Delamanid

Registered South African indications:

• Pulmonary multi-drug resistant tuberculosis (MDR-TB)

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Severe hepatic impairment
• Serum albumin <2,8g/dl
• Cardiac failure
• Uncontrolled brady- or tachydysrhythmias
• Congenital QT prolongation 
• Coadministration with agents known to prolong the QTc interval to time intervals known to induce serious dysrhythmias
• Coadministration with strong CYP3A4 inducers (e.g. carbamazepine)

Cautions

• Pregnancy
• Women of childbearing potential
• Breastfeeding
• Moderate to severe renal impairment
• Moderate hepatic impairment
• Elderly
• Treatment for more than 24 consecutive weeks
• Treatment of extrapulmonary tuberculosis (e.g. central nervous system, bone) 
• Treatment of infections due to mycobacterial species other than those of the M. tuberculosis complex
• Treatment of latent infection with M. tuberculosis
• Use as part of combination regimens used to treat drug-susceptible M. tuberculosis
• Resistance to delamanid (See additional prescribing points)
• QTc interval duration exceeds 450/470ms during treatment
• QTcF >500ms or QTcF interval increase of >60ms from baseline
• Known congenital prolongation of the QTc-interval or any clinical condition known to prolong the QTc interval or QTc >500ms
• History of symptomatic cardiac dysrhythmias or with clinically relevant bradycardia
• Any predisposing cardiac conditions for arrhythmia such as
  - Severe hypertension 
  - Left ventricular hypertrophy (including hypertrophic cardiomyopathy) 
  - Congestive cardiac failure accompanied by reduced left ventricle ejection fraction 
• Electrolyte disturbances (particularly, hypokalemia, hypocalcemia, and hypomagnesaemia)
• Pre-existing hypoalbuminaemia (serum albumin <3.4g/dl) (See additional prescribing points)
• Coadministration with medicinal agents that are known to prolong the QTc interval (See additional prescribing points)
• Galactose intolerance (e.g. galactosaemia)
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct

Pulmonary multi-drug resistant tuberculosis (MDR-TB)
- As part of an appropriate combination regimen when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability

• Oral (fct): 100mg, 12hrly; Treatment duration: 24 weeks

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Delamanid should be taken with food

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Delamanid must always preferably by direct observed therapy (DOT) be administered as part of an appropriate combination regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB)

Not established for use in children below 18 years

Pregnancy 

• Caution; not recommended
• Safety in pregnancy has not been established. Delamanid should not be used in pregnant women
• Women of childbearing potential should not be treated with delamanid unless they are using a reliable form of contraception for the duration of the treatment

Breastfeeding

• Caution; not recommended 
• Safety in breastfeeding has not been established. Mothers should not breastfeed their babies during treatment with delamanid

Fertility

• No information available

Renal Impairment 

• Mild (CrCl>50-<80ml/min): No dose adjustment recommended 
  Less than 5% of an oral dose of delamanid is recovered from urine. Does not appear to affect delamanid exposure
• Moderate: Caution; no dose adjustment recommended 
  It is not known whether delamanid and metabolites will be significantly removed by haemodialysis or peritoneal dialysis
• Severe: Caution; not recommended

Hepatic Impairment

• Mild: No dose adjustment recommended 
• Moderate: Caution; not recommended 
• Severe: Contraindicated 

Elderly 

• Caution; no information available 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Paraesthesia
• Tremor
• Peripheral neuropathy
• Somnolence
• Hypoaesthesia
• Lethargy
• Balance disorder
• Radicular pain
• Poor quality sleep
• Insomnia
• Psychotic disorder
• Agitation
• Anxiety and anxiety disorder
• Depression and depressed mood
• Restlessness
• Aggression
• Persecutory type delusional disorder
• Panic disorder
• Adjustment disorder with depressed mood
• Neurosis
• Dysphoria
• Mental disorder
• Sleep disorder
• Malaise

Cardiovascular Disorders 

• Palpitations
• First-degree atrioventricular block
• Ventricular extrasystoles
• Supraventricular extrasystoles
• Hypertension
• Hypotension
• Haematoma
• Hot flushes
• Prolonged QT electrocardiogram
• Electrocardiogram ST-segment depression
• Increased blood pressure

Respiratory Disorders 

• Haemoptysis
• Dyspnoea
• Cough
• Oropharyngeal pain
• Throat irritation
• Dry throat
• Rhinorrhoea
• Chest pain
• Chest discomfort

Gastrointestinal Disorders 

• Nausea and vomiting
• Diarrhoea
• Upper abdominal pain
• Gastritis
• Constipation
• Abdominal pain
• Lower abdominal pain
• Dyspepsia
• Abdominal discomfort
• Dysphagia
• Oral paraesthesia
• Abdominal tenderness
• Oropharyngeal candidiasis

Hepatobiliary Disorders 

• Abnormal hepatic function
• Increased aminotransferases
• Increased gamma-glutamyltransferase

Genitourinary Disorders

• Haematuria
• Urinary retention
• Dysuria
• Nocturia
• Increased libido

Endocrine and Metabolic Disorders

• Hypokalaemia
• Decreased appetite
• Hyperuricaemia
• Hypertriglyceridaemia
• Dehydration
• Hypocalcaemia
• Hypercholesterolaemia
• Increased blood cortisol
• Decreased blood cortisol

Musculoskeletal Disorders 

• Arthralgia
• Myalgia
• Osteochondrosis
• Muscular weakness
• Musculoskeletal pain
• Flank pain
• Pain in extremity

Skin and Subcutaneous Tissue Disorders 

• Tinea versicolor
• Dermatitis
• Urticaria
• Pruritic rash 
• Pruritus
• Maculopapular rash
• Rash
• Acne
• Hyperhidrosis
• Alopecia
• Eosinophilic pustular folliculitis
• Generalised pruritus 
• Erythematous rash

Immune, Blood and Lymphatic System Disorders

• Herpes zoster
• Reticulocytosis
• Anaemia
• Eosinophilia
• Leukopenia
• Thrombocytopenia
• Pyrexia
• Peripheral oedema
• Prolonged activated partial thromboplastin time

Sensory Disorders

• Dry eye
• Photophobia
• Allergic conjunctivitis
• Tinnitus
• Ear pain

Others

• Feeling hot

• Agents known to prolong the QTc interval
• Strong CYP3A4 inducers 
• Carbamazepine
• Rifampicin
• Lopinavir/ritonavir

• Electrocardiogram (See additional prescribing points)
• Electrolytes (at baseline)

Resistance to delamanid

• Delamanid must only be used in an appropriate combination regimen for MDR-TB treatment to prevent the development of resistance to delamanid

Electrocardiogram 

• 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 >500ms is observed either before the first dose of delamanid or during delamanid treatment or a QTcF interval increase of >60ms from the baseline with treatment, treatment with delamanid should either not be started or should be discontinued
• If the QTc interval duration exceeds 450/470ms for male/female patients during delamanid treatment, more frequent ECG monitoring should be administered

Pre-existing hypoalbuminaemia 

• The presence of hypoalbuminaemia is associated with an increased risk of prolongation of the QTc interval in delamanid treated patients.  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

Coadministration with medicinal agents 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 medicines
• Certain antimicrobial medicines, including macrolides (e.g. erythromycin, clarithromycin)
• Moxifloxacin, sparfloxacin or other fluoro-quinolones
• Bedaquiline
• Triazole antifungal medicines
• 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 and arsenic trioxide

Delamanid inhibits the synthesis of mycobacterial cell wall components, methoxy-mycolic and keto-mycolic acid. The identified metabolites of delamanid do not show anti-mycobacterial activity.

Film coated tablet 50mg

• Deltyba (Mylan) originator