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Pharmacotherapeutic group: Antimycobacterials, antibiotics. ATC code: J04AK06.
Pharmacology: Pharmacodynamics: Mode 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 Precautions). Delamanid does not show cross-resistance with any of the currently used anti-tuberculosis drugs.
Susceptibility testing breakpoints: In clinical trials resistance to delamanid has been defined as any growth in the presence of a delamanid concentration of 0.2 μg/mL that is greater than 1% of that on drug-free control cultures on Middlebrook 7H11 medium.
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 two-month 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 μg/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 European Medicines Agency has deferred the obligation to submit the results of studies with Deltyba in one or more subsets of the paediatric population in (treatment in multi-drug resistant tuberculosis) (see Dosage & Administration on paediatric use).
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.
Pharmacokinetics: Absorption: Oral bioavailability of delamanid improves when administered with a standard meal, by about 2.7 fold compared to fasting conditions. 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 medications, 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 t½ of 30-38 hours. Delamanid is not excreted in urine.
Special populations: Paediatric population: No studies have been performed in paediatric patients.
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.
Toxicology: 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 repolarization 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.
