Deltyba

Delamanid.

Each film-coated tablet contains 50 mg delamanid.
Excipient(s) with known effect: Each film-coated tablet contains 100 mg lactose ( as hydrate).
Excipients/Inactive Ingredients: Tablet core: Hypromellose phthalate, Povidone, Tocopherol, Microcrystalline cellulose, Sodium starch glycolate, Carmellose calcium, Light anhydrous silicic acid, Magnesium stearate, Lactose hydrate.
Film coating: Hypromellose, Macrogol 6000, Titanium oxide, Talc, Yellow ferric oxide.

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 t_½ 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 C_max for delamanid in breast milk was 4-fold higher than that of the blood.

Deltyba is indicated for use as part of an appropriate combination regimen for pulmonary multi-drug resistant tuberculosis (MDR-TB) in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability (see Pharmacology: Pharmacodynamics under Actions, Dosage & Administration and Precautions).
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 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 Pharmacology: Pharmacodynamics under Actions, and Precautions). 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: The recommended dose for adults is 100 mg twice daily for 24 weeks.
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 Pharmacology: Pharmacokinetics under Actions, and Precautions).
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 Pharmacology: Pharmacokinetics under Actions, and Precautions).
Paediatric population: The safety and efficacy of delamanid in children and adolescents below 18 years has not yet been established. No data are available.
Method of administration: For oral use.
Delamanid should be taken with food.

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.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Serum albumin <2.8 g/dL (see Precautions regarding use in patients with serum albumin ≥2.8 g/dL).
Taking medicinal products that are strong inducers of CYP3A (e.g. carbamazepine).

There are no data on treatment with delamanid for more than 24 consecutive weeks.
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 6-10 weeks of treatment and remains stable thereafter. QTc prolongation is very closely correlated with the major delamanid metabolite DM-6705. Plasma albumin and CYP3A regulate the formation and metabolism of DM-6705 respectively (see Special Considerations as follows).
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 Precautions regarding use with other fluoroquinolones), triazole antifungal agents, pentamidine, saquinavir; certain non-sedating antihistamines (e.g. terfenadine, astemizole, mizolastine); 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 Contraindications). 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 CYP3A: Co-administration of delamanid with a strong inhibitor of CYP3A (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 CYP3A 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 Pharmacology: Pharmacokinetics under Actions and Dosage & Administration).
Biotransformation and elimination: The complete metabolic profile of delamanid in man has not yet been fully elucidated (see Pharmacology: Pharmacokinetics under Actions, and Interactions). Therefore the potential for drug-drug interactions of clinical significance to occur with delamanid and the possible consequences, including the total effect on the QTc interval, cannot be predicted with confidence.
Excipients: Deltyba film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Effects on the ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. However, 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).

Pregnancy: There are very limited data from the use of delamanid in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Deltyba is not recommended in pregnant women or in women of childbearing potential unless they are using a reliable form of contraception.
Breast-feeding: It is unknown whether this medicinal product or its metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of delamanid and/or its metabolites in milk. Because a potential risk to the breast-feeding infant cannot be ruled out, it is recommended that women should not breastfeed during treatment with Deltyba.
Fertility: Deltyba had no effect on male or female in animals (see Pharmacology: Toxicology: Preclinical safety data under Actions). There are no clinical data on the effects of delamanid on fertility in humans.

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 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 (≥1/1000 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. (See table.)

Click on icon to see table/diagram/image

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 >60ms 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.
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. If the patient experience any adverse reactions after taking the drug, he or she should report the events to healthcare professional immediately for appropriate follow up.

The complete metabolic profile and mode of elimination of delamanid has not yet been fully elucidated (see Pharmacology: Pharmacokinetics under Actions, and Precautions).
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 medicines: In clinical drug-drug interaction studies in healthy subjects, delamanid was administered alone (100 mg twice daily) and with tenofovir (300 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 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(p-gp), 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 medicines: 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 steady state plasma concentrations of ethambutol by approximately 25%, the clinical relevance is unknown.
Anti-HIV medicines: In a clinical drug-drug interaction study in healthy subjects, delamanid was administered alone (100 mg twice daily) and tenofovir (300 mg), lopinavir/ritonavir (400/100 mg) for 14 days and with efavirenz for 10 days (600 mg daily). Delamanid given in combination with the anti-HIV-medicines, tenofovir, 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 Precautions). 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.

Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.

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

Anti-TB Agents

J04AK06 - delamanid ; Belongs to the class of other drugs used in the systemic treatment of tuberculosis.

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