Pretomanid

In vitro studies show that pretomanid is an inducer of CYP2C8 while the studies are inconclusive regarding the potential of pretomanid to induce CYP2C9 and 2C19. In vivo induction cannot be excluded as no clinical studies have been performed. If pretomanid is co-administered with substrates of CYP2C8, 2C9 and 2C19, e.g., paclitaxel, warfarin, mephenytoin, prescribers and their patients should be observant for potentially reduced efficacy of these substrates.

In vitro studies indicate that pretomanid is an inhibitor of BCRP, OATP1B3 and P-gp. No clinical studies have been performed to investigate these interactions. Therefore, it cannot be excluded that co-administration of pretomanid with sensitive OATP1B3 substrates (e.g., valsartan, statins), BCRP substrates (e.g. rosuvastatin, prazosin, glyburide, sulfasalazine) and P-gp substrates (e.g. digoxin, dabigatran etexilate, verapamil) may increase their exposure. If pretomanid is co-administered with substrates of OATP1B3, BCRP or P-gp, monitoring for drug-related adverse reactions to the co-administered medicinal product should be performed.

Pretomanid is an inhibitor of the OAT3 transporter in vitro, which could result in increased concentrations of OAT3 substrate medicinal products clinically and may increase the risk of adverse reactions of these medicines. If pretomanid is co-administered with OAT3 substrate medicinal products (e.g., methotrexate, benzylpenicillin, indomethacin, ciprofloxacin), monitoring for OAT3 substrate drug-related adverse reactions should be performed and dosage reductions for OAT3 substrate medicinal product should be considered, if needed.

Pretomanid is metabolized in part by CYP3A4. In consequence, exposure to pretomanid may be reduced during co-administration with inducers of CYP3A4. In interaction studies of multiple-dose pretomanid with multiple-dose rifampicin or efavirenz, the AUC_0-24h of pretomanid was reduced by 66% or 35%, respectively. Due to the possibility of a reduction of the therapeutic effect of pretomanid due to a decrease in systemic exposure, co-administration of pretomanid and moderate or strong CYP3A4 inducers (e.g. efavirenz, etravirine, rifamycins including rifampicin, rifapentine and rifabutin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum)) used systemically should be avoided.

In an interaction study of multiple-dose pretomanid with multiple-dose ritonavir-boosted-lopinavir, the AUC_0-24h of pretomanid was reduced by 17%.

The safety and efficacy of pretomanid in populations with hepatic impairment have not been established.

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.

Alcohol and hepatotoxic medicinal products (including herbal supplements), other than those specified in the indication statement, should be avoided while on the regimen, especially in patients with impaired hepatic function.

There are very limited amount of data from the use of pretomanid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryo-foetal development.

Pretomanid should be used during pregnancy only if the benefit to the patient is considered to outweigh the potential risk to the foetus.

It is unknown whether pretomanid/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of pretomanid in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue pretomanid therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of pretomanid on fertility are available. Oral administration of pretomanid caused markedly reduced fertility in male rats.

Pretomanid may have a minor influence on the ability to drive and use machines. Dizziness has been reported in some patients taking pretomanid and some patients experienced visual impairment. This should be considered when assessing a patient’s ability to drive or operate machinery.

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.

Pretomanid Adverse Drug Reactions from Clinical Studies:

^* 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, musculoskeletal stiffness); fatigue (fatigue, asthenia); oral candidiasis (oral candidiasis, oral fungal infection, angular cheilitis).

∆: ADRs that are attributed to linezolid

Description of selected adverse reactions

Increased transaminases

In the Nix-TB trial in which 109 patients were treated with pretomanid in combination with bedaquiline and linezolid, combined with the ZeNix patients treated within the arms dosed for 26 weeks with linezolid, 19 % of patients experienced the ADR of increased transaminases (very common). Except for one patient who died due to pneumonia and sepsis, all patients who experienced increased transaminases were able to continue or resume therapy after interruption, and complete the full course of treatment.

ECG QT interval prolongation

QT prolongation is a known adverse reaction of bedaquiline. Bedaquiline in combination with pretomanid appears to result in a higher QT prolongation than expected with bedaquiline alone. However, the impact of pretomanid has not been fully characterised. In the Nix-TB trial, 6 patients (5.5%, common) experienced transient treatment-emergent adverse events (TEAEs) of electrocardiogram QT prolongation. In the entire Nix-TB trial, no patient was reported to have a treatment emergent QTcF exceeding 480 ms. One patient was reported to have a change from baseline of QTcF exceeding 60 ms. In the ZeNix trial, no electrocardiogram QT prolongation was observed in the patients from the 26- week treatment arm.

Myelosuppression

Myelosuppression is a known adverse reaction of linezolid. In the Nix-TB trial, 37% (very common) of patients experienced anaemia, as the most common ADR of hematopoietic cytopenia attributed to linezolid. The majority of cytopenias began after 2 weeks of treatment. Overall, three patients experienced cytopenias that were considered serious: neutropenia in 1 patient and anaemia in 2 patients. All 3 serious adverse events resulted either in interruption of linezolid or in interruption of pretomanid, bedaquiline, and linezolid, and all resolved.

In the ZeNix trial, there was a greater incidence of events of myelosuppression, 28.9% versus 13.3%, for the 1200 mg compared to the 600 mg linezolid 26-week group. Most of the myelosuppression TEAEs were either grade 1 or grade 2 in severity. Overall, the majority of first myelosuppression TEAEs occurred within the first 9 weeks of treatment, except in the 1200 mg 26-week treatment group which showed approximately half the events occurring after Week 9.

In the combined study data, 2 patients reported serious events of anaemia with linezolid 1200 mg, and none were reported in the 600 mg group.

Peripheral neuropathy

Peripheral neuropathy is a known ADR of linezolid. In the Nix-TB trial, 81% (very common) of patients experienced peripheral neuropathy. In the ZeNix trial, 17 (37.8%) % of patients reported a treatment emergent event of peripheral neuropathy in the 1200 mg 26-week treatment group; one of these events led to treatment discontinuation. In the 600 mg 26-week treatment group, a lower number of patients reported peripheral neuropathy, 11 (24.4%), and none required linezolid treatment interruption or treatment discontinuation.

Most of these adverse reactions were grade 1 and occurred after 8 weeks.

Optic neuropathy

Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%, common) in the Nix-TB trial developed optic neuropathy, both after 16 weeks of treatment. Both were serious, confirmed on retinal examination as optic neuropathy/neuritis, and resulted in discontinuation of linezolid; both adverse reactions resolved.

In the ZeNix trial overall, 4 (2.2%) patients reported a treatment emergent event of optic neuropathy. All 4 patients were in the 1200 mg linezolid 26-week treatment group (8.9%). The maximum severity was grade 1 (mild) for 1 patient, grade 2 (moderate) for 2 patients, and grade 3 (severe) for 1 patient. All patients had linezolid permanently discontinued except 1 who had already completed treatment when the event occurred. Onset of the event occurred after 3 months of treatment, and all resolved. No events of optic neuropathy were reported when linezolid was dosed at 600 mg in the ZeNix trial.