DELTYBA Film-coated tablet Ref.[7597] Active ingredients: Delamanid

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 drugsusceptible 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 coadministration is considered to be unavoidable in order to construct an adequate treatment regimen for MDRTB 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.

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 medicines tenofovir disoproxil and efavirenz but was slightly increased with the combination anti-HIV medicine 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(pgp), BCRP, OATP1, OATP3, OCT1, OCT2, OATP1B1, OATP1B3 and BSEP, at concentrations of approximately 5 to 20 fold greater than the C_max at steady state. However, since the concentrations in the gut can potentially be much greater than these multiples of the C_max, 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 anti-HIV-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 medicines 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.

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.

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).

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 (delamanid plus OBR, n=662 vs placebo plus OBR n=330). 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:

^* The frequency for these events was lower for the combined delamanid plus OBR 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 Appendix V.

Not applicable.