DOVPRELA

Treatment with pretomanid should be initiated and monitored by a physician experienced in the management of TB due to drug-resistant M. tuberculosis. Pretomanid should be administered by directly observed therapy (DOT) or in accordance with local practice.

Posology The recommended dosage is 200 mg (one tablet) pretomanid once daily, for 26 weeks. 1). Pretomanid should be administered only in combination with bedaquiline (400 mg once daily for 2 weeks followed by 200 mg 3 times per week [with at least 48 hours between doses] orally for a total of 26 weeks) and linezolid (600 mg daily orally for up to 26 weeks).

The product information for bedaquiline and linezolid should be consulted for additional information on the use of these medicinal products. 1 for details of the study. 1) • If either bedaquiline or pretomanid is discontinued for any reason, the entire combination regimen should be discontinued.

• If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, the entire combination regimen should be discontinued. • If linezolid is discontinued after the initial four weeks of consecutive treatment, the regimen may be continued with only bedaquiline and pretomanid.

Missed doses Any missed doses of pretomanid and bedaquiline should be made up at the end of treatment. Doses of linezolid that are missed due to linezolid adverse reactions should not be made up at the end of treatment. Refer to the product information of bedaquiline and linezolid for additional information on these medicinal products.

Treatment duration The total duration of treatment with pretomanid in combination with bedaquiline and linezolid is 26 weeks. Data on longer treatment duration is limited. 1). Elderly population (≥ 65 years of age) There is limited clinical data on the use of pretomanid in elderly patients.

Hence, the safety and efficacy of pretomanid in elderly patients have not been established. 4). Renal impairment The safety and efficacy of pretomanid in populations with renal impairment have not been established. No data are available.

Use in patients with renal impairment is not recommended. Paediatric population The safety and efficacy of pretomanid in children and adolescents have not yet been established. No data are available. Method of administration For oral use.

The most frequent adverse drug reactions during treatment with pretomanid in combination with bedaquiline and linezolid were nausea, vomiting and transaminases increased. Patients experienced peripheral neuropathy and anaemia, which are known adverse reactions to linezolid, respectively.

Nausea, vomiting and transaminases increased are possible adverse reactions to all three medicinal products in the regimen. Refer to the Summary of Product Characteristics of bedaquiline and linezolid for more information on adverse reactions caused by these two medicinal products.

Tabulated list of pretomanid adverse reactions Adverse drug reactions (ADRs) reported in 109 patients treated with pretomanid in combination with bedaquiline and linezolid (1 200 mg daily) for 26 weeks from the uncontrolled phase 3 trial Nix-TB, together with ADRs reported in 45 patients treated with pretomanid in combination with bedaquiline and linezolid (1 200 mg daily) for 26 weeks and in 45 patients treated with pretomanid in combination with bedaquiline and linezolid (600 mg daily) for 26 weeks in the phase 3 trial ZeNix, are summarized in the table below by system organ class and frequency.

The adverse drug reactions list below reflects in part the safety profile of the BPaL study regimen as it is hard to separate causality of one drug from another. ADRs considered attributed to linezolid are marked with Δ.

Table 1:

Pretomanid Adverse Drug Reactions from Clinical Studies System Organ Class Very Common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Infections and infestations Oral candidiasis* Blood and lymphatic system disorder Anaemia* ∆ Leukopenia ∆, neutropenia* ∆, thrombocytopenia *∆ Lymphopenia ∆, pancytopenia ∆ System Organ Class Very Common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Metabolic and nutrition disorders Decreased appetite Hypoglycaemia, lactic acidosis *∆, hypomagnesaemia Dehydration, hypocalcaemia, hypovolaemia, Psychiatric disorders Insomnia Anxiety, depression Nervous system disorders Peripheral neuropathy* ∆ Dysgeusia, dizziness, headache Eye disorders Visual impairment*, eye irritation, eye pain, optic neuropathy*∆, dry eye Lens disorder, eye pruritis, eye swelling, papilloedema, presbyopia Ear and labyrinth disorder Deafness Cardiac disorder Palpitations, sinus tachycardia Vascular disorders Hypotension Respiratory, thoracic and mediastinal disorders Cough, epistaxis Gastrointestina l disorders Nausea, vomiting, dyspepsia Gastritis*, diarrhoea, constipation, gastrooesophageal reflux disease, pancreatitis*, abdominal pain* Abdominal distension, glossodynia, haematemesis Hepatobiliary disorders Transaminase increased* Hyperbilirubinaemia* Hepatomegaly, jaundice Skin and subcutaneous tissue disorder Acne* Dry skin, alopecia, pruritus*, rash* Dermatitis allergic, skin hyperpigmentation Musculoskeleta l and connective tissue disorders Musculoskeletal pain*, muscle spasms* Reproductive system and breast disorder Erectile dysfunction, metrorrhagia General Fatigue* Malaise System Organ Class Very Common ≥1/10 Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 disorders and administration site conditions Investigations Gamma- glutamyltransferase increased, electrocardiogram QT prolonged, blood alkaline phosphatase increased, blood creatine phosphokinase increased, blood urea increased, lipase increased*, amylase increased*, blood creatinine increased Albumin urine present, blood creatine phosphokinase MB increased, blood uric acid increased, creatinine renal clearance decreased *Selected terms are collapsed as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy); gastritis (gastritis, chronic gastritis); acne (acne, dermatitis acneiform); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity, musculoskeletal pain); transaminases increased (alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, drug- induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular, nodular rash); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness); visual impairment (vision blurred, visual acuity reduced, visual impairment); amylase increased (amylase increased, hyperamylasaemia); lipase increased (hyperlipasaemia, lipase increased); optic neuropathy (optic neuropathy, optic neuritis); pancreatitis (pancreatitis, haemorrhagic pancreatitis); anaemia (anaemia, haemoglobin decrease); thrombocytopenia (thrombocytopenia, platelet count decreased); neutropenia (neutropenia, neutrophil count decreased); hyperbilirubinemia (hyperbilirubinemia, blood bilirubin increased); lactic acidosis (lactic acidosis, acidosis); muscle spasms (muscle spasms, muscuoloskeletal stiffness); fatigue (fatigue, asthenia); oral candidiasis (oral candidiasis, oral fungal infection, angular cheilitis).

Safety and effectiveness of pretomanid have not been established for its use in combination with medicinal products other than bedaquiline and linezolid as part of the recommended dosing regimen, and thus pretomanid should not be used as part of any other regimen.

Hepatotoxicity Hepatotoxicity may occur with use of the regimen consisting of pretomanid, bedaquiline and linezolid. Liver-related laboratory tests should be monitored. 1), should be avoided while on the regimen, especially in patients with impaired hepatic function.

Symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) should be addressed throughout treatment. Laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) should be monitored at initiation of treatment, and at a minimum once every week during the first month of treatment, every other week during month 2, and monthly thereafter while on treatment, and as needed.

If evidence of new or worsening liver dysfunction occurs, a test for viral hepatitis should be performed and other hepatotoxic medicinal products should be discontinued. Treatment with the entire regimen should be interrupted if: • Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit of normal.

• Aminotransferase elevations are greater than 8 times the upper limit of normal. • Aminotransferase elevations are greater than 5 times the upper limit of normal and persist beyond 2 weeks. Treatment may be re-initiated under close surveillance when hepatic enzymes and clinical symptoms normalize.

Modification/interruption due to linezolid adverse reactions Modification or interruption of linezolid dosing may be needed during the course of therapy to manage the known linezolid toxicities. 1). Myelosuppression Complete blood counts should be monitored at a minimum at start of treatment, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen.

1.