Ozawade - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Ozawade 4.5 mg film-coated tablets

Ozawade 18 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Ozawade 4.5 mg film-coated tablet

Each tablet contains pitolisant hydrochloride equivalent to 4.45 mg of pitolisant.

Ozawade 18 mg film-coated tablet

Each tablet contains pitolisant hydrochloride equivalent to 17.8 mg of pitolisant.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Ozawade 4.5 mg film-coated tablet

White, round, biconvex film-coated tablet, 3.7 mm diameter, marked with “5” on one side.

Ozawade 18 mg film-coated tablet

White, round, biconvex film-coated tablet, 7.5 mm diameter marked with “20” on one side.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Ozawade is indicated to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients with obstructive sleep apnoea (OSA) whose EDS has not been satisfactorily treated by, or who have not tolerated, OSA primary therapy, such as continuous positive airway pressure (CPAP).

4.2 Posology and method of administration

Treatment should be initiated by a healthcare professional experienced in the treatment of OSA and cardiovascular risk. OSA disease should be annually reassessed.

Ozawade is not a therapy for the underlying airway obstruction in patients with OSA. Primary OSA therapy should be maintained or periodically rechallenged in patients not tolerating primary OSA therapy.

Posology

Pitolisant should be used at the lowest effective dose, depending on individual patient response and tolerance, according to an up-titration scheme, without exceeding the dose of 18 mg/day:

• – Week 1: initial dose of 4.5 mg (one 4.5 mg tablet) per day.

• – Week 2: the dose may be increased to 9 mg (two 4.5 mg tablets) per day.

• – Week 3: the dose may be increased to 18 mg (one 18 mg tablet) per day or decreased to 4.5 mg

(one 4.5 mg tablet) per day.

At any time the dose can be decreased (down to 4.5 mg per day) or increased (up to 18 mg per day) according to the physician assessment and the patient’s response.

The total daily dose should be administered as a single dose in the morning during breakfast.

Maintenance of efficacy

As long-term efficacy data are limited (see section 5.1), the continued efficacy of treatment should be regularly evaluated by the physician.

Special populations

Elderly

Limited data are available in elderly. Therefore, dosing should be adjusted according to their individual response and tolerance.

Insomnia has been reported in higher rate in the elderly and dosing should be adjusted accordingly (see section 4.8).

Renal impairment

No dose adjustment is necessary.

Hepatic impairment

No dosage adjustment is required in patients with mild hepatic impairment.

In patients with moderate hepatic impairment (Child-Pugh B), the titration period should be two weeks up-titration steps instead of one after initiation of treatment, due to expected longer half-life and higher exposure, and a dosage adjustment in patients with moderate hepatic impairment could eventually be considered depending on individual response and tolerance (see section 5.2).

Pitolisant is contraindicated in patients with severe hepatic impairment (Child-Pugh C) (see section 4.3).

Paediatric population

There is no relevant use of Ozawade in the paediatric population in Obstructive Sleep Apnoea (OSA).

CYP2D6 metabolizers phenotype (If known)

By comparison to CYP2D6 extensive metabolizers, higher systemic exposure (up to 3 fold) is observed in CYP2D6 poor metabolizers and lower exposure (by 0.8-fold) is observed in CYP2D6 ultra-rapid metabolizers. No differences in systemic exposure is observed between CYP2D6 extensive and intermediate metabolizers.

In the up-titration scheme, dose increment should take into account the higher exposure in CYP2D6 poor metabolizers, and a dosage adjustment in patients with known poor CYP2D6 metabolizer genotype could be considered depending on individual response and tolerance (see section 5.2). Furthermore, no dose recommendation can currently be given for CYP2D6 ultra-rapid metabolizers taking a CYP3A inducer, because the PK is currently unknown in this subpopulation.

Method of administration

For oral use.

4.3 Contraindications

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

Severe hepatic impairment (Child-Pugh C).

Breastfeeding (see section 4.6).

4.4 Special warnings and precautions for use

Psychiatric disorders

Pitolisant should be administered with caution in patients with history of psychiatric disorders such as severe anxiety or severe depression with suicidal ideation risk. Suicidal ideation has been reported in patients with psychiatric history treated with pitolisant.

Hepatic impairment

Pitolisant should be administered with caution in patients with moderate hepatic impairment (Child-Pugh B) and dosing regimen should be adapted according to section 4.2.

Gastrointestinal disorders

Gastric disorders reactions have been reported with pitolisant, therefore it should be administered with caution in patients with acid related gastric disorders (see section 4.8) or when co-administered with gastric irritants such as corticosteroids or NSAID (see section 4.5).

Nutrition disorders

Pitolisant should be administered with caution in patients with severe obesity or severe anorexia (see section 4.8). In case of significant weight change, treatment should be re-evaluated by the physician.

Cardiac disorders

In two dedicated QT studies, supra-therapeutic doses of pitolisant (6–12-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10–13 ms). Patients with cardiac disease, hypertension, at risk of major adverse cardiovascular events (MACE), co-medicated with other QT-prolonging medicinal products or known to increase the risk of repolarization disorders, or co-medicated with medicinal products that significantly increase pitolisant Cmax and AUC ratio (see section 4.5) or patients with severe renal or moderate hepatic impairment (see section 4.4) should be carefully monitored (see section 4.5).

Epilepsy

Convulsions were reported at high doses in animal models (see section 5.3). In clinical studies, one epilepsy aggravation was reported in one epileptic patient. Caution should be taken for patients with severe epilepsy.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and at least up to 21 days after treatment discontinuation (based on pitolisant/me­tabolites half-life). Pitolisant may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman patient is using hormonal contraceptives (see sections 4.5 and 4.6).

Drug-drug interactions

The combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic margin should be avoided (see section 4.5).

Drug abuse, rebound effect

In a specific study, pitolisant showed no or very low signal suggestive of abuse at the current therapeutic dose of 36 mg and at doses up to 216 mg; consequently, potential for drug abuse or recreational drug with pitolisant is very low.

No rebound effect was reported during clinical studies. However, treatment discontinuation should be monitored.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Antidepressants

Tri or tetracyclic antidepressants with anti-histaminic H1-receptor properties (e.g. imipramine, clomipramine, mirtazapine) may impair the efficacy of pitolisant because they may decrease the effect of endogenous histamine released in brain by the treatment and alternative should be used.

Anti-histamines

Anti-histamines (H1-receptor antagonists) crossing the haemato-encephalic barrier (e.g. pheniramine maleate, chlorpheniramine, diphenhydramine, promethazine, mepyramine, doxylamine) may impair the efficacy of pitolisant and alternative should be used.

QT-prolonging substances or known to increase the risk of repolarization disorders (e.g. haloperidol, risperidone, erythromycine, clarithromycine, roxithromycine, loratadine, sildenafil)

Combination with pitolisant should be made with a careful monitoring (see section 4.4).

Pharmacokinetic interactions

In subjects that are CYP2D6 intermediate, extensive (normal) or ultra-rapid metabolizers, CYP2D6 is the main enzyme involved in the biotransformation of pitolisant, CYP3A is involved to a lesser extent. In subjects that are CYP2D6 poor metabolizers or are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking CYP3A inducers, CYP3A is significantly involved in the biotransformation of pitolisant and CYP2D6 is involved to a lesser extent.

Medicinal products affecting pitolisant metabolism

• – CYP2D6 inhibitors

CYP2D6 inhibitors will most likely have an effect on the pharmacokinetics of pitolisant in subjects that are CYP2D6 intermediate, extensive metabolizers or ultra-rapid metabolizers and taking no CYP3A inducers, but not in subjects that are CYP2D6 poor metabolizers or intermediate, extensive metabolizers or CYP2D6 ultra-rapid metabolizers and taking CYP3A inducers. A dosage adjustment during the combination could eventually be considered depending on individual response and tolerance.

Co-administration of pitolisant with paroxetine significantly increases pitolisant mean Cmax and AUC0—72h ratio about 1.5 fold and 2 fold, respectively. Given the 2-fold increase of pitolisant exposure, its coadministration with CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, venlafaxine, duloxetine, bupropion, quinidine, terbinafine, cinacalcet) should be done with caution.

• – Enzyme inducers

CYP3A inducers will most likely have an effect on the pharmacokinetics of pitolisant in CYP2D6 poor metabolizers and CYP2D6 ultra-rapid metabolizers and their effect in these populations is currently unknown. A clinical monitoring should be made when both active substances are combined and, eventually a dosage adjustment during the combination and one week after the inducer treatment. Co-administration of pitolisant with rifampicin in multiple doses significantly decreases pitolisant mean Cmax and AUC ratio about 0.6 fold and 0.5 fold, respectively. Therefore, co-administration of pitolisant with potent CYP3A4 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) should be done with caution. With St John’s Wort (Hypericum perforatum ), due to its strong CYP3A4 inducing effect, caution should be exercised when taken concurrently with pitolisant.

• – CYP3A4 inhibitors

CYP3A inhibitors will most likely have an effect on the pharmacokinetic of pitolisant in CYP2D6 poor metabolizers and their effect in this population is currently unknown.

The combination of pitolisant with grapefruit juice and itraconazole was evaluated in healthy volunteers. No clinically relevant pharmacokinetic drug-drug interaction was evidenced with any of these combinations. However, based on the biotransformation pathway caution should be exercised in subjects that are CYP2D6 poor metabolizers due to a significant decrease in clearance and an increase in exposure.

• – Other

In a clinical multiple dose study, the combination of pitolisant with probenecid decreases the AUC of pitolisant by about 0.7 fold. The underlying mechanism is unknown. A dosage adjustment during the combination could eventually be considered depending on individual response and tolerance.

Medicinal products that pitolisant may affect metabolism – CYP3A4 and CYP2B6 substrates

A clinical induction study showed that pitolisant is a weak inducer of CYP3A (0.2-fold reduction in midazolam exposure). Therefore, the combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic margin (e.g. immunosuppressants, docetaxel, kinase inhibitors, cisapride, pimozide, halofantrine) should be avoided (see section 4.4). With other CYP3A4, CYP2C (e.g. repaglinide, phenytoin, warfarin), P-gp (e.g. dabigatran, digoxin) and UGT (e.g. morphine, paracetamol, irinotecan) substrates, caution should be made with a clinical monitoring of their efficacy.

Pitolisant might decrease the exposure to oral contraceptives and an additional further reliable contraceptive method should be used (see section 4.6).

• – Substrates of OCT1

Pitolisant may be a clinically relevant inhibitor of OCT1 based on in vitro data and a clinically relevant interaction may occur with substrates of OCT1 (e.g. metformin).

Even if the clinical relevance of this effect is not established, caution is advised when pitolisant is administered with a substrate of OCT1 (e.g. metformin (biguanides)) (see section 5.2).

• – Other

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and at least up to 21 days after treatment discontinuation (based on pitolisant/me­tabolites half-life).

Pitolisant/me­tabolites may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman is using hormonal contraceptives (see section 4.5).

Pregnancy

There are no or limited amount of data from the use of pitolisant in pregnant women. Studies in animals have shown reproductive toxicity, including teratogenicity. In rats, pitolisant/me­tabolites were shown to cross the placenta (see section 5.3).

Pitolisant should not be used during pregnancy unless the potential benefit outweighs the potential risk for foetus.

Breast-feeding

Animal study has shown excretion of pitolisant/me­tabolites in milk. Therefore, breastfeeding is contraindicated during treatment with pitolisant (see section 4.3).

Fertility

Study in animals has shown effects on semen parameters, without a significant impact on reproductive performance in males and reduction on the percentage of live foetuses in treated females (see section 5.3).

4.7 Effects on ability to drive and use machines

Pitolisant has minor influence on the ability to drive and use machines.

Patients with abnormal levels of sleepiness who take pitolisant should be advised that their level of wakefulness may not return to normal. Patients with excessive daytime sleepiness, including those taking pitolisant should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity.

4.8 Undesirable effects

Summary of the safety profile

The most frequent adverse reactions are headache 12.4%, insomnia (all types) 8.9%, nausea 3.3%, anxiety 2.2%, abdominal pain 2.8%, vertigo 1.7% and diarrhoea 1%.

Tabulated list of adverse reactions

The following adverse reactions have been reported with pitolisant during clinical studies are listed below as MedDRA preferred term by system organ class and frequency; frequencies are defined as: 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); within each frequency group, adverse reactions are presented in order of decreasing seriousness:

Description of selected adverse reactions

Headache and insomnia

During clinical studies in OSA indication, episodes of headache and insomnia have been reported (12.4 % and 8.9%) more frequently in women (headache and insomnia) and in elderly (insomnia) patients. Most of these adverse reactions were mild to moderate (see section 4.2). Dosing should be adjusted accordingly.

Gastric disorders

Gastric disorders presumably caused by hyperacidity have been reported during clinical studies in 3.5% of the patients receiving pitolisant. Higher rates of nausea are reported in women. These effects were mostly mild to moderate. If they persist, a corrective treatment with proton pump inhibitor could be initiated.

Patients with low/normal Body Mass Index (BMI) (<25)

Headache, insomnia, nausea and anxiety have been reported in higher rates in patients with low/normal BMI. Dosing should be adjusted accordingly.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

Symptoms

Symptoms of pitolisant overdose may include headache, insomnia, irritability, nausea and abdominal pain.

Management

In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX11.

Mechanism of action

Pitolisant is an orally active histamine H3-receptor antagonist/inverse agonist which, via its blockade of histamine auto-receptors enhances the activity of brain histaminergic neurons, a major arousal system with widespread projections to the whole brain. Pitolisant also modulates various neurotransmitter systems, increasing acetylcholine, noradrenaline and dopamine release in the brain.

Clinical efficacy

The efficacy of pitolisant in the_treatment of Excessive Daytime Sleepiness (EDS) in patients with Obstructive Sleep Apnoea (OSA) has been studied in two pivotal clinical studies: HAROSA I and HAROSA II.

HAROSA I studied the efficacy and safety of pitolisant in the treatment of EDS in patients with Obstructive Sleep Apnoea syndrome (OSA), and treated by Continuous Positive Airway Pressure (CPAP), but still complaining of EDS. This was a prospective, multicenter, randomized, double-blind study of pitolisant versus placebo, 12-week double-blind phase. 244 patients were analyzed (183 pitolisant, 61 placebo), 83% male, average of 53 years old, 12% over 65 years. Patients had EDS (an Epworth Sleepiness Scale [ESS] score greater than or equal to 12) and were submitted to nCPAP therapy for a minimum period of 3 months and still complaining of EDS despite the efforts made beforehand to obtain an efficient nCPAP.

The primary efficacy variable was the change in Epworth Sleepiness Scale (ESS) Score between baseline and end of treatment. During the double-blind phase, the maximum dose prescribed was 18 mg for 79.8% of the patient in the active treatment group and for 88.5% of the patients in the placebo group. The maximum dose is reached after a three-week titration, starting with 4.5 mg.

After 12 weeks DB treatment, a significant improvement of the ESS was reported with pitolisant compared to placebo (table 1).

Table 1: overview of Efficacy results after 12 weeks in HAROSA I

Figure 1 Changes in Epworth Sleepiness Scale (ESS) score in P09–08 study

Double-Blind Phase – ITT Population (N=244)

HAROSA II studied the efficacy and safety of pitolisant in the treatment of EDS in patients with Obstructive Sleep Apnoea syndrome (OSA) refusing the Continuous Positive Airway Pressure (CPAP) therapy. This was a prospective, multicenter, randomized, double-blind study of pitolisant versus placebo, 12-week double-blind phase followed by a 40-week open-label extension phase. 268 patients were analyzed (201 pitolisant, 67 placebo), 75% male, average of 52 years, 12% over 65 years. Patients had an Epworth Sleepiness Scale [ESS] score greater than or equal to 12 and were refusing to be treated by nCPAP therapy, and still complaining of EDS.

The primary efficacy variable was the change in Epworth Sleepiness Scale (ESS) score between baseline and end of treatment. During the double-blind phase, the maximum dose prescribed was 18 mg for 82.5% of the patient in the active treatment group and for 86.6% of the patients in the placebo group.

After 12 weeks DB treatment, a significant improvement of the ESS was reported with pitolisant compared to placebo (ANCOVA model adjusting for ESS and BMI at V2 and study center as random effect) (Table 2).

Table 2: overview of Efficacy results after 12 weeks in HAROSA II

Figure 2 Changes in Epworth Sleepiness Scale (ESS) score in P09–09 study Double-Blind Phase – ITT Population (N=268)

Mean (±SE) ESS at Each Visit in the Double Blind Phase

In an extended analysis the two HAROSA studies were compared and combined, showing significant improvements by pitolisant compared with placebo on the main parameters (ESS, OSleR test, Pichot Fatigue Scale and CGI).

Table 3: Main efficacy results in pooled analysis HAROSA I – HAROSA II

1) mean ratio pitolisant/placebo

2) treatment effect

3) difference pitolisant-placebo

Open-label data

Patients who participated in the double-blind 12 weeks period of HAROSA I and HAROSA II studies, could participate in the 40 week open-label phase. The primary objective of the open-label phase was long-term safety and effectiveness of pitolisant up to 18 mg/day. Maintenance of effect of pitolisant in EDS in OSA patients has not been established in blinded, placebo-controlled studies. In HAROSA I, 1.5% of patients discontinued study participation during the open-label phase, due to lack of efficacy and 4.0% due to adverse events. In HAROSA II, 1.3% of patients discontinued study participation during the open-label phase due to lack of efficacy and 2.5% due to adverse events.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Ozawade in all subsets of the paediatric population in Obstructive Sleep Apnoea (OSA) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

The exposure to pitolisant in healthy volunteers was assessed in studies involving more than 200 subjects that received doses of pitolisant in single administration up to 216 mg and for a duration up to 28 days.

Absorption

Pitolisant is well and rapidly absorbed with peak plasma concentration reached approximately three hours after administration. The steady-state (geometric mean, CV%) Cmax and AUCof the therapeutic dose (18 mg) is 35.5 ng/mL (59.2%) and 378 ng x h/mL (86.3%), respectively.

Upon repeated administrations, the steady state is achieved after 5–6 days of administration leading to an increased serum level around 2-fold. Inter individual variability is rather high (Geom CV% of 59.2 and 86.3 for Cmax and AUC0–24h respectively), some volunteers showing outlier high profile (without tolerance issues).

The pharmacokinetics of pitolisant is not influenced by concomitant food intake.

Distribution

Pitolisant exhibits high serum protein binding (91.4–95.2%) and demonstrates approximately equal distribution between red blood cells and plasma.

Pitolisant is widely distributed with an apparent volume of distribution of 5–10 L/kg.

Biotransformation

The metabolism of pitolisant in humans is well characterized and represents the major route of elimination. The major non-conjugated metabolites are cleaved forms of pitolisant leading to inactive major carboxylic acid metabolites, three of which being major and in a lesser extent five hydroxylated/N-oxide derivatives in several positions found in urine and serum. By combining the contribution of enzyme determined in vitro with the exposure of the main metabolites identified in the mass balance study, the estimated overall contribution of CYP enzymes in pitolisant metabolism is of 60% for CYP2D6 and of ~ 30% for CYP3A4/3A5 when CYP2D6 phenotype is extensive metabolizer. Several conjugated metabolites were identified, the major ones (inactive) being two glycine conjugates of carboxylic acid metabolites of pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant.

Inhibition/In­duction

On liver microsomes, pitolisant and its major metabolites do not significantly inhibit the activities of the cytochromes CYP1A2, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2E1 or CYP3A4 and of uridine diphosphate glucuronosyl transferases isoforms UGT1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 up to the concentration of 13.3 pM, a level considerably higher than the levels achieved with therapeutic dose. Pitolisant is an inhibitor of CYP2D6 with moderate potency (IC50 = 2.6 pM).

Based on in vitro data, pitolisant and its main metabolites may induce CYP3A4 and CYP2B6 at therapeutic concentrations and by extrapolation, CYP2C, UGTs and P-gp. A clinical study was conducted to assess the effect of pitolisant on CYP3A4 and CYP2B6 using midazolam and bupropion as a CYP3A4 and a CYP2B6 model substrate, respectively. Pitolisant does not affect the pharmacokinetic of bupropion and consequently is not a CYP2B6 or a CYP1A2 inducer and should be considered a borderline/weak inducer at clinically relevant concentrations.

In vitro studies indicate that pitolisant is neither a substrate nor an inhibitor of human P-glycoprotein and breast cancer resistance protein (BCRP). Pitolisant is not a substrate of OATP1B1, OATP1B3. Pitolisant is not a significant inhibitor of OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2K at the tested concentration. Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 pM, the extrapolated IC50 of pitolisant is 0.795 pM (see section 4.5).

Elimination

Pitolisant has a plasma half-life of 10–12 hours. The elimination is mainly achieved via urine (approximately 90%) through pharmacologically inactive-non conjugated and glycine and glucuronide conjugated metabolites. A small fraction (2.3%) was recovered in faeces.

Linearity/non-linearity

A cross-study assessment of single-dose data shows that pitolisant exposures increase proportionally with doses between 18 and 216 mg pitolisant but slightly more than dose-proportionally over the clinical dose range of 4.5 to 18 mg.

Special populations

There are unlikely to be any clinically relevant differences in the PK of pitolisant due to sex. Pitolisant has not been studied in obese population with BMI >40 kg/m2.

Elderly

In 68 to 80 years old healthy volunteers the pharmacokinetics of pitolisant is not different compared to younger patients (18 to 45 years of age). Above 80 years old, kinetics show a slight variation without clinical relevance. Limited data are available in elderly. Therefore, dosing should be adjusted according to their hepatic status (see section 4.2 and 4.4).

Renal impairment

In patients with impaired renal function (stages 2 to 4 according to the international classification of chronic kidney disease, i.e. creatinine clearance between 15 and 89 ml/min), Cmax and AUC tended to be increased by a factor of 2.5 (see section 4.2). The underlying mechanism is unknown.

Hepatic impairment

In patients with mild hepatic impairment (Child-Pugh A), AUC increased by a factor 1.4 while Cmax remained unchanged, compared with normal healthy volunteers.

In patients with moderate hepatic impairment (Child-Pugh B), AUC increased by a factor 2.4, while Cmax remained unchanged (see section 4.2). Pitolisant pharmacokinetics after repeated administration in patients with hepatic impairment has not been evaluated yet.

Race

All studies have been performed mainly in Caucasians (Caucasians = 270; Black = 38; Asian = 20; Other = 3). Based on the data provided by the Applicant, the exposure appears to be similar between the different races.

CYP2D6 phenotypes and CYP3A polymorphism

The exposure to pitolisant was higher in the CYP2D6 poor metabolizers after a single dose and at steady state; Cmax and AUC(0-tau) was approximately 2.7-fold and 3.2-fold greater on Day 1 and 2.1-fold and 2.4-fold on Day 7. The serum pitolisant half-life was longer in CYP2D6 poor metabolizers compared to the extensive metabolizers.

In subjects that are CYP2D6 intermediate, extensive (normal) or ultra-rapid metabolizers, CYP2D6 is the main enzyme involved in the biotransformation of pitolisant, CYP3A is involved to a lesser extent. CYP3A4 and CYP3A5 genetic polymorphisms are unlikely to have significant effect on the pharmacokinetic of pitolisant.

In these subjects, CYP2D6 inhibitors will have an effect on the pharmacokinetic of pitolisant, not CYP3A inhibitors. In subjects that are CYP2D6 ultra-rapid metabolizers, CYP3A inducers may lead to an even more rapid elimination of pitolisant and lower exposures compared to the other subgroups. This may result in exposures below therapeutic concentrations.

In subjects that are CYP2D6 poor metabolizers or are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking CYP3A inducers, CYP3A is significantly involved in the biotransformation of pitolisant and CYP2D6 is involved to a lesser extent. Only under these conditions, genetic polymorphisms in CYP3A4 and 3A5 may have a significant effect on the pharmacokinetic of pitolisant.

In subjects that are CYP2D6 poor metabolizers, CYP3A inhibitors and inducers will have an effect on the pharmacokinetic of pitolisant and CYP2D6 inhibitors to a much lesser extent. In subjects that are CYP2D6 intermediate, extensive or ultra-rapid metabolizers taking a CYP3A inducer, a CYP3A inhibitor will lead to a decrease in the contribution of CYP3A to the overall metabolism. However, the exposure is most likely similar to that in subjects that are not taking a CYP3A inducer. Thus, in this subpopulation, CYP3A inhibition is unlikely to affect the pharmacokinetic of pitolisant.

5.3 Preclinical safety data

In rats, transient reversible convulsive episodes occurred at Tmax , that may be attributable to a metabolite abundant in this species but not in humans. In monkeys, at the highest doses, transient CNS related clinical signs including emesis, tremors and convulsions were reported. At the highest doses, rats presented some limited histopathological changes in some organs (liver, duodenum, thymus, adrenal gland and lung).

Pitolisant blocked hERG channel with an IC50 exceeding therapeutic concentrations and induced a slight QTc prolongation in dogs.

In preclinical studies, drug dependence and drug abuse liability studies were conducted in mice, rats and monkeys. However, no definitive conclusion could be drawn on tolerance, dependence and selfadministration studies.

Pitolisant was neither genotoxic nor carcinogenic.

Teratogenic effect of pitolisant was observed at maternally toxic doses (teratogenicity safety margins 7.3 and 2.6 in rats and in rabbits, respectively). At high doses, pitolisant induced sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats and it decreased the percentage of live conceptuses and increased post-implantation loss in female rats (safety margin of 2.3). It caused a delay in post-natal development (safety margin of 2.3).

Pitolisant/me­tabolites were shown to cross the placenta barrier and secreted in breast milk in animals.

Juvenile toxicity studies

Juvenile toxicity studies in rats revealed that the administration of pitolisant at high doses induced a dose related mortality and convulsive episode that may be attributable to a metabolite abundant in rats but not in humans.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Microcrystalline cellulose (E 460)

Crospovidone type A (E 1202)

Talc (E 553b)

Magnesium stearate

Colloidal anhydrous silica (E 551)

Coating

Poly(vinyl alcohol) (E 1203)

Titanium dioxide (E 171)

Macrogol 3350 (E 1521)

Talc (E 553b)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a tamper evident, child-resistant, polypropylene screw cap fitted with desiccant (silica gel).

Ozawade 4.5 mg

Available in packs containing 1 bottle of 30 tablets or 1 bottle of 90 tablets.

Ozawade 18 mg

Available in packs containing 1 bottle of 30 tablets or 1 bottle of 90 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bioprojet Pharma

9, rue Rameau

75002 Paris

France

Tel: +33 (0)1 47 03 66 33

Fax: +33 (0)1 47 03 66 30

e-mail:

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1546/001

EU/1/21/1546/002

EU/1/21/1546/003

EU/1/21/1546/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: