Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.3 · PDF-Seite 4

HOS-144811 · Präparat HOS-099268

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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.5 · PDF-Seite 6

HOS-144812 · Präparat HOS-099268

Effects of other medicinal products on pretomanid

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.5 · PDF-Seite 6

HOS-144813 · Präparat HOS-099268

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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): carbamazepine (HOS-085618) rifabutin (HOS-086262) etravirine (HOS-088088) rifamycins (HOS-144814) rifapentine (HOS-116386) efavirenz (HOS-087947) phenytoin (HOS-084531)

Wechselwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.5 · PDF-Seite 6

HOS-144815 · Präparat HOS-099268

In an interaction study of multiple-dose pretomanid with multiple-dose ritonavir-boosted-lopinavir, the AUC0-24h of pretomanid was reduced by 17%.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): lopinavir (HOS-086269)

Wechselwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.5 · PDF-Seite 6

HOS-144816 · Präparat HOS-099268

Effects of pretomanid on other medicinal products

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.5 · PDF-Seite 6

HOS-144817 · Präparat HOS-099268

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): mephenytoin (HOS-109801) paclitaxel (HOS-087959) warfarin (HOS-085950)

Wechselwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.5 · PDF-Seite 6

HOS-144818 · Präparat HOS-099268

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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): ciprofloxacin (HOS-085177) indomethacin (HOS-086115) methotrexate (HOS-087522)

Wechselwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.5 · PDF-Seite 6

HOS-144820 · Präparat HOS-099268

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): sulfasalazine (HOS-089673) prazosin (HOS-127968) rosuvastatin (HOS-086307) digoxin (HOS-086172) glyburide (HOS-109273) valsartan (HOS-088810) dabigatran etexilate (HOS-086233) verapamil (HOS-090602)

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 7

HOS-144822 · Präparat HOS-099268

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 7

HOS-144823 · Präparat HOS-099268

Refer to the Summary of Product Characteristics of bedaquiline, linezolid and moxifloxacin for more information on adverse reactions caused by these medicinal products.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 7

HOS-144824 · Präparat HOS-099268

Tabulated list of pretomanid adverse reactions

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 7

HOS-144825 · Präparat HOS-099268

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 7–8

HOS-144826 · Präparat HOS-099268

7 ADRs attributed to moxifloxacin are marked with §.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 8

HOS-144827 · Präparat HOS-099268

Table 1: Adverse Drug Reactions from Clinical Studies

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 8

HOS-144828 · Präparat HOS-099268

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 candidiasis* Blood and Leukopenia* ∆, Neutropenia* ∆, Pancytopenia ∆ lymphatic anaemia* ∆, eosinophilia, system disorders lymphopenia ∆ thrombocytopenia* ∆ Metabolism and Hyponatraemia Δ, Dehydration, nutrition hypernatraemia Δ, hypovolaemia, disorders hypocalcaemia, hypoalbuminaemia Δ, hyperkalaemia § Δ, hypokalaemia Δ, decreased appetite, hyperglycaemia § Δ, hypoglycaemia, lactic acidosis* ∆, hypomagnesaemia Psychiatric Depression, insomnia Anxiety disorders Nervous system Headache, Dysgeusia, dizziness, disorders peripheral tremor § neuropathy* ∆, Eye disorders Visual impairment* Lens disorder, eye pruritis, eye swelling, papilloedema, presbyopia, eye irritation, eye pain*, optic neuropathy*∆, cataract Ear and Deafness* labyrinth disorders Cardiac Palpitations Sinus bradycardia, sinus disorders tachycardia Vascular Hypertension* Hypotension disorders Respiratory, Haemoptysis, epistaxis Cough* thoracic and mediastinal disorders Gastrointestinal Nausea, vomiting, Gastritis*, diarrhoea, Gastrooesophageal reflux disorders constipation, pancreatitis, disease, abdominal abdominal pain*, dyspepsia distension, glossodynia, haematemesis, eructation

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 8–9

HOS-144829 · Präparat HOS-099268

8  System Organ Very Common Common Uncommon Class ≥1/10 ≥1/100 to <1/10 ≥1/1,000 to <1/100 Hepatobiliary Transaminase Hyperbilirubinaemia Hepatomegaly, jaundice disorders increased* Immune system Hypersensitivity disorders Skin and Rash* Acne*, dry skin, , pruritus*, Alopecia, dermatitis subcutaneous urticaria allergic, erythema, skin tissue disorders hyperpigmentation, angioedema Musculoskeletal Musculoskeletal Muscle spasms* Polyarthritis* and connective pain* tissue disorders General Chest pain*, fatigue* disorders and administration site conditions Investigations Electrocardiogram Gamma- Blood creatine QT prolonged glutamyltransferase phosphokinase increased, increased, , blood alkaline albumin urine present, phosphatase increased, blood creatine blood urea increased, lipase phosphokinase MB increased*, amylase increased, blood uric acid increased*, blood creatinine increased, increased § Δ, creatinine renal clearance decreased *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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 9–10

HOS-144830 · Präparat HOS-099268

9 Δ: ADRs that are attributed to linezolid. §: ADRs that are attributed to Moxifloxacin

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 10

HOS-144831 · Präparat HOS-099268

Description of selected adverse reactions

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 10

HOS-144832 · Präparat HOS-099268

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Nebenwirkungen · Dovprela (previously Pretomanid FGK)

Dovprela 200 mg tablet · Abschnitt 4.8 · PDF-Seite 10

HOS-144833 · Präparat HOS-099268

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.