatic impairment classified as Child-Pugh A and B. In these patients, the total PDE4inhibitory activity was increased by about 20% in patients with Child-Pugh A and about 90% inpatients with Child-Pugh B. Simulations suggest dose proportionality between roflumilast 250 and500 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 classifiedas Child-Pugh B or C should not take roflumilast (see section 4.3).

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. Noepididymal toxicity or changes in semen parameters were present in any other rodent or non-rodentspecies including monkeys in spite of higher exposures.

In one of two rat embryofetal development studies, a higher incidence of incomplete skull boneossification was seen at a dose producing maternal toxicity. In one of three rat studies on fertility andembryofetal development, post-implantation losses were observed. Post-implantation losses were notseen 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 andexposure than that intended for clinical use. These findings consisted mainly of gastrointestinalfindings (i.e. vomiting, increased gastric secretion, gastric erosions, intestine inflammation) andcardiac findings (i.e. focal haemorrhages, haemosiderin deposits and lympho-histiocytic cellinfiltration 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 carcinogenicitystudies. This effect seems to be due to an ADCP (4-Amino-3,5-dichloro-pyridine) N-oxideintermediate specifically formed in rodent olfactory mucosa, with special binding affinity in thesespecies (i.e. mouse, rat and hamster).

Core

Lactose monohydrate

Maize starch

Povidone

Magnesium stearate

Hypromellose

Macrogol (4000)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

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.

No special requirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

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

Date of first authorisation: 05 July 2010

Date of latest renewal: 20 May 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu