Deltyba - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Deltyba 50 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg delamanid.

Excipient with known effect : each film-coated tablet contains 100 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Round, yellow, film-coated tablet, 11.7 mm in diameter, debossed with „DLM“ and „50“ on one side.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Deltyba is indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adults, adolescents, children and infants with a body weight of at least 10 kg when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability (see sections 4.2, 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Treatment with delamanid should be initiated and monitored by a physician experienced in the management of multidrug-resistant Mycobacterium tuberculosis.

Delamanid must always be administered as part of an appropriate combination regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) (see sections 4.4 and 5.1). Treatment with an appropriate combination regimen should continue after completion of the 24-week delamanid treatment period according to WHO guidelines.

It is recommended that delamanid is administered by directly observed therapy (DOT).

Posology

Adults

The recommended dose for adults is 100 mg twice daily for 24 weeks.

Adolescents and children

Paediatric patients with a body weight of

• – > 30 to < 50 kg: the recommended dose is 50 mg twice daily for 24 weeks

• – > 50 kg: the recommended dose is 100 mg twice daily for 24 weeks

For patients with a body weight below 30 kg please see the SmPC for Deltyba 25 mg dispersible tablets.

Elderly patients (> 65 years of age)

No data are available in the elderly.

Renal impairment

No dose adjustment is considered necessary in patients with mild or moderate renal impairment. There are no data on the use of delamanid in patients with severe renal impairment and its use is not recommended (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is considered necessary in patients with mild hepatic impairment. Delamanid is not recommended in patients with moderate to severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Deltyba in children with a body weight below 10 kg have not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Oral use.

Delamanid should be taken with food.

4.3 Contraindications

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

• – Serum albumin < 2.8 g/dL (see section 4.4 regarding use in patients with serum albumin

>2.8 g/dL).

• – Coadministration of medicinal products that are strong inducers of CYP3A4 (e.g. carbamazepine).

4.4 Special warnings and precautions for use

There are no data on treatment with delamanid for more than 24 consecutive weeks. (see section 4.2).

There are no clinical data on the use of delamanid to treat

• – extra pulmonary tuberculosis (e.g. central nervous system, bone)

• – infections due to Mycobacterial species other than those of the M. tuberculosis complex

• – latent infection with M. tuberculosis

There are no clinical data on the use of delamanid as part of combination regimens used to treat drug-susceptible M. tuberculosis.

Resistance to delamanid

Delamanid must only be used in an appropriate combination regimen for MDR-TB treatment as recommended by WHO to prevent development of resistance to delamanid.

QT prolongation

QT prolongation has been observed in patients treated with delamanid. This prolongation increases slowly over time in the first 6 to 10 weeks of treatment and remains stable therafter. QTc prolongation is very closely correlated with the major delamanid metabolite DM-6705. Plasma albumin and CYP3A4 regulate the formation and metabolism of DM-6705 respectively (see Special Considerations below).

General recommendations

It is recommended that electrocardiograms (ECG) should be obtained before initiation of treatment and monthly during the full course of treatment with delamanid. If a QTcF >500 ms is observed either before the first dose of delamanid or during delamanid treatment, treatment with delamanid should either not be started or should be discontinued. If the QTc interval duration exceeds 450/470 ms for male/female patients during delamanid treatment, these patients should be administered more frequent ECG monitoring. It is also recommended that serum electrolytes, e.g. potassium, are obtained at baseline and corrected if abnormal.

Special Considerations

Cardiac risk factors

Treatment with delamanid should not be initiated in patients with the following risk factors unless the possible benefit of delamanid is considerd to outweigh the potential risks. Such patients should receive very frequent monitoring of ECG throughout the full delamanid treatment period.

• – Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval or QTc > 500 ms.

• – History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia.

• – Any predisposing cardiac conditions for arrhythmia such as severe hypertension, left ventricular hypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failure accompanied by reduced left ventricle ejection fraction.

• – Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia.

• – Taking medicinal products that are known to prolong the QTc interval. These include (but are not limited to):

• – Antiarrhythmics (e.g. amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, hydroquinidine, sotalol).

• – Neuroleptics (e.g. phenothiazines, sertindole, sultopride, chlorpromazine, haloperidol, mesoridazine, pimozide, or thioridazine), antidepressive agents.

• – Certain antimicrobial agents, including:

• – macrolides (e.g. erythromycin, clarithromycin)

• – moxifloxacin, sparfloxacin (see section 4.4 regarding use with other fluoroquinolones)

• – bedaquiline

• – triazole antifungal agents

• – pentamidine

• – saquinavir

• – Certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine)

• – Certain antimalarials with QT-prolonging potential (e.g. halofantrine, quinine, chloroquine, artesunate/amo­diaquine, dihydroartemi­sinin/piperaqu­ine).

– Cisapride, droperidol, domperidone, bepridil, diphemanil, probucol, levomethadyl, methadone, vinca alkaloids, arsenic trioxide.

Hypoalbuminaemia

In a clinical study, the presence of hypoalbuminaemia was associated with an increased risk of prolongation of the QTc interval in delamanid treated patients. Delamanid is contraindicated in patients with albumin <2.8 g/dL (see section 4.3). Patients who commence delamanid with serum albumin <3.4 g/dL or experience a fall in serum albumin into this range during treatment should receive very frequent monitoring of ECGs throughout the full delamanid treatment period.

Co-administration with strong inhibitors of CYP3A4

Co-administration of delamanid with a strong inhibitor of CYP3A4 (lopinavir/ri­tonavir) was associated with a 30% higher exposure to the metabolite DM-6705, which has been associated with QTc prolongation. Therefore if co-administration of delamanid with any strong inhibitor of CYP3A4 is considered necessary it is recommended that there is very frequent monitoring of ECGs, throughout the full delamanid treatment period.

Co-administration of delamanid with quinolones

All QTcF prolongations above 60 ms were associated with concomitant fluoroquinolone use. Therefore if co-administration is considered to be unavoidable in order to construct an adequate treatment regimen for MDR-TB it is recommended that there is very frequent monitoring of ECGs throughout the full delamanid treatment period.

Hepatic impairment

Deltyba is not recommended in patients with moderate to severe hepatic impairment (see sections 4.2 and 5.2).

Renal impairment

There are no data on the use of delamanid in patients with severe renal impairment and its use is not recommended (see sections 4.2 and 5.2).

Excipients

Deltyba film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on Deltyba

Cytochrome P450 3A4 inducers

Clinical drug-drug interactions studies in healthy subjects indicated a reduced exposure to delamanid, of up to 45% following 15 days of concomitant administration of the strong inducer of cytochrome P450 (CYP) 3A4 (rifampicin 300 mg daily) with delamanid (200 mg daily). No clinically relevant reduction in delamanid exposure was observed with the weak inducer efavirenz when administered at a dose of 600 mg daily for 10 days in combination with delamanid 100 mg twice daily.

Anti-HIV medicinal products

In clinical drug-drug interaction studies in healthy subjects, delamanid was administered alone (100 mg twice daily) and with tenofovir disoproxil (245 mg daily) or lopinavir/ritonavir (400/100 mg daily) for 14 days and with efavirenz for 10 days (600 mg daily). Delamanid exposure remained unchanged (<25% difference) with anti-HIV medicinal products tenofovir disoproxil and efavirenz but was slightly increased with the combination anti-HIV medicinal products containing lopinavir/rito­navir.

Effects of Deltyba on other medicinal products

In-vitro studies showed that delamanid did not inhibit CYP450 isozymes.

In-vitro studies showed that delamanid and metabolites did not have any effect on the transporters MDR1(p-gp), BCRP, OATP1, OATP3, OCT1, OCT2, OATP1B1, OATP1B3 and BSEP, at concentrations of approximately 5 to 20 fold greater than the Cmax at steady state. However, since the concentrations in the gut can potentially be much greater than these multiples of the Cmax, there is a potential for delamanid to have an effect on these transporters.

Anti-Tuberculosis medicinal products

In a clinical drug-drug interaction study in healthy subjects, delamanid was administred alone (200 mg daily) and with rifampicin/iso­niazid/pyrazi­namide (300/720/1800 mg daily) or ethambutol (1100 mg daily) for 15 days. Exposure of concomitant anti-TB drugs (rifampicin [R]/ isoniazid [H]/ pyrazinamide [Z]) was not affected. Co-administration with delamanid significantly increased steady state plasma concentrations of ethambutol by approximately 25%, the clinical relevance is unknown.

Anti-HIV medicinal products

In a clinical drug-drug interaction study in healthy subjects, delamanid was administred alone (100 mg twice daily) and tenofovir disoproxil (245 mg daily), lopinavir/ritonavir (400/100 mg daily) for 14 days and with efavirenz for 10 days (600 mg daily). Delamanid given in combination with the antiHIV-medicines, tenofovir disoproxil, lopinavir/ritonavir and efavirenz, did not affect the exposure to these medicinal products.

Medicinal products with the potential to prolong QTc

Care must be taken in using delamanid in patients already receiving medicinal products associated with QT prolongation (see section 4.4). Co-administration of moxifloxacin and delamanid in MDR-TB patients has not been studied. Moxifloxacin is not recommended for use in patients treated with delamanid.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of delamanid in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Deltyba is not recommended in pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether delamanid/meta­bolites are excreted in human milk. Available pharmacokinetic/to­xicological data in animals have shown excretion of delamanid and/or its metabolites in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. It is recommended that women should not breastfeed during treatment with Deltyba.

Fertility

Deltyba had no effect on male or female fertility in animals (see section 5.3). There are no clinical data on the effects of delamanid on fertility in humans.

4.7 Effects on ability to drive and use machines

Deltyba is expected to have a moderate influence on the ability to drive and use machines. Patients should be advised not to drive or use machines if they experience any adverse reaction with a potential impact on the ability to perform these activities (e.g. headache and tremor are very common).

4.8 Undesirable effects

Summary of the safety profile

The most frequently observed adverse drug reactions in patients treated with delamanid + Optimised Background Regimen (OBR) (i.e. incidence > 10%) are nausea (32,9%), vomiting (29,9%), headache (27.6%), insomnia (27.3%), dizziness (22.4%), tinnitus (16.5%), hypokalaemia (16.2%), gastritis (15.0%), decreased appetite (13.1%), and asthenia (11.3%).

Tabulated list of adverse reactions

The list of adverse drug reactions and frequencies are based on the results from 2 double-blind placebo controlled clinical trials. The adverse drug reactions are listed by MedDRA System Organ Class and Preferred Term. Within each System Organ Class, adverse reactions are listed under frequency categories of 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) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table: Adverse drug reactions to delamanid

System Organ Class	Frequency uncommon	Frequency common	Frequency very common
Infections and infestations	Herpes zoster Oropharyngeal candidiasis Tinea versicolor*	–	–

System Organ Class	Frequency uncommon	Frequency common	Frequency very common
Blood and lymphatic system disorders	Leukopenia Thrombocytopaenia	Anaemia* Eosinophilia*	Reticulocytosis
Metabolism and nutrition disorders	Dehydration Hypocalcaemia Hypercholeste­rolaemia	Hypertriglyce­ridaemia	Hypokalaemia Decreased appetite Hyperuricaemia*
Psychiatric disorders	Aggression Delusional disorder, persecutory type Panic disorder Adjustment disorder with depressed mood Neurosis Dysphoria Mental disorder Sleep disorder Libido increased*	Psychotic disorder Agitation Anxiety and anxiety disorder Depression and depressed mood Restlessness Hallucination	Insomnia
Nervous system disorders	Lethargy Balance disorder Radicular pain Poor quality sleep	Neuropathy peripheral Somnolence* Hypoaesthesia	Dizziness* Headache Paraesthesia Tremor
Eye disorders	Conjunctivitis allergic*	Dry eye* Photophobia
Ear and labyrinth disorders	–	Ear pain	Tinnitus
Cardiac disorders	Atrioventricular block first degree Ventricular extrasystoles* Supraventricular extrasystoles	–	Palpitations
Vascular disorders	–	Hypertension Hypotension Haematoma* Hot flush*	–
Respiratory, thoracic and mediastinal disorders	–	Dyspnoea Cough Oropharyngeal pain Throat irritation Dry throat* Rhinorrhoea*	Haemoptysis
Gastrointestinal disorders	Dysphagia Paraesthesia oral Abdominal tenderness*	Gastritis* Constipation* Abdominal pain Abdominal pain lower Dyspepsia Abdominal discomfort	Vomiting Diarrhoea* Nausea Abdominal pain upper
Hepatobiliary disorders	Hepatic function abnormal	–	–

System Organ Class	Frequency uncommon	Frequency common	Frequency very common
Skin and subcutaneous tissue disorders	Alopecia* Eosinophilic pustular folliculitis* Pruritus generalised* Rash erythematous	Dermatitis Urticaria Rash pruritic Pruritus Rash maculo-papular Rash Acne Hyperhidrosis	–
Musculoskeletal and connective tissue disorders	–	Osteochondrosis Muscular weakness Musculoskeletal pain* Flank pain Pain in extremity	Arthralgia* Myalgia*
Renal and urinary disorders	Urinary retention Dysuria* Nocturia	Haematuria*	–
General disorders and administration site conditions	Feeling hot	Pyrexia* Chest pain Malaise Chest discomfort* Oedema peripheral*	Asthenia
Investigations	Electrocardiogram ST segment depression Transaminases increased* Activated partial thromboplastin time prolonged* Gamma-glutamyltransferase increased* Blood cortisol decreased Blood pressure increased	Blood cortisol increased	Electrocardiogram QT prolonged
* The frequency for t	hese events was lower for the combined delamanid plus OB		R group in comparison

to the placebo plus OBR group.

Description of selected adverse reactions

ECG QT interval prolongation

In patients receiving 200 mg delamanid total daily dose in the phase 2 and 3 trials, the mean placebo corrected increase in QTcF from baseline ranged from 4.7 – 7.6 ms at 1 month and 5.3 ms – 12.1 ms at 2 months, respectively. The incidence of a QTcF interval > 500 ms ranged from 0.6% (1/161) – 2.1% (7/341) in patients receiving delamanid 200 mg total daily dose versus 0% (0/160) – 1.2% (2/170) of patients receiving placebo + OBR, while the incidence of QTcF change from baseline > 60 ms ranged from 3.1% (5/161) – 10.3% (35/341) in patients receiving delamanid 200 mg total daily dose versus 0% (0/160) – 7.1% (12/170) in patients receiving placebo.

Palpitations

For patients receiving 100 mg delamanid + OBR twice daily, the frequency was 8.1% (frequency category common) in comparison to a frequency of 6.3% in patients receiving placebo + OBR twice daily.

Paediatric population

Based on a study (see section 5.1) in 37 paediatric patients aged 0 to 17 years, the frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Cases of hallucination have been reported predominantly in the paediatric population during postmarketing. The incidence of hallucination in clinical trials was common for children (5.4%) and adults (1%).

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

No cases of delamanid overdose have been observed in clinical trials. However, additional clinical data showed that in patients receiving 200 mg twice daily, i.e. total 400 mg delamanid per day, the overall safety profile is comparable to that in patients receiving the recommended dose of 100 mg twice daily. Albeit, some reactions were observed at a higher frequency and the rate of QT prolongation increased in a dose-related manner. Treatment of overdose should involve immediate measures to remove delamanid from the gastrointestinal tract and supportive care as required. Frequent ECG monitoring should be performed.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterials, drugs for treatment of tuberculosis, ATC code: J04AK06.

Mechanism of action

The pharmacological mode of action of delamanid involves inhibition of the synthesis of the mycobacterial cell wall components, methoxy-mycolic and keto-mycolic acid. The identified metabolites of delamanid do not show anti-mycobacterial activity.

Activity against specific pathogens

Delamanid has no in vitro activity against bacterial species other than mycobacteria.

Resistance

Mutation in one of the 5 coenzyme F420 genes is suggested as the mechanism for resistance against delamanid in mycobacteria. In mycobacteria, the in vitro frequencies of spontaneous resistance to delamanid were similar to those for isoniazid, and were higher than those for rifampicin. Resistance to delamanid has been documented to occur during treatment (see section 4.4). Delamanid does not show cross-resistance with any of the currently used anti-tuberculosis medicinal products except pretomanid. In vitro studies have shown cross-resistance with pretomanid. This is likely to be due to delamanid and pretomanid being activated via the same pathway.

Susceptibility testing interpretive criteria

When 7H11 agar medium is used for drug susceptibility testing, the recommended epidemiological cut-off (ECOFF) and susceptibility testing interpretive criteria for delamanid are:

ECOFF:            0.016 mg/L

Clinical breakpoint: S < 0.016 mg/L; R > 0.016 mg/L

S = susceptible; R = resistant

Data from clinical studies

Delamanid has been evaluated in two, double-blind, placebo controlled trials for the treatment of MDR-TB. The analyses of SCC were conducted on the modified intent to treat population which included patients who had positive cultures at baseline and the isolate was resistant to both isoniazid and rifampicin, i.e., had MDR-TB.

In the first trial (Trial 204), 64/141 (45.4%) patients randomised to receive delamanid 100 mg BID + OBR and 37/125 (29.6%) of patients randomised to receive placebo (PLC) + OBR achieved twomonth sputum culture conversion (SCC) (i.e. growth of Mycobacterium tuberculosis to no growth over the first 2 months and maintained for 1 more month) (p=0.0083). The time to SCC for the group randomised to 100 mg BID was also found to be faster than for the group randomised to receive placebo + OBR (p=0.0056).

In the second trial (Trial 213), delamanid was administered orally at 100 mg BID as an add-on therapy to an OBR for 2 months followed by 200 mg once daily for 4 months. The median time to SCC was 51 days in the delamanid + OBR group compared with 57 days in the PLC + OBR group (p = 0.0562 using the stratified modified Peto-Peto modification of Gehan’s Wilcoxon rank sum test). The proportion of patients achieving SCC (sputum culture conversion) after the 6-month treatment period was 87.6% (198/226) in the delamanid + OBR treatment group compared to 86.1% (87/101) in the placebo + OBR treatment group (p=0.7131).

All missing cultures up to the time of SCC were assumed to be positive cultures in the primary analysis. Two sensitivity analyses were conducted – a last-observation-carried-forward (LOCF) analysis and an analysis using “bookending” methodology (which required that the previous and subsequent cultures were both observed negative cultures to impute a negative result, otherwise a positive result was imputed). Both showed a 13-day shorter median time to SCC in the delamanid + OBR group (p=0.0281 for LOCF and p=0.0052 for “bookending”).

Delamanid resistance (defined as MIC > 0.2 pig/ml) has been observed at baseline in 2 of 316 patients in Trial 204 and 2 of 511 patients in Trial 213 (4 of 827 patients [0.48%]). Delamanid resistance emerged in 4 of 341 patients (1.2%) randomised to receive delamanid for 6 months in Trial 213. These four patients were only receiving two other medicinal products in addition to delamanid.

Paediatric population

The pharmacokinetics, safety and efficacy of delamanid in combination with a background regimen (BR) were evaluated in trial 242–12 –232 (10 days pharmacokinetics) followed by trial –233 (pharmacokinetics, efficacy and safety), both single-arm, open-label trials, which included 37 patients who had a median age of 4.55 years (range 0.78 to 17.60 years), 25 (67.6%) were Asian and 19 (51.4%) were female.

Paediatric patients were enrolled in four groups:

Group 1: 12 to 17 years (7 patients), group 2: 6 to 11 years (6 patients), group 3: 3 to 5 years (12 patients) and group 4: 0 to 2 years (12 patients). The overall mean baseline body weight of subjects was 19.5 kg and in groups 1, 2, 3, and 4 the mean body weights were 38.4, 25.1, 14.8, and 10.3 kg, respectively.

The patients had confirmed or probable MDR-TB infection and were to complete 26 weeks of treatment with delamanid + OBR, followed by OBR only in accordance with the WHO recommendation. Patients in groups 1 and 2 received film-coated tablets. The delamanid dose in group 1 was 100 mg twice daily and 50 mg twice daily in group 2. The doses administered were higher than the currently recommended weight-based dosage in the paediatric population. Patients in groups 3 and 4 received dispersible tablets. This paediatric formulation is not bio-equivalent with the film-coated tablets. Patients in group 3 were administered 25 mg twice daily and patients in group 4 were administered doses between 10 mg twice daily and 5 mg once daily based on body weight. The doses administered in group 4 were below the currently recommended weight-based dosage in the paediatric population.

A population PK analysis was performed on data from the 2 paediatric trials to determine the doses in paediatric subjects which would provide delamanid exposures similar to those observed in adult subjects with MDR-TB. Data in children with a body weight of less than 10 kg were too limited to determine doses for that patient population.

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Absorption

Oral bioavailability of delamanid improves when administered with a standard meal, by about 2.7 fold compared to fasting conditions. The peak plasma concentrations are reached in approximately 4 hours post-dose, regardless of food intake.

Linearity/non-linearity

Delamanid plasma exposure increases less than proportionally with increasing dose.

Distribution

Delamanid highly binds to all plasma proteins with a binding to total proteins of >99.5%. Delamanid has a large apparent volume of distribution (Vz/F of 2,100 L).

Biotransformation

Delamanid is primarily metabolised in plasma by albumin and to a lesser extent by CYP3A4. The complete metabolic profile of delamanid has not yet been elucidated, and there is a potential for drug interactions with other co-administered medicinal products, if significant unknown metabolites are discovered. The identified metabolites do not show anti-mycobacterial activity but some contribute to QTc prolongation, mainly DM-6705. Concentra­tions of the identified metabolites progressively increase to steady state after 6 to 10 weeks.

Elimination

Delamanid disappears from plasma with a t1/2 of 30 to 38 hours. Delamanid is not excreted in urine.

Special populations

Paediatric population

During treatment with the recommended delamanid doses to adolescents and children with a body weight of at least 10 kg (see section 4.2), similar plasma exposure were obtained as in adults.

Patients with renal impairment

Less than 5% of an oral dose of delamanid is recovered from urine. Mild renal impairment

(50 mL/min < CrCLN < 80 mL/min) does not appear to affect delamanid exposure. Therefore no dose adjustment is needed for patients with mild or moderate renal impairment. It is not known whether delamanid and metabolites will be significantly removed by haemodialysis or peritoneal dialysis.

Patients with hepatic impairment

No dose adjustment is considered necessary for patients with mild hepatic impairment. Delamanid is not recommended in patients with moderate to severe hepatic impairment.

Elderly patients (> 65 years)

No patients of > 65 years of age were included in clinical trials.

5.3 Preclinical safety data

Non-clinical data reveal no specific hazard for humans based on conventional studies for genotoxicity and carcinogenic potential. Delamanid and/or its metabolites have the potential to affect cardiac repolarisation via blockade of hERG potassium channels. In the dog, foamy macrophages were observed in lymphoid tissue of various organs during repeat-dose toxicity studies. The finding was shown to be partially reversible; the clinical relevance of this finding is unknown. Repeat-dose toxicity studies in rabbits revealed an inhibitory effect of delamanid and/or its metabolites on vitamin K-dependent blood clotting. In rabbits reproductive studies, embryo-fetal toxicity was observed at maternally toxic dosages. Pharmacokinetic data in animals have shown excretion of delamanid

/metabolites into breast milk. In lactating rats, the Cmax for delamanid in breast milk was 4-fold higher than that of the blood. In juvenile toxicity studies in rats, all delamanid treatment-related findings were consistent with those noted in adult animals.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Hypromellose phthalate

Povidone

all-rac-a-Tocopherol

Cellulose, microcrystalline

Sodium starch glycolate (type A)

Carmellose calcium

Silica, colloidal hydrated

Magnesium stearate

Lactose monohydrate

Film coating

Hypromellose

Macrogol 8000

Titanium dioxide

Talc

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

5 years

6.4 Special precautions for storage

Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Aluminium/Aluminium blister:

48 tablets.

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

Otsuka Novel Products GmbH

Erika-Mann-Straße 21

80636 München

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/875/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28 April 2014

Date of latest renewal: 13 April 2021