Delamanid

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
    • 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.

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.

There are no data on the use of delamanid in patients with severe renal impairment and its use is not recommended.

Delamanid is not recommended in patients with moderate to severe hepatic impairment.

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.

There are no or limited amount of data from the use of delamanid in pregnant women. Studies in animals have shown reproductive toxicity. Delamanid is not recommended in pregnancy and in women of childbearing potential not using contraception.

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. A risk to the newborns/infants cannot be excluded. It is recommended that women should not breastfeed during treatment with delamanid.

Fertility

Delamanid had no effect on male or female fertility in animals. There are no clinical data on the effects of delamanid on fertility in humans.

Delamanid 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 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%).