DELTYBA 50mg tablets medication leaflet

Deltyba 50 mg film-coated tablets

Each film-coated tablet contains 50 mg delamanid.

Each film-coated tablet contains 100 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

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

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

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

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

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

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

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 dispersibletablets.

The total duration of treatment with delamanid is 24 weeks. Data on longer treatment duration is verylimited. When treatment with delamanid is considered necessary beyond 24 weeks to obtain a curativetreatment, a longer duration of therapy may be considered.

Elderly patients (> 65 years of age)

No data are available in the elderly.

No dose adjustment is considered necessary in patients with mild or moderate renal impairment. Thereare no data on the use of delamanid in patients with severe renal impairment and its use is notrecommended (see sections 4.4 and 5.2).

No dose adjustment is considered necessary in patients with mild hepatic impairment. Delamanid isnot recommended in patients with moderate to severe hepatic impairment (see sections 4.4 and 5.2).

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

Oral use.

Delamanid should be taken with food.

- 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).

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 asrecommended by WHO to prevent development of resistance to delamanid.

QT prolongation has been observed in patients treated with delamanid. This prolongation increasesslowly over time in the first 6 to 10 weeks of treatment and remains stable thereafter. QTcprolongation is very closely correlated with the major delamanid metabolite DM-6705. Plasmaalbumin and CYP3A4 regulate the formation and metabolism of DM-6705 respectively (see Special

Considerations below).

It is recommended that electrocardiograms (ECG) should be obtained before initiation of treatmentand monthly during the full course of treatment with delamanid. If a QTcF > 500 ms is observed eitherbefore the first dose of delamanid or during delamanid treatment, treatment with delamanid shouldeither not be started or should be discontinued. If the QTc interval duration exceeds 450/470 ms formale/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 atbaseline and corrected if abnormal.

Special considerations

Cardiac risk factors

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

- Known congenital prolongation of the QTc-interval or any clinical condition known to prolongthe 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 ventricularhypertrophy (including hypertrophic cardiomyopathy) or congestive cardiac failureaccompanied 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 arenot 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 otherfluoroquinolones)

- 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 ofprolongation of the QTc interval in delamanid treated patients. Delamanid is contraindicated inpatients with albumin < 2.8 g/dL (see section 4.3). Patients who commence delamanid with serumalbumin < 3.4 g/dL or experience a fall in serum albumin into this range during treatment shouldreceive 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) wasassociated 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 CYP3A4is considered necessary it is recommended that there is very frequent monitoring of ECGs, throughoutthe 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 adequatetreatment regimen for MDR-TB it is recommended that there is very frequent monitoring of ECGsthroughout the full delamanid treatment period.

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

There are no data on the use of delamanid in patients with severe renal impairment and its use is notrecommended (see sections 4.2 and 5.2).

Paradoxical drug reaction

Post-marketing cases of paradoxical drug reactions (clinical or radiological worsening of existinglesions or development of new lesions in a patient who had previously shown improvement withappropriate antimycobacterial treatment) have been reported with Deltyba. Paradoxical drug reactionsare often transient and should not be misinterpreted as failure to respond to treatment. If a paradoxicalresponse is suspected, continuation of planned combination therapy is recommended and symptomatictherapy to suppress the exaggerated immune reaction should be initiated if necessary (see section 4.8).

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

Effects of other medicinal products on delamanid

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 relevantreduction in delamanid exposure was observed with the weak inducer efavirenz when administered ata 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 mgdaily) for 14 days and with efavirenz for 10 days (600 mg daily). Delamanid exposure remainedunchanged (< 25% difference) with anti-HIV medicinal products tenofovir disoproxil and efavirenzbut was slightly increased with the combination anti-HIV medicinal products containinglopinavir/ritonavir.

Effects of delamanid 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, atconcentrations of approximately 5 to 20-fold greater than the Cmax at steady state. However, since theconcentrations in the gut can potentially be much greater than these multiples of the Cmax, there is apotential 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 administered 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 steadystate 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 administered 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 theanti-HIV-medicines, tenofovir disoproxil, lopinavir/ritonavir and efavirenz, did not affect the exposureto these medicinal products.

Medicinal products with the potential to prolong QTc

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

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

Deltyba is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

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

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

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

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(28.4%), sleep disorders and disturbances (28.2%), dizziness (22.4%), gastritis (15.9%) and decreasedappetite (13.1%).

The list of adverse drug reactions and frequencies are based on the results from 2 double-blind placebocontrolled clinical trials and on spontaneous reports. The adverse drug reactions are listed by

MedDRA System Organ Class and Preferred Term. Within each System Organ Class, adversereactions 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 notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

Table: Adverse drug reactions to delamanid

System Organ Frequency Frequency Frequency Frequency not

Class very common common uncommon known

Endocrine - Hypothyroidisma - -disorders

Metabolism and Decreased appetite - - -nutrition disorders

Psychiatric Sleep disorders and Psychotic disorderc - -disorders disturbancesb Anxietyd

Depressione

Hallucinationf

Nervous system Dizziness Hypoaesthesia Lethargy -disorders Headacheg Tremor

Cardiac disorders - Atrioventricular - -block first degree

Ventricularextrasystoles

Palpitations

Respiratory, - Throat irritation - -thoracic andmediastinaldisorders

Gastrointestinal Nausea Dyspepsia - -disorders Vomiting

Gastritish

Musculoskeletal - Muscular weakness - -and connective Muscle spasmstissue disorders

General disorders - Chest pain - Paradoxical drugand administration reactionsite conditions

Investigations - Cortisol increasedi - -

Electrocardiogram

QT prolonged

Event terms that represent the same medical concept or condition were grouped together and reportedas a single adverse drug reaction in Table ‘Adverse drug reactions to delamanid’. Preferred termsactually reported in the double-blind clinical trials and contributing to the relevant adverse drug reactionare indicated in parentheses, as listed below:

a. Hypothyroidism (hypothyroidism, primary hypothyroidism)

b. Sleep disorders and disturbances (initial insomnia, insomnia, sleep disorder, nightmare)

c. Psychotic disorder (acute psychosis, psychotic disorder, reactive psychosis, substance-inducedpsychotic disorder)

d. Anxiety (anxiety, anxiety disorder, generalised anxiety disorder)

e. Depression (adjustment disorder with depressed mood, depressed mood, depression, majordepression, mixed anxiety and depressive disorder, persistent depressive disorder, schizoaffectivedisorder depressive type)

f. Hallucination (hallucination; hallucination, auditory; hallucination, visual; hallucination tactile;hallucination mixed; hypnopompic hallucination; hypnagogic hallucination)g. Headache (head discomfort, headache, migraine, sinus headache, tension headache, vascularheadache)h. Gastritis (chronic gastritis, gastritis, gastritis erosive)i. Cortisol increased (Cushing's syndrome, hyperadrenocorticism, cortisol increased)

ECG QT interval prolongation

In patients receiving 200 mg delamanid total daily dose in the phase 2 and 3 trials, the mean placebocorrected increase in QTcF from baseline ranged from 4.7 - 7.6 ms at 1 month and 5.3 ms - 12.1 ms at2 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) ofpatients receiving placebo + OBR, while the incidence of QTcF change from baseline > 60 ms rangedfrom 3.1% (5/161) - 10.3% (35/341) in patients receiving delamanid 200 mg total daily dose versus0% (0/160) - 7.1% (12/170) in patients receiving placebo.

Palpitations

For patients receiving delamanid + OBR in the phase 2 and 3 trials, the frequency was 7.9%(frequency category common) in comparison to a frequency of 6.7% in patients receiving placebo +

OBR.

Based on a study (see section 5.1) in 37 paediatric patients aged 0 to 17 years, the frequency, type andseverity 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 post-marketing. The incidence of hallucination in clinical trials was common for children (5.4%) and adults(1%).

Cases of nightmare have been reported predominantly in the paediatric population during post-marketing.

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.

No cases of delamanid overdose have been observed in clinical trials. However, additional clinicaldata showed that in patients receiving 200 mg twice daily, i.e. total 400 mg delamanid per day, theoverall safety profile is comparable to that in patients receiving the recommended dose of 100 mgtwice daily. Albeit, some reactions were observed at a higher frequency and the rate of QTprolongation increased in a dose-related manner. Treatment of overdose should involve immediatemeasures to remove delamanid from the gastrointestinal tract and supportive care as required.

Frequent ECG monitoring should be performed.

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

J04AK06.

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

Activity against specific pathogens

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

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

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) fordelamanid and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx

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 whichincluded patients who had positive cultures at baseline and the isolate was resistant to both isoniazidand 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 two-month sputum culture conversion (SCC) (i.e. growth of Mycobacterium tuberculosis to no growthover the first 2 months and maintained for 1 more month) (p = 0.0083). The time to SCC for the grouprandomised to 100 mg BID was also found to be faster than for the group randomised to receiveplacebo + OBR (p = 0.0056).

In the second trial (Trial 213), delamanid was administered orally at 100 mg BID as an add-on therapyto an OBR for 2 months followed by 200 mg once daily for 4 months. The median time to SCC was51 days in the delamanid + OBR group compared with 57 days in the PLC + OBR group (p = 0.0562using the stratified modified Peto-Peto modification of Gehan’s Wilcoxon rank sum test). Theproportion of patients achieving SCC (sputum culture conversion) after the 6-month treatment periodwas 87.6% (198/226) in the delamanid + OBR treatment group compared to 86.1% (87/101) in theplacebo + OBR treatment group (p = 0.7131).

All missing cultures up to the time of SCC were assumed to be positive cultures in the primaryanalysis. Two sensitivity analyses were conducted - a last-observation-carried-forward (LOCF)analysis and an analysis using ‘bookending’ methodology (which required that the previous andsubsequent cultures were both observed negative cultures to impute a negative result, otherwise apositive 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 µg/mL) has been observed at baseline in 2 of 316 patientsin Trial 204 and 2 of 511 patients in Trial 213 (4 of 827 patients [0.48%]). Delamanid resistanceemerged in 4 of 341 patients (1.2%) randomised to receive delamanid for 6 months in Trial 213. Thesefour patients were only receiving two other medicinal products in addition to delamanid.

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 patientswho 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 ofsubjects was 19.5 kg and in groups 1, 2, 3, and 4 the mean body weights were 38.4, 25.1, 14.8, and10.3 kg, respectively.

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

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

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

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

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

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

Delamanid is primarily metabolised in plasma by albumin and to a lesser extent by CYP3A4. Thecomplete metabolic profile of delamanid has not yet been elucidated, and there is a potential for druginteractions with other co-administered medicinal products, if significant unknown metabolites arediscovered. The identified metabolites do not show anti-mycobacterial activity but some contribute to

QTc prolongation, mainly DM-6705. Concentrations of the identified metabolites progressivelyincrease to steady state after 6 to 10 weeks.

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

Delamanid plasma exposure increases less than proportionally with increasing dose.

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

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 doseadjustment is needed for patients with mild or moderate renal impairment. It is not known whetherdelamanid and metabolites will be significantly removed by haemodialysis or peritoneal dialysis.

No dose adjustment is considered necessary for patients with mild hepatic impairment. Delamanid isnot 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.

Non-clinical data reveal no specific hazard for humans based on conventional studies for genotoxicityand carcinogenic potential. Delamanid and/or its metabolites have the potential to affect cardiacrepolarisation via blockade of hERG potassium channels. In the dog, foamy macrophages wereobserved in lymphoid tissue of various organs during repeat-dose toxicity studies. The finding wasshown to be partially reversible; the clinical relevance of this finding is unknown. Repeat-dose toxicitystudies 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 atmaternally toxic dosages. Pharmacokinetic data in animals have shown excretion ofdelamanid/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-relatedfindings were consistent with those noted in adult animals.

Hypromellose phthalate

Povidoneall-rac-α-Tocopherol

Cellulose, microcrystalline

Sodium starch glycolate (type A)

Carmellose calcium

Silica, colloidal hydrated

Magnesium stearate

Lactose monohydrate

Hypromellose

Macrogol 8000

Titanium dioxide

Talc

Iron oxide yellow (E172)

Not applicable.

5 years

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

Aluminium/Aluminium blister:

48 tablets.

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

Otsuka Novel Products GmbH

Erika-Mann-Straße 2180636 München

Germany

EU/1/13/875/004

Date of first authorisation: 28 April 2014

Date of latest renewal: 26 February 2024

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

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