Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Mylan IRE Healthcare Limited, Unit 35/36 Grange Parade, Baldoyle Industrial Estate, Dublin 13, Ireland
Hypersensitivity to the active substance, other nitroimidazoles, or to any of the excipients listed in section 6.1.
Safety and effectiveness of pretomanid have not been established for its use in combination with medicinal products other than bedaquiline, linezolid and with or without moxifloxacin as part of the recommended dosing regimen, and thus pretomanid should not be used as part of any other regimen.
Hepatotoxicity may occur with use of the regimen consisting of pretomanid, bedaquiline, linezolid and with or without moxifloxacin. 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:
Treatment may be re-initiated under close surveillance when hepatic enzymes and clinical symptoms normalize.
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).
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.
When improvement in the myelosuppression is observed, consider resuming linezolid at the initial dose or at half the initial dose.
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, linezolid and with or without moxifloxacin. 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 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 was reported with the combination regimen of pretomanid, bedaquiline, linezolid and with or without moxifloxacin. QT prolongation is a known adverse reaction of bedaquiline and moxifloxacin. 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, linezolid and with or without moxifloxacin. 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:
The entire regimen of pretomanid, bedaquiline, linezolid and with or without moxifloxacin 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).
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".
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 AUC0-24h 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 AUC0-24h of pretomanid was reduced by 17%.
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.
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.
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.
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.
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 (ADRs) 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. The most frequent ADRs during treatment with pretomanid in combination with bedaquiline, linezolid and moxifloxacin were transaminases increased and QTc prolongation.
Refer to the Summary of Product Characteristics of bedaquiline, linezolid and moxifloxacin for more information on adverse reactions caused by these medicinal products.
The table below displays ADRs, by system organ class and frequency, which are considered at least possibly related to the treatment regimens BPaL and BPaLM (Bedaquiline, Pretomanid, Linezolid and Moxifloxacin) and have been observed during the following clinical trials:
The ADR list below reflects in part the safety profile of the study regimens as it is hard to separate causality of one drug from another. An overall population of 472 patients receiving BPaL regimen with or without moxifloxacin has been included.
ADRs considered attributed to linezolid are marked with Δ.
ADRs attributed to moxifloxacin are marked with §.
Table 1. 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 | Vulvovaginal candidiasis§, oral candidiasis* | ||
| Blood and lymphatic system disorders | Leukopenia*∆, anaemia*∆, lymphopenia∆ | Neutropenia*∆, eosinophilia, thrombocytopenia*∆ | Pancytopenia∆ |
| Metabolism and nutrition disorders | HyponatraemiaΔ, hypernatraemiaΔ, hypocalcaemia, hypoalbuminaemiaΔ, hyperkalaemia§Δ, hypokalaemiaΔ, decreased appetite, hyperglycaemia§Δ, hypoglycaemia, lactic acidosis*∆, hypomagnesaemia | Dehydration, hypovolaemia | |
| Psychiatric disorders | Depression, insomnia | Anxiety | |
| Nervous system disorders | Headache, peripheral neuropathy*∆ | Dysgeusia, dizziness, tremor§ | |
| Eye disorders | Visual impairment* | Lens disorder, eye pruritis, eye swelling, papilloedema, presbyopia, eye irritation, eye pain*, optic neuropathy*∆, cataract | |
| Ear and labyrinth disorders | Deafness* | ||
| Cardiac disorders | Palpitations | Sinus bradycardia, sinus tachycardia | |
| Vascular disorders | Hypertension* | Hypotension | |
| Respiratory, thoracic and mediastinal disorders | Haemoptysis, epistaxis | Cough* | |
| Gastrointestinal disorders | Nausea, vomiting | Gastritis*, diarrhoea, constipation, pancreatitis, abdominal pain*, dyspepsia | Gastrooesophageal reflux disease, abdominal distension, glossodynia, haematemesis, eructation |
| Hepatobiliary disorders | Transaminase increased* | Hyperbilirubinaemia | Hepatomegaly, jaundice |
| Immune system disorders | Hypersensitivity | ||
| Skin and subcutaneous tissue disorders | Rash* | Acne*, dry skin, pruritus*, urticaria | Alopecia, dermatitis allergic, erythema, skin hyperpigmentation, angioedema |
| Musculoskeletal and connective tissue disorders | Musculoskeletal pain* | Muscle spasms* | Polyarthritis* |
| General disorders and administration site conditions | Chest pain*, fatigue* | ||
| Investigations | Electrocardiogram QT prolonged | Gamma- glutamyltransferase increased, blood alkaline phosphatase increased, blood urea increased, lipase increased*, amylase increased*, blood creatinine increased§Δ, creatinine renal clearance decreased | Blood creatine phosphokinase increased, albumin urine present, blood creatine phosphokinase MB increased, blood uric acid increased |
* Selected terms are collapsed as follows: leukopenia (leukopenia, white blood cell count decreased); lymphopenia (lymphopenia, lymphocyte count decreased); peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor 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, muscle strain); 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, rash pustular, nodular rash); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort); 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 decreased); thrombocytopenia (thrombocytopenia, platelet count decreased); neutropenia (neutropenia, neutrophil count decreased); hyperbilirubinemia (hyperbilirubinemia, blood bilirubin increased); lactic acidosis (lactic acidosis, acidosis, blood lactic acid increased, blood lactate increased); muscle spasms (muscle spasms, musculoskeletal stiffness); fatigue (fatigue, asthenia, malaise); oral candidiasis (oral candidiasis, oral fungal infection, angular cheilitis); erythema (erythema, palmar erythema); polyarthritis (polyarthritis, arthropathy); chest pain (chest pain, angina pectoris); pancreatitis (pancreatitis, haemorrhagic pancreatitis); eye pain (eye pain, periorbital pain); peripheral swelling (oedema peripheral, peripheral swelling); deafness (deafness, deafness unilateral, conductive deafness); dry skin (dry skin, xerosis); dermatitis allergic (dermatitis allergic, dermatitis); hyperglycaemia (hyperglycaemia, blood glucose increased); cough (cough, productive cough); hypertension (hypertension, blood pressure increased).
Δ: ADRs that are attributed to linezolid.
§: ADRs that are attributed to Moxifloxacin.
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.
In the TB-PRACTECAL trial in which moxifloxacin was administered along with BPaL regimen, ADRs of increased transaminases were reported in 58 (38.4%) patients in BPaLM arm, where one patient could have reported more than one PT which were collapsed into category of Increased transaminases. The majority of the events were of grade 1 or grade 2 category, 6 patients had reported grade 3 severity, the outcome in 5 patients was resolved and in one patient outcome was not known.
QT prolongation is a known adverse reaction of bedaquiline. Bedaquiline in combination with pretomanid with or without moxifloxacin 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. In the TB-PRACTECAL trial, 46 (30.5%) patients reported QT prolongation related to study drugs, out of which only 1 patient reported grade 3 severity of QT prolongation, outcome was resolved.
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.
In the TB-PRACTECAL trial, 52 patients reported ADRs of myelosuppression in the BPaLM arm, out of which 27 (18%) patients reported leukopenia, 26 (17.2%) patients reported neutropenia and 21 (14%) patients reported anaemia, one patient could have reported more than one PT. Grade 3 or more severity was observed in 6 patients and outcome was resolved in 4 patients in 2 patients the outcome was not known.
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. When pretomanid in BPaL regimen was administered along with moxifloxacin in the TB-PRACTECAL trial in BPaLM arm, 13 (8.6%) patients reported PTs collapsed to peripheral neuropathy, most of the events were of grade 1 or grade 2 severity and all the events resolved.
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 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.
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