Dovprela (previously Pretomanid FGK) · 4.1 Therapeutic indications · 1

HOS-099275 · has-adverse-reaction-information · PDF-Seite 7

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. Tabulated list of pretomanid adverse reactions 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: • Nix-TB: 109 patients treated with pretomanid in combination with bedaquiline and linezolid (1 200 mg daily) for 26 weeks • ZeNix: 45 patients treated with pretomanid in combination with bedaquiline and linezolid (1 200 mg daily) for 26 weeks and 45 patients treated with pretomanid in combination with bedaquiline and linezolid (600 mg daily) • TB-PRACTECAL: 273 patients treated with pretomanid in combination with bedaquiline, linezolid (600 mg) with or without moxifloxacin (400 mg) for 24 weeks (N=151 patients in BPaLM arm + N=122 patients in BPaL arm) 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. 7 ADRs attributed to moxifloxacin are marked with §. Table 1: Adverse Drug Reactions from Clinical Studies System Organ Very Common Common Uncommon Class ≥1/10 ≥1/100 to <1/10 ≥1/1,000 to <1/100 Infections and Vulvovaginal candidiasis§, infestations oral candid

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HOS-099271 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance, other nitroimidazoles, or to any of the excipients listed in section 6.1.

HOS-099270 · has-indication-information · PDF-Seite 2

Dovprela is indicated in combination with bedaquiline, linezolid and moxifloxacin for the treatment of − adults with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant to rifampicin, with or without resistance to isoniazid. Dovprela is indicated in combination with bedaquiline and linezolid for the treatment of − adults with pulmonary TB due to M. tuberculosis resistant to rifampicin and a fluoroquinolone, with or without resistance to isoniazid (see sections 4.2, 4.4 and 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-099273 · has-interaction-information · PDF-Seite 6

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 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%. 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

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HOS-099274 · has-pregnancy-information · PDF-Seite 6

Pregnancy 6 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).

HOS-099272 · has-warning-information · PDF-Seite 4

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 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: • 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 th

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