Delamanid

Chemical formula: C₂₅H₂₅F₃N₄O₆  Molecular mass: 534.492 g/mol 

Interactions

Delamanid interacts in the following cases:

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
      • 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.

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.

Severe renal impairment

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

Moderate hepatic impairment, severe hepatic impairment

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

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.

Pregnancy

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.

Nursing mothers

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.

Carcinogenesis, mutagenesis and fertility

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.

Effects on ability to drive and use machines

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).

Adverse reactions


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:

System
Organ Class
Frequency
very common
Frequency
common
Frequency
uncommon
Infections and
infestations
- - Herpes zoster
Oropharyngeal
candidiasis
Tinea versicolor*
Blood and
lymphatic
system
disorders
ReticulocytosisAnaemia*
Eosinophilia*
Leukopenia
Thrombocytopaenia
Metabolism
and nutrition
disorders
Hypokalaemia
Decreased appetite
Hyperuricaemia*
Hypertriglyceridaemia Dehydration
Hypocalcaemia
Hypercholesterolaemia
Psychiatric
disorders
Insomnia Psychotic disorder
Agitation
Anxiety and anxiety
disorder
Depression and
depressed mood
Restlessness
Hallucination
Aggression
Delusional disorder,
persecutory type
Panic disorder
Adjustment disorder with
depressed mood
Neurosis
Dysphoria
Mental disorder
Sleep disorder
Libido increased*
Nervous
system
disorders
Dizziness*
Headache
Paraesthesia
Tremor
Neuropathy peripheral
Somnolence*
Hypoaesthesia
Lethargy
Balance disorder
Radicular pain
Poor quality sleep
Eye disorders - Dry eye*
Photophobia
Conjunctivitis allergic*
Ear and
labyrinth
disorders
Tinnitus Ear pain-
Cardiac
disorders
Palpitations- Atrioventricular block
first degree
Ventricular
extrasystoles*
Supraventricular
extrasystoles
Vascular
disorders
- Hypertension
Hypotension
Haematoma*
Hot flush*
-
Respiratory,
thoracic and
mediastinal
disorders
Haemoptysis Dyspnoea
Cough
Oropharyngeal pain
Throat irritation
Dry throat*
Rhinorrhoea*
-
Gastrointestinal
disorders
Vomiting
Diarrhoea*
Nausea
Abdominal pain upper
Gastritis*
Constipation*
Abdominal pain
Abdominal pain lower
Dyspepsia
Abdominal discomfort
Dysphagia
Paraesthesia oral
Abdominal tenderness*
Hepatobiliary
disorders
- - Hepatic function
abnormal
Skin and
subcutaneous
tissue
disorders
- Dermatitis
Urticaria
Rash pruritic*
Pruritus*
Rash maculo-papular*
Rash*
Acne
Hyperhidrosis
Alopecia*
Eosinophilic pustular
folliculitis*
Pruritus generalised*
Rash erythematous
Musculoskeletal and
connective
tissue
disorders
Arthralgia*
Myalgia*
Osteochondrosis
Muscular weakness
Musculoskeletal pain*
Flank pain
Pain in extremity
-
Renal and
urinary
disorders
- Haematuria* Urinary retention
Dysuria*
Nocturia
General
disorders and
administration site
conditions
Asthenia Pyrexia*
Chest pain
Malaise
Chest discomfort*
Oedema peripheral*
Feeling hot
Investigations Electrocardiogram QT
prolonged
Blood cortisol increased Electrocardiogram ST
segment depression
Transaminases
increased*
Activated partial
thromboplastin time
prolonged*
Gammaglutamyltransferase
increased*
Blood cortisol decreased
Blood pressure increased

* 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%).

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