Pretomanid

Registered South African indications:

• Pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB)
  (See additional prescribing points)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Pretomanid used in the combination regimen with bedaquiline and linezolid is contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated (refer to the bedaquiline and linezolid professional information)
• Coadministration with strong or moderate CYP3A4 inducers, such as rifampicin or efavirenz

South African recommendations

Caution in the following patient groups

• Renal impairment
• Hepatic impairment
• Elderly

Risks Associated with the combination treatment regimen

• Pretomanid is used as part of a regimen with bedaquiline and linezolid
• Refer to the professional information for bedaquiline and linezolid for additional risk information
• Warnings and precautions for bedaquiline and linezolid also apply to their use in combination with pretomanid

Hepatotoxicity

• Hepatic adverse reactions reported with the combination regimen of pretomanid, bedaquiline, and linezolid
• Avoid alcohol and hepatotoxic medicines, including herbal supplements, while on pretomanid
• Monitor liver function at baseline, two weeks, monthly during treatment, and as needed
• If liver dysfunction worsens, test for viral hepatitides and discontinue other hepatotoxic medications
• Interrupt treatment if: Aminotransferase elevations are accompanied by total bilirubin elevation >2 times upper limit of normal, Aminotransferase >8 times upper limit, or persist >2 weeks

Myelosuppression

• Myelosuppression including anaemia, leukopenia, thrombocytopenia, and pancytopenia reported with the combination regimen
• Complete blood counts should be monitored at baseline, two weeks, and monthly
• Decrease or interrupt linezolid dosing if myelosuppression develops or worsens

Peripheral and optic neuropathy

• Peripheral and reversible optic neuropathy reported with the combination regimen
• Neuropathy is a known adverse reaction of long-term linezolid use
• Monitor visual function in all patients receiving the regimen
• If visual impairment occurs, interrupt linezolid dosing and obtain ophthalmologic evaluation

QT prolongation

• QT prolongation reported with the combination regimen
• ECG monitoring is required before treatment and at 2, 12, and 24 weeks
• Serum potassium, calcium, and magnesium should be measured at baseline and corrected if abnormal
• Risk factors for QT prolongation include history of Torsade de Pointes, congenital long QT syndrome, bradydysrhythmia, or hypothyroidism
• Discontinue treatment if ventricular bradydysrhythmia or QTcF >500ms is detected

Interactions

• Avoid co-administration with strong or moderate CYP3A4 inducers like rifampicin or efavirenz

Reproductive effects

• Pretomanid caused testicular atrophy and impaired fertility in male rats
• Potential effects on human male fertility have not been adequately evaluated

Lactic acidosis

• Lactic acidosis has been reported with the combination regimen
• Recurrent nausea or vomiting should prompt medical evaluation, including lactic acid levels
• Interrupt treatment if lactic acidosis is suspected or confirmed

Lactose

• Patients with the rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take pretomanid

Effects on ability to drive and use machines

• Pretomanid may cause dizziness and visual impairment. Patients should be cautioned about operating hazardous machinery, including motor vehicles until they are reasonably certain that pretomanid does not adversely affect them

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

South African registered indications and dosages

Pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB) (Additional agents required)
- As part of a combination regimen with bedaquiline and linezolid

• Oral (tab): 200mg, dly swallowed whole with water; Treatment duration: 26 weeks

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Important administration instructions
Pretomanid must be used only in combination with bedaquiline and linezolid as part of the recommended dosing regimen. Emphasize the need for compliance with the full course of therapy to patients. Administer the combination regimen of pretomanid, bedaquiline, and linezolid by directly observed therapy (DOT)

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Combination regimen
Pretomanid as above
Bedaquiline: 400mg, daily for 2 weeks followed by 200mg 3 times per week, with at least 48 hours between doses, for 24 weeks for a total of 26 weeks
Linezolid: Initial: 1200mg, daily for 26 weeks, with dose adjustments to 600mg daily and further reduction to 300mg daily or interruption of dosing as necessary for known linezolid adverse reactions of myelosuppression, peripheral neuropathy, and reversible optic neuropathy
Dosing of the combination regimen can be extended beyond 26 weeks, if necessary
The combination regimen should be taken with food

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Discontinuation of dosing
If either bedaquiline or pretomanid are discontinued, the entire combination regimen should also be discontinued. If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, bedaquiline and pretomanid should also be discontinued. If linezolid is discontinued after the initial four weeks of consecutive treatment, continue administering bedaquiline and pretomanid

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See additional prescribing points for limitations of use

Safety and effectiveness in paediatric patients have not been established

Pregnancy

South African recommendations

• Contraindicated
• Pretomanid should not be used during pregnancy
• There are risks associated with active tuberculosis during pregnancy
• When pretomanid are administered in combination with bedaquiline and linezolid, the pregnancy information for bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolid professional information for more information on bedaquiline and linezolid associated risks of use during pregnancy
• In animal reproduction studies, there was increased post- implantation loss in the presence of maternal toxicity (reduced bodyweight and feed consumption) with oral administration of pretomanid during organogenesis in rats at doses about 4 times the exposure at the recommended dose in humans. There were no adverse embryo fetal effects in rats or rabbits dosed with oral pretomanid during organogenesis at doses up to approximately 2 times the exposure in humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown
• Clinical considerations: Disease-associated maternal and/or embryo/foetal risk active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anaemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death

Breastfeeding

South African recommendations

• Contraindicated
• Pretomanid should not be used during breastfeeding
• Women taking pretomanid should not breastfeed their babies
• There is no information regarding the presence of pretomanid in human milk, or its effects on milk production or the breastfed infant
• Pretomanid was detected in rat milk. When a medicine is present in animal milk, it is likely that the medicine will be present in human milk. When pretomanid are administered in combination with bedaquiline and linezolid, information on lactation for bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolid prescribing information for more information on their use during lactation

Fertility

South African recommendations

• In males reduced fertility and/or testicular toxicity were observed in male rats and mice treated with oral pretomanid
• These effects were associated with hormonal changes including decreased serum inhibin B and increased serum follicle stimulating hormone and luteinizing hormone in rodents
• Reduced fertility and testicular toxicity cannot be definitively ruled out in male human subjects. Male patients should consider sperm conservation before starting treatment with pretomanid

South African recommendations

• Caution; no information available
  The effect of renal impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known

South African recommendations

• Caution; no information available
  The effect of hepatic impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known

South African recommendations

• Caution; no information available
  Clinical studies of the combination regimen of pretomanid, bedaquiline, and linezolid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects

Infections and Infestations

Less frequent

• Fungal infection
• Oral candidiasis
• Oral fungal infection

Blood and Lymphatic System Disorders

Frequent

• Anaemia Δ
• Leukopenia Δ
• Neutropenia Δ
• Thrombocytopenia Δ

Less frequent

• Lymphopenia Δ
• Pancytopenia Δ

Metabolism and Nutrition Disorders

Frequent

• Decreased appetite
• Hypoglycaemia
• Lactic acidosis Δ

Less frequent

• Acidosis Δ
• Dehydration
• Hypocalcaemia
• Hypovolaemia
• Hypomagnesaemia

Psychiatric Disorders

Frequent

• Insomnia

Less frequent

• Anxiety
• Depression

Nervous System Disorders

Frequent

• Peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy) Δ
• Headache
• Dysgeusia
• Dizziness

Eye Disorders

Frequent

• Visual impairment (blurred vision, reduced visual acuity, visual impairment)
• Eye irritation
• Eye pain
• Optic neuropathy (optic neuropathy, optic neuritis) Δ

Less frequent

• Lens disorder
• Dry eye
• Eye pruritis
• Eye swelling
• Papilloedema
• Presbyopia

Ear and Labyrinth Disorders

Less frequent

• Deafness

Cardiac Disorders

Less frequent

• Palpitations
• Sinus tachycardia

Vascular Disorders

Less frequent

• Hypotension

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Cough
• Epistaxis

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Dyspepsia
• Abdominal pain (lower/ upper abdominal pain, abdominal tenderness)
• Gastritis (gastritis, chronic gastritis)
• Diarrhoea
• Constipation
• Gastrooesophageal reflux disease
• Pancreatitis (pancreatitis, haemorrhagic pancreatitis)

Less frequent

• Abdominal distension
• Glossodynia
• Haematemesis

Hepato-biliary Disorders

Frequent

• Transaminase increased (increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), drug-induced liver injury, increased hepatic enzyme, abnormal hepatic function, increased liver function test, increased transaminases)
• Hyperbilirubinaemia

Less frequent

• Hepatomegaly
• Jaundice

Skin and Subcutaneous Tissue Disorders

Frequent

• Acne (acne, acneiform dermatitis)
• Pruritus (pruritus, generalised pruritus, pruritic rash)
• Rash (rash, erythematous rash, maculopapular rash, papular rash, vesicular rash)
• Dry skin
• Alopecia

Less frequent

• Allergic dermatitis
• Skin hyperpigmentation

Musculoskeletal and Connective Tissue Disorders

Frequent

• Musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity)
• Muscle spasms

Less frequent

• Musculoskeletal stiffness

Reproductive System and Breast Disorders

Less frequent

• Erectile dysfunction
• Metrorrhagia

General Disorders and Administration Site Conditions

Frequent

• Fatigue
• Asthenia

Less frequent

• Malaise

Investigations

Frequent

• Gamma-glutamyltransferase increased
• Amylase increased (increased amylase, hyperamylasaemia)
• Electrocardiogram QT prolonged
• Blood alkaline phosphatase increased
• Blood creatine phosphokinase increased
• Blood urea increased
• Lipase increased (hyperlipasaemia, increased lipase)

Less frequent

• Albumin urine present
• Blood creatinine increased
• Blood creatine phosphokinase MB increased
• Blood uric acid increased
• Creatinine renal clearance decreased

Note: Adverse reactions marked with Δ are attributed to linezolid

• Strong or moderate CYP3A4 inducers
• Rifampicin
• Efavirenz
• Lopinavir/Ritonavir
• Methotrexate
• OAT3 substrate agents

• Complete blood count (at baseline, at 2 weeks, and then monthly while on treatment)
• Liver function tests (at baseline, at 2 weeks, and then monthly while on treatment)
  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AST)
  • Alkaline phosphatase
  • Bilirubin
• Electrocardiogram (ECG) prior to initiation of treatment and ≥2, 12, and 24 weeks after starting treatment
• Obtain serum calcium, magnesium, and potassium at baseline; repeat testing if QT prolongation occurs

Specific cases may require

• Test for viral hepatitides
  • If evidence of new or worsening hepatic dysfunction occurs, test for viral hepatitides

Additional observations

• Monitor visual function

Limited population (limitations of use)

• Pretomanid is indicated for use in a specific population of patients
• Pretomanid is not indicated in patients with the following conditions
  • Drug-sensitive (DS) tuberculosis
  • Latent infection due to Mycobacterium tuberculosis
  • Extra-pulmonary infection due to Mycobacterium tuberculosis
  • MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy
• Safety and effectiveness of pretomanid have not been established for its use in combination with medicines other than bedaquiline and linezolid as part of the recommended dosing regimen

Pretomanid is a nitroimidazooxazine antimycobacterial medicine. Pretomanid kills actively replicating M. tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Under anaerobic conditions, against non-replicating bacteria, pretomanid acts as a respiratory poison following nitric oxide release. All of these activities require nitro-reduction of pretomanid within the mycobacterial cell by the deazaflavin-dependent nitroreductase, Ddn, which is dependent on the reduced form of the cofactor F420. Reduction of F420 is accomplished by the F420-dependent glucose-6-phosphate dehydrogenase, Fgd1.

Spectrum of activity: Mycobacterium tuberculosis