DOVPRELA Tablet Ref.[111585] Active ingredients: Pretomanid

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. Alcohol and hepatotoxic medicinal products (including herbal supplements), other than those specified in the indication statement (see section 4.1), 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. The recommendations below reflect the procedures used in the ZeNix study (section 5.1).

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. Haematologic parameters are variable from measurement to measurement, and decreases should be evaluated in the context of the patient’s overall medical condition. Guidelines below may be considered when it is likely that linezolid has caused the decrease in blood count. Consider pausing or reducing the dose of linezolid to 300 mg in the following situations.

• Anaemia – if haemoglobin falls below 80 g/l or more than 25% below the start of treatment.
• Leukopenia – if the Absolute Neutrophil Count (ANC) falls below 0.75 × 10⁹/l or significantly below baseline. Confirm with a repeat test before making further decisions as ANCs can have diurnal and other variability.
• Thrombocytopenia – if platelets fall below 50 × 10⁹/l or significantly below baseline. Ideally confirm with a repeat test before making further decisions.

When improvement in the myelosuppression is observed, consider resuming linezolid at the initial dose or at half the initial dose.

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy associated with linezolid is generally reversible or improved with interruption, dose reduction, or discontinuation of linezolid dosing. When improvement in the peripheral neuropathy is observed, consider resuming linezolid at 300 mg (half the initial dose). In the clinical studies (section 5.1), the incidence of interruption/reduction/discontinuation of linezolid due to peripheral neuropathy increased steadily from around 2 months of therapy throughout the completion of therapy. Monitor visual symptoms in all patients receiving the combination regimen of pretomanid, bedaquiline, and linezolid. If a patient experiences symptoms of visual impairment, interrupt linezolid dosing and obtain prompt ophthalmologic examination to evaluate for signs of optic neuropathy.

Lactic acidosis

Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea or vomiting should receive immediate medical evaluation, including evaluation of bicarbonate and lactic acid levels, and interruption of linezolid should be considered. Linezolid may be reinitiated at a lower dose with close monitoring when signs and symptoms of lactic acidosis resolve.

QT prolongation

QT prolongation was reported with the combination regimen of pretomanid, bedaquiline, and linezolid. 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 characterized.

An ECG should be obtained before initiation of treatment, and at least monthly during treatment with the combination regimen of pretomanid, bedaquiline, and linezolid. Serum potassium, calcium, and magnesium should be obtained at baseline and corrected if abnormal. Follow-up monitoring of electrolytes should be performed if QT prolongation is detected.

The following may increase the risk for QT prolongation:

• a history of Torsade de Pointes,
• a personal or family history of congenital long QT syndrome,
• a history of or ongoing hypothyroidism,
• ongoing bradyarrhythmia,
• heart failure or known structural heart disease,
• QT-interval as corrected by the Fridericia method (QTcF) >450 ms (confirmed by repeat electrocardiogram) or
• serum calcium, magnesium, or potassium levels below the lower limits of normal.

The entire regimen of pretomanid, bedaquiline, and linezolid must be discontinued if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG). If syncope occurs, an ECG should be obtained to detect QT prolongation.

The QT prolongation risk for the combination regimen has not been established at exposures higher than therapeutic levels. The risk may be increased if the systemic exposure of pretomanid is elevated (see sections 4.5 and 5.2).

Excipients

Dovprela contains lactose. Patients with rare hereditary problems such as galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Dovprela contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Effects of other medicinal products on pretomanid

CYP3A4 inducers

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 (see section 4.4).

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

Effects of pretomanid on other medicinal products

Effect on CYP2C8, 2C9 and 2C19 substrates

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.

Effect on OAT3, OATP1B3, P-gp and BCRP substrates

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 (see section 4.4).

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.

Pregnancy

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 (see section 5.3).

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

Breast-feeding

It is unknown whether pretomanid/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of pretomanid in milk (see section 5.3). 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 (see section 5.3).

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 (see section 4.8).

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:

^* 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.