Leaflet DOVPRELA 200mg tablets
Indicated for: tuberculosis
Route of administration: oral
Substance: pretomanid (anti-tuberculosis agent)
ATC: J04AK08 (Antiinfectives for systemic use | Drugs for treatment of tuberculosis | Other drugs for treatment of tuberculosis)
This medicine may have important interactions with other medicines.
Periodic laboratory tests may be required during treatment.
Use during pregnancy only on medical advice.
Pretomanid is an antibiotic used only with other medicines for certain forms of treatment-resistant pulmonary tuberculosis. It acts against Mycobacterium tuberculosis and helps kill the bacteria when standard regimens are not effective or cannot be tolerated. It is not used alone, for latent tuberculosis or for tuberculosis that is sensitive to standard treatment.
It is taken by mouth, usually once daily with food, as part of a regimen chosen by a tuberculosis specialist, for example with bedaquiline and linezolid. Taking every medicine exactly as prescribed and for the full duration is critical. Missing doses or stopping early can cause treatment failure and make the infection harder to treat because of additional resistance.
Side effects may include nausea, vomiting, headache, rash, tiredness, weight loss, liver problems or abnormal blood tests. Some important effects may come from the other medicines in the regimen, such as tingling or numbness, vision problems, anaemia or heart rhythm changes. Contact your doctor if you develop yellow skin or eyes, dark urine, abdominal pain, fainting, palpitations or persistent numbness.
Treatment requires close monitoring, including liver tests, blood counts and sometimes electrocardiograms. Avoid alcohol and tell your doctor about all medicines and supplements you use. Women should discuss pregnancy, breastfeeding and contraception before treatment. Pretomanid should be taken only under specialised tuberculosis supervision.
General data about DOVPRELA 200mg
- Substance: pretomanid
- Date of latest medicines list: 01-06-2026
- Product code: W71454001
- Concentration: 200mg
- Pharmaceutical form: tablets
- Quantity: 26
- Product type: Original
- Price: 16133.19 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Leaflet DOVPRELA 200mg
Contents of the package leaflet for the medicine DOVPRELA 200mg tablets
1. NAME OF THE MEDICINAL PRODUCT
Dovprela 200 mg tablet
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 200 mg pretomanid.
Excipients with known effectEach tablet contains 294 mg lactose (as monohydrate) and 5 mg sodium.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablets.
White to off-white oval tablet debossed with M on one side and P200 on the other side.
Tablet dimensions: 18 × 9 mm.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Dovprela is indicated in combination with bedaquiline, linezolid and moxifloxacin for the treatment of− adults with pulmonary tuberculosis (TB) due to Mycobacterium tuberculosis resistant torifampicin, 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 afluoroquinolone, with or without resistance to isoniazid (see sections 4.2, pct. 4.4 and 5.1).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Treatment with pretomanid should be initiated and monitored by a physician experienced in themanagement of TB due to drug-resistant M. tuberculosis.
Pretomanid should be administered by directly observed therapy (DOT) or in accordance with localpractice.
PosologyThe recommended dosage is 200 mg (one tablet) pretomanid once daily, for 26 weeks.
Pretomanid should be administered only in combination with bedaquiline (400 mg once daily for2 weeks followed by 200 mg 3 times per week [with at least 48 hours between doses] orally for a totalof 26 weeks) and linezolid (600 mg daily orally for up to 26 weeks), with or without moxifloxacin(400 mg once daily for 26 weeks). See also below, on treatment duration.
In case of confirmed pulmonary TB resistant to rifampicin and a fluoroquinolone, with or withoutresistance to isoniazid, pretomanid should be combined with bedaquiline and linezolid, andmoxifloxacin should be omitted.
The product information for bedaquiline, linezolid and moxifloxacin should be consulted foradditional information on the use of these medicinal products.
In addition, see section 4.4 for information on the dose modification of linezolid that was appliedduring the ZeNix clinical study and see section 5.1 for details of the study.
Discontinuation of the pretomanid-bedaquiline-linezolid +/- moxifloxacin treatment regimen (seealso sections 4.4, pct. 4.8 and 5.1)
* If either bedaquiline or pretomanid is discontinued for any reason, the entire combinationregimen should be discontinued.
* If linezolid is permanently discontinued during the initial four consecutive weeks oftreatment, the entire combination regimen should be discontinued.
* If linezolid is discontinued after the initial four weeks of consecutive treatment, the regimenmay be continued with only bedaquiline, pretomanid and with or without moxifloxacin.
Missed dosesAny missed doses of pretomanid, bedaquiline and moxifloxacin should be made up at the end oftreatment. Doses of linezolid that are missed due to linezolid adverse reactions should not be made upat the end of treatment.
Refer to the product information of bedaquiline, linezolid and moxifloxacin for additional informationon these medicinal products.
Treatment durationThe total duration of treatment with pretomanid in combination with bedaquiline, linezolid and with orwithout moxifloxacin is 26 weeks. Pretomanid in combination with bedaquiline and linezolid can beextended to a total of 39 weeks. This extension is justified in cases of failure to convert culturebetween months 4 and 6 while on treatment and it can be based on the clinical judgement of thetreating physician. (see section 5.1).
Elderly population (≥ 65 years of age)
There is limited clinical data on the use of pretomanid in elderly patients. Hence, the safety andefficacy of pretomanid in elderly patients have not been established.
Hepatic impairmentThe safety and efficacy of pretomanid in populations with hepatic impairment have not beenestablished (see section 4.4).
Renal impairmentThe 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.
Paediatric populationThe safety and efficacy of pretomanid in children and adolescents have not yet been established.
No data are available.
Method of administrationFor oral use.
Pretomanid should be taken with food (see section 5.2).
Tablets should be swallowed with water. If the patient has trouble swallowing a whole tablet, crushingthe tablets and mixing with water for administration may be an acceptable alternative. Intake shouldoccur immediately after crushing and mixing with water.
4.3 Contraindications
Hypersensitivity to the active substance, other nitroimidazoles, or to any of the excipients listed insection 6.1.
4.4 Special warnings and precautions for use
Safety and effectiveness of pretomanid have not been established for its use in combination withmedicinal products other than bedaquiline, linezolid and with or without moxifloxacin as part of therecommended dosing regimen, and thus pretomanid should not be used as part of any other regimen.
HepatotoxicityHepatotoxicity may occur with use of the regimen consisting of pretomanid, bedaquiline, linezolid andwith or without moxifloxacin. Liver-related laboratory tests should be monitored. Alcohol andhepatotoxic medicinal products (including herbal supplements), other than those specified in theindication statement (see section 4.1), should be avoided while on the regimen, especially in patientswith impaired hepatic function.
Symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness andhepatomegaly) should be addressed throughout treatment. Laboratory tests (alanine aminotransferase[ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) should be monitored atinitiation of treatment, and at a minimum once every week during the first month of treatment, everyother week during month 2, and monthly thereafter while on treatment, and as needed. If evidence ofnew or worsening liver dysfunction occurs, a test for viral hepatitis should be performed and otherhepatotoxic medicinal products should be discontinued. Treatment with the entire regimen should beinterrupted if:
* Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 timesthe 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 persistbeyond 2 weeks.
Treatment may be re-initiated under close surveillance when hepatic enzymes and clinical symptomsnormalize.
Modification/interruption due to linezolid adverse reactions
Modification or interruption of linezolid dosing may be needed during the course of therapy to managethe known linezolid toxicities. The recommendations below reflect the procedures used in the ZeNixstudy (section 5.1).
MyelosuppressionComplete blood counts should be monitored at a minimum at start of treatment, at two weeks, andthen monthly in patients receiving linezolid as part of the combination regimen. Haematologicparameters are variable from measurement to measurement, and decreases should be evaluated in thecontext of the patient’s overall medical condition. Guidelines below may be considered when it islikely that linezolid has caused the decrease in blood count. Consider pausing or reducing the dose oflinezolid 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 significantlybelow baseline. Confirm with a repeat test before making further decisions as ANCs can havediurnal and other variability.
* Thrombocytopenia - if platelets fall below 50 × 109/l or significantly below baseline. Ideallyconfirm with a repeat test before making further decisions.
When improvement in the myelosuppression is observed, consider resuming linezolid at the initialdose 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 peripheralneuropathy is observed, consider resuming linezolid at 300 mg (half the initial dose). In the clinicalstudies (section 5.1), the incidence of interruption/reduction/discontinuation of linezolid due toperipheral neuropathy increased steadily from around 2 months of therapy throughout the completionof 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 visualimpairment, interrupt linezolid dosing and obtain prompt ophthalmologic examination to evaluate forsigns of optic neuropathy.
Lactic acidosis
Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea orvomiting should receive immediate medical evaluation, including evaluation of bicarbonate and lacticacid levels, and interruption of linezolid should be considered. Linezolid may be reinitiated at a lowerdose with close monitoring when signs and symptoms of lactic acidosis resolve.
QT prolongationQT prolongation was reported with the combination regimen of pretomanid, bedaquiline, linezolid andwith or without moxifloxacin. QT prolongation is a known adverse reaction of bedaquiline andmoxifloxacin. Bedaquiline in combination with pretomanid appears to result in a higher QTprolongation than expected with bedaquiline alone. However, the impact of pretomanid has not beenfully characterized.
An ECG should be obtained before initiation of treatment, and at least monthly during treatment withthe 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:
* 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 repeatelectrocardiogram) or
* serum calcium, magnesium, or potassium levels below the lower limits of normal.
The entire regimen of pretomanid, bedaquiline, linezolid and with or without moxifloxacin must bediscontinued if the patient develops clinically significant ventricular arrhythmia or a QTcF interval ofgreater than 500 ms (confirmed by repeat ECG). If syncope occurs, an ECG should be obtained todetect QT prolongation.
The QT prolongation risk for the combination regimen has not been established at exposures higherthan therapeutic levels. The risk may be increased if the systemic exposure of pretomanid is elevated(see sections 4.5 and 5.2).
ExcipientsDovprela contains lactose. Patients with rare hereditary problems such as galactose intolerance, totallactase 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”.
4.5 Interaction with other medicinal products and other forms of interaction
Effects of other medicinal products on pretomanid
CYP3A4 inducersPretomanid is metabolized in part by CYP3A4. In consequence, exposure to pretomanid may bereduced during co-administration with inducers of CYP3A4. In interaction studies of multiple-dosepretomanid with multiple-dose rifampicin or efavirenz, the AUC0-24h of pretomanid was reduced by66% or 35%, respectively. Due to the possibility of a reduction of the therapeutic effect of pretomaniddue to a decrease in systemic exposure, co-administration of pretomanid and moderate or strong
CYP3A4 inducers (e.g. efavirenz, etravirine, rifamycins including rifampicin, rifapentine andrifabutin, carbamazepine, phenytoin, St. John’s wort (Hypericum perforatum)) used systemicallyshould 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 inconclusiveregarding the potential of pretomanid to induce CYP2C9 and 2C19. In vivo induction cannot beexcluded as no clinical studies have been performed. If pretomanid is co-administered with substratesof CYP2C8, 2C9 and 2C19, e.g., paclitaxel, warfarin, mephenytoin, prescribers and their patientsshould 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 increasedconcentrations of OAT3 substrate medicinal products clinically and may increase the risk of adversereactions 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 adversereactions should be performed and dosage reductions for OAT3 substrate medicinal product should beconsidered, if needed (see section 4.4).
In vitro studies indicate that pretomanid is an inhibitor of BCRP, OATP1B3 and P-gp. No clinicalstudies have been performed to investigate these interactions. Therefore, it cannot be excluded thatco-administration of pretomanid with sensitive OATP1B3 substrates (e.g., valsartan, statins), BCRPsubstrates (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 withsubstrates of OATP1B3, BCRP or P-gp, monitoring for drug-related adverse reactions to the co-administered medicinal product should be performed.
4.6 Fertility, pregnancy and lactation
There are very limited amount of data from the use of pretomanid in pregnant women. Animal studiesdo not indicate direct or indirect harmful effects with respect to embryo-foetal development (seesection 5.3).
Pretomanid should be used during pregnancy only if the benefit to the patient is considered tooutweigh the potential risk to the foetus.
Breast-feedingIt is unknown whether pretomanid/metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of pretomanid in milk (seesection 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether todiscontinue breastfeeding or to discontinue pretomanid therapy, taking into account the benefit ofbreastfeeding for the child and the benefit of therapy for the woman.
FertilityNo human data on the effect of pretomanid on fertility are available. Oral administration ofpretomanid caused markedly reduced fertility in male rats (see section 5.3).
4.7 Effects on ability to drive and use machines
Pretomanid may have a minor influence on the ability to drive and use machines. Dizziness has beenreported in some patients taking pretomanid and some patients experienced visual impairment. Thisshould be considered when assessing a patient’s ability to drive or operate machinery (see section 4.8).
4.8 Undesirable effects
The most frequent adverse drug reactions (ADRs) during treatment with pretomanid in combinationwith bedaquiline and linezolid were nausea, vomiting and transaminases increased. Patientsexperienced peripheral neuropathy and anaemia, which are known adverse reactions to linezolid,respectively. Nausea, vomiting and transaminases increased are possible adverse reactions to all threemedicinal products in the regimen. The most frequent ADRs during treatment with pretomanid incombination with bedaquiline, linezolid and moxifloxacin were transaminases increased and QTcprolongation.
Refer to the Summary of Product Characteristics of bedaquiline, linezolid and moxifloxacin for moreinformation 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 leastpossibly 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 withbedaquiline 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 separatecausality of one drug from another. An overall population of 472 patients receiving BPaL regimenwith 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 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 Anxietydisorders
Nervous system Headache, Dysgeusia, dizziness,disorders peripheral tremor §neuropathy* ∆,
Eye disorders Visual impairment* Lens disorder, eyepruritis, eye swelling,papilloedema, presbyopia,eye irritation, eye pain*,optic neuropathy*∆,cataract
Ear and Deafness*labyrinthdisorders
Cardiac Palpitations Sinus bradycardia, sinusdisorders tachycardia
Vascular Hypertension* Hypotensiondisorders
Respiratory, Haemoptysis, epistaxis Cough*thoracic andmediastinaldisorders
Gastrointestinal Nausea, vomiting, Gastritis*, diarrhoea, Gastrooesophageal refluxdisorders constipation, pancreatitis, disease, abdominalabdominal pain*, dyspepsia distension, glossodynia,haematemesis, eructation
System Organ Very Common Common Uncommon
Class ≥1/10 ≥1/100 to <1/10 ≥1/1,000 to <1/100
Hepatobiliary Transaminase Hyperbilirubinaemia Hepatomegaly, jaundicedisorders increased*
Immune system Hypersensitivitydisorders
Skin and Rash* Acne*, dry skin, , pruritus*, Alopecia, dermatitissubcutaneous urticaria allergic, erythema, skintissue disorders hyperpigmentation,angioedema
Musculoskeletal Musculoskeletal Muscle spasms* Polyarthritis*and connective pain*tissue disorders
General Chest pain*, fatigue*disorders andadministrationsite conditions
Investigations Electrocardiogram Gamma- Blood creatine
QT prolonged glutamyltransferase phosphokinase increased,increased, , blood alkaline albumin urine present,phosphatase increased, blood creatineblood urea increased, lipase phosphokinase MBincreased*, amylase increased, blood uric acidincreased*, blood creatinine increased,increased § Δ, creatininerenal clearance decreased
*Selected terms are collapsed as follows: leukopenia (leukopenia, white blood cell count decreased);lymphopenia (lymphopenia, lymphocyte count decreased); peripheral neuropathy (burningsensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motorneuropathy, 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 (alanineaminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, drug-induced liverinjury, hepatic enzyme increased, hepatic function abnormal, liver function test increased,transaminases increased); rash (rash, rash erythematous, rash maculo-papular, rash papular, rashvesicular, rash pustular, nodular rash); pruritus (pruritus, pruritus generalized, rash pruritic);abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominaldiscomfort); visual impairment (vision blurred, visual acuity reduced, visual impairment); amylaseincreased (amylase increased, hyperamylasaemia); lipase increased (hyperlipasaemia, lipaseincreased); 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, oralfungal 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 (oedemaperipheral, peripheral swelling); deafness (deafness, deafness unilateral, conductive deafness); dryskin (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
Description of selected adverse reactionsIncreased transaminases
In the Nix-TB trial in which 109 patients were treated with pretomanid in combination withbedaquiline and linezolid, combined with the ZeNix patients treated within the arms dosed for 26weeks with linezolid, 19 % of patients experienced the ADR of increased transaminases (verycommon). Except for one patient who died due to pneumonia and sepsis, all patients who experiencedincreased transaminases were able to continue or resume therapy after interruption, and complete thefull 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 onepatient could have reported more than one PT which were collapsed into category of Increasedtransaminases. The majority of the events were of grade 1 or grade 2 category, 6 patients had reportedgrade 3 severity, the outcome in 5 patients was resolved and in one patient outcome was not known.
ECG QT interval prolongation
QT prolongation is a known adverse reaction of bedaquiline. Bedaquiline in combination withpretomanid with or without moxifloxacin appears to result in a higher QT prolongation than expectedwith 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 tohave a treatment emergent QTcF exceeding 480 ms. One patient was reported to have a change frombaseline of QTcF exceeding 60 ms. In the ZeNix trial, no electrocardiogram QT prolongation wasobserved 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 3severity of QT prolongation, outcome was resolved.
MyelosuppressionMyelosuppression 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 tolinezolid. The majority of cytopenias began after 2 weeks of treatment. Overall, three patientsexperienced cytopenias that were considered serious: neutropenia in 1 patient and anaemia in2 patients. All 3 serious adverse events resulted either in interruption of linezolid or in interruption ofpretomanid, 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 groupwhich 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, andnone were reported in the 600 mg group.
In the TB-PRACTECAL trial, 52 patients reported ADRs of myelosuppression in the BPaLM arm, outof 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 moreseverity was observed in 6 patients and outcome was resolved in 4 patients in 2 patients the outcomewas not known.
Peripheral neuropathyPeripheral neuropathy is a known ADR of linezolid. In the Nix-TB trial, 81% (very common) ofpatients experienced peripheral neuropathy. In the ZeNix trial, 17 (37.8%) % of patients reported atreatment emergent event of peripheral neuropathy in the 1200 mg 26-week treatment group; one ofthese events led to treatment discontinuation. In the 600 mg 26-week treatment group, a lower numberof patients reported peripheral neuropathy, 11 (24.4%), and none required linezolid treatmentinterruption 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 peripheralneuropathy, most of the events were of grade 1 or grade 2 severity and all the events resolved.
Optic neuropathy
Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%, common) in the Nix-TBtrial developed optic neuropathy, both after 16 weeks of treatment. Both were serious, confirmed onretinal examination as optic neuropathy/neuritis, and resulted in discontinuation of linezolid; bothadverse 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 severitywas 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 treatmentwhen the event occurred. Onset of the event occurred after 3 months of treatment, and all resolved. Noevents of optic neuropathy were reported when linezolid was dosed at 600 mg in the ZeNix trial.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no experience of acute overdose with pretomanid. General measures should be taken tosupport basic vital functions including monitoring of vital signs and ECG in case of deliberate oraccidental overdose.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antimycobacterials, drugs for treatment of tuberculosis, ATC code:
J04AK08.
Mechanism of actionThe mechanism of action of pretomanid is thought to involve inhibition of the synthesis of cell walllipids under aerobic conditions and generation of reactive nitrogen species under anaerobic conditions.
Reductive activation of pretomanid by a mycobacterial deazaflavin (F420)-dependent nitro-reductaseis required for activity under both aerobic and anaerobic conditions (see also mechanism of resistance,below).
ResistanceThe activation of pretomanid, which takes place within the bacterial cell, is dependent on enzymesencoded by 5 genes: a co-factor F420-dependent nitroreductase named Ddn; a glucose-6-phosphatedehydrogenase named Fgd1; and the enzymes of the F420 biosynthetic pathway (FbiA, FbiB, and
FbiC). Mutations in the 5 genes encoding these enzymes (ddn, fgd1, fbiA, fbiB, fbiC) have beenassociated with high level pretomanid resistance in vitro.
Not all isolates with increased minimum inhibitory concentrations (MICs) have mutations in thesegenes, suggesting the existence of at least one other mechanism of resistance.
Pretomanid does not show cross-resistance with any currently used anti-tuberculosis drugs, except fordelamanid where cross-resistance has been demonstrated in vitro. This is likely to be due topretomanid and delamanid being activated via the same pathway, see above. Only one case ofacquisition of pretomanid resistance has been observed thus far in trials sponsored by TB Alliance.
Susceptibility testing breakpoint
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) forpretomanid and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx.
Clinical efficacy and safetyNix-TB trial
Pretomanid was evaluated in a multicentre, open-label study conducted in patients with− pulmonary TB due to M. tuberculosis resistant to isoniazid, rifampicin, a fluoroquinolone anda second line injectable antibacterial drug (extensively drug-resistant TB (XDR-TB), pre-2021
World Health Organisation (WHO) definition),− or patients with pulmonary TB due to M. tuberculosis resistant to isoniazid and rifampicin,who were treatment-intolerant or non-responsive to standard therapy (TI/NR MDR-TB).
The patients received the indicated pretomanid-bedaquiline-linezolid regimen for 6 months(extendable to 9 months) with 24 months of follow-up; linezolid starting dose was either 600 mg twicedaily or 1 200 mg once daily. A total of 109 patients was treated during the course of the study.
The primary efficacy endpoint for the study was treatment failure, defined as the incidence ofbacteriologic failure, bacteriological relapse (culture conversion to positive status after completion oftherapy with same Mycobacterium tuberculosis strain, after conversion to negative during therapy), orclinical failure through follow-up until 6 months after the End of Treatment. Patients consideredtreatment failures were categorised as having an unfavourable outcome.
The mean age of the patients was 35.6 years with 48% being female and 52% male. The meanduration since initial TB diagnosis was 24 months. 47%/38% of patients had unilateral/bilateralcavities and 51% of patients were HIV-positive (with a mean CD4 cell count of 396 cells/µl).
Outcome of the primary efficacy analysis is presented in the table below.
Table 2: Primary Efficacy Analysis for Nix-TB
Total XDR TI/NR MDR
N 109 71 (65%) 38 (35%)
Unassessable 2 1 1
Total Assessable 107 70 37
Favourable 98 (92%) 63 (90%) 35 (95%)
Unfavourable 9 (8%) 7 (10%) 2 (5%)
XDR (pre-2021 WHO definition): extensively drug resistant (resistance to isoniazid, rifampicin, afluoroquinolone, and a second line injectable antibacterial drug)
TI/NR MDR: treatment-intolerant or nonresponsive multidrug-resistant (resistance to both isoniazid andrifampicin and with treatment-intolerance or nonresponsive to standard therapy)
The outcomes were similar in both HIV negative and HIV positive patients. Of the 9 unfavourableoutcomes, 6 were deaths while receiving treatment. Two additional patients relapsed in follow-up afterthe End of Treatment; one of those patients later died.
ZeNix trial
Pretomanid was evaluated in a phase 3 partially blinded, randomized trial assessing the safety andefficacy of various doses and treatment durations of linezolid plus bedaquiline and pretomanid (BPaL)in patients with− pulmonary TB due to M. tuberculosis resistant to isoniazid, rifampicin, a fluoroquinolone anda second line injectable antibacterial drug (extensively drug-resistant TB (XDR-TB), pre-2021
WHO definition),− or pulmonary TB due to M. tuberculosis resistant to rifampicin and either a fluoroquinolone ora second line injectable antibacterial drug (pre-XDR-TB, pre-2021 WHO definition),− or pulmonary TB due to M. tuberculosis resistant to both isoniazid and rifampicin who weretreatment intolerant or non-responsive to standard therapy (TI/NR MDR-TB).
A total of 181 patients were randomized to receive one of the 4 treatment arms, of which 45 eachreceived 1 200 mg or 600 mg linezolid in the BPaL regimen for 26 weeks, and 46 and 45 patientsreceived 1 200 mg or 600 mg linezolid in the BPaL regimen for 9 weeks, respectively. The mean ageof the patients was 37.1 years with 67.4% being males. The majority of participants were white(63.5%), and the remaining participants were black (36.5%). Most participants had a current TBdiagnosis (a stratification factor) of pulmonary TB due to M. tuberculosis resistant to rifampicin andeither a fluoroquinolone or a second line injectable antibacterial drug (47.0%) or pulmonary TB due to
M. tuberculosis resistant to isoniazid, rifampicin, a fluoroquinolone and a second line injectableantibacterial drug (41.4%), and the remainder of participants having pulmonary TB due to M.tuberculosis resistant to isoniazid and rifampicin who were treatment intolerant or non-responsive tostandard therapy(5.0% and 6.6%, respectively).
The primary efficacy endpoint was the incidence of treatment failure (unfavourable outcome) definedas bacteriologic failure or relapse or clinical failure at 6 months (26 weeks) after the end of therapy.
Participants were classified as having a favourable, unfavourable, or unassessable status at 6 months(26 weeks) after the end of treatment.
The outcome of primary efficacy analysis is presented in the table below.
Table 3: Primary Efficacy Analysis for ZeNix
Linezolid Linezolid Linezolid Linezolid1 200 mg 1 200 mg 600 mg 600 mg Total26 weeks 9 weeks 26 weeks 9 weeks (N = 181)(N = 45) (N = 46) (N = 45) (N = 45) n (%)n (%) n (%) n (%) n (%)
Unassessable 1 1 0 1 3
Total assessable 44 45 45 44 178
Favourable 41 (93.2%) 40 (88.9%) 41 (91.1%) 37 (84.1%) 159 (89.3%)
Unfavourable 3 (6.8%) 5 (11.1%) 4 (8.9%) 7 (15.9%) 19 (10.7%)81.3% to 75.9% to 78.8% to 69.9% to 83.8% to95% CI for Favourable 98.6% 96.3% 97.5% 93.4% 93.4%
CI = confidence interval; N = total number of participants in the relevant analysis population; n = numberof participants in each category.
Favourable and unfavourable status as defined in the statistical analysis plan for the modified intent-to-treatpopulation.
TB-PRACTECAL trial
Pretomanid was evaluated in an open-label, phase 2-3, multicentre, randomized, controllednoninferiority trial for patients with rifampicin-resistant tuberculosis. Patients’ age from the study wasranging from 15 to 72 years. 40.4% of total patients were female. 28% of total patients were diagnosedwith HIV.
A BPaLM treatment arm was compared to an arm with WHO standard care treatment. Participants inthe standard care group received locally accepted treatments, updated as per WHO guidance. Initially,standard care regimens included both shorter, standardised (36 to 44-week) regimens as well as longer,individualised (72 to 80-week) regimens. From 2017 to 2019, these regimens generally included asecond-line injectable agent and criteria for including bedaquiline were stringent. From 2019,participants received all-oral versions of these regimens, and most regimens included bedaquiline.
The primary efficacy outcome was an unfavourable status (a composite of death, treatment failure,treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks afterrandomization. In the modified intention-to-treat-excludes-switches population, 56 of 137 patients inthe standard-care group (40.9%) and 16 of 138 patients in the BPaLM group (11.7%) had anunfavourable status. The secondary efficacy outcomes, the risk of a composite unfavourable outcomeevent at 24 and 108 weeks was broadly consistent with that with the primary outcome.
Limitations of the trial include the open-label design, the lack of follow up after treatmentdiscontinuation, and the early stopping for efficacy after an unplanned interim analysis.
Table 4 shows the primary outcome results in patients randomized to BPaLM or SoC during either thephase 2 part or the phase 3 part of the trial.
Table 4: Primary Outcome Results in TB-PRACTECALmITT-excludes-switches Population*
Standard care (n=137) BPaLM (n=138)n (%) n (%)
No unfavourable outcome 81 (59.1%) 121 (87.7%)
Unfavourable outcome 56 (40.9%) 16 (11.6%)
Non-assessable 0 (0%) 1 (0.7%)
Reasons for unfavourable outcome
Deaths 5 (3.7%) 0 (0%)
Early discontinuations 50 (36.5%) 11 (8.0%)
Lost to follow-up at 72 weeks 1 (0.7%) 4 (2.9%)
Recurrence 0 (0%) 1 (0.7%)
* mITT-exclude-switches Population: modified intent-to-treat population excluding patients in the standard ofcare arm who were switched to Practecal arm-1 (BPaLM) after 18th March 2021, when enrolment to the studywas stopped. It was used as the primary population when reporting mITT outcomes.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies withpretomanid in one or more subsets of the paediatric population in treatment of multi-drug-resistanttuberculosis (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetic properties of pretomanid are similar in adult healthy patients and in adulttuberculosis-infected patients.
AbsorptionThe absolute bioavailability of pretomanid has not been established. Two mass balance studies haveindicated that the absolute bioavailability is greater than 53% and 64%.
The median tmax values range from 4 to 5 hours.
Administration of 200 mg pretomanid with a high-fat, high-calorie meal increased mean Cmax by 76%and mean AUC0-inf by 88% as compared with administration in the fasted state.
DistributionThe binding of pretomanid to human plasma proteins is 86.4%, so the fraction unbound (fu) is 13.6%.
Human serum albumin binding was similar (82.7%), indicating that binding to albumin is responsiblefor the human plasma protein binding of pretomanid.
The mean apparent volume of distribution (Vd/F) after a single dose of 200 mg in the fed state was97 L when the mean weight was 72 kg.
BiotransformationThe metabolic profile of pretomanid has not been completely elucidated. Pretomanid is extensivelymetabolised with over 19 metabolites identified through multiple metabolic pathways. In the mass-balance study, pretomanid had a half-life of 16 hours, while that of total radioactivity was 18 days,indicating the presence of partially unidentified long-lived metabolites.
In vitro, pretomanid was moderately metabolized by CYP3A4. A role of CYP3A4 was furthersupported by a clinical drug interaction study with CYP3A4 inducers. Nitro-reduction within
Mycobacterium tuberculosis and potentially in gastrointestinal microflora is also involved in themetabolism of pretomanid.
Pretomanid is not a substrate of cytochrome P450 (CYP) 2C9, 2C19 or 2D6 in vitro.
EliminationThe recovery of total radioactivity following a single dose of 14C-preotmanid was approximately 90%with about 53-65% excreted in the urine and 26-38% in faeces.
Pretomanid, at clinically relevant concentrations, is not a substrate or inhibitor for the transporters, bilesalt export pump (BSEP), multidrug and toxin extrusion protein (MATE)1, MATE2-K, organic aniontransporter (OAT)1, OAT1B1 and organic cation transporter (OCT)1. Pretomanid is not a substrate of
OAT3, breast cancer resistance protein (BCRP), P-glycoprotein (P gp), OCT2 and organic anion-transporting polypeptide (OATP)1B3. The potential of pretomanid to inhibit P gp, OATP1B3, OCT2and BCRP has not been investigated at clinically relevant concentrations.
Apparent clearance (CL/F) after a single dose was 7.6 and 3.9 l/h in the fasted and fed states,respectively. The elimination half-life was 17 hours.
Non-linearity
In the fasted state, bioavailability decreased with increasing doses (50 to 1500 mg/day), withabsorption saturation above 1000 mg. In the fed state, there were no significant changes inbioavailability across doses of 50 mg through 200 mg.
Special populationsHepatic impairment
The pharmacokinetics of pretomanid has not been established in patients with impaired hepaticfunction.
Renal impairmentThe pharmacokinetics of pretomanid has not been established in patients with impaired renal function.
Paediatric populationThe pharmacokinetics of pretomanid have not been established in the paediatric population.
ElderlyThere is limited clinical data (n=5) on the use of pretomanid in elderly patients (≥65 years).
RaceThere were no clinically meaningful differences in the pharmacokinetics of pretomanid between Blackand Caucasian patients. The pharmacokinetics of pretomanid have not been established in other racialpopulations.
5.3 Preclinical safety data
Cataracts developed in rats given pretomanid at 300 mg/kg/day for 13 weeks with 7-fold themaximum recommended human dose (MRHD) exposure and at 100 mg/kg/day for 26 weeks with3-4-fold MRHD exposure. The cataracts were not present at the end of dosing in monkeys given oralpretomanid at 450 mg/kg/day (10.5-fold of MRHD exposure) for 4 weeks and 300 mg/kg/day(5.4-fold MRHD exposure) for 12 more weeks, but observed in 2 of 12 monkeys during the 13-weekpost treatment recovery period. In a subsequent study in monkeys, cataracts were not observedfollowing 13 weeks treatment with up to 300 mg/kg/day oral pretomanid (5-fold of MRHD exposure)or during the 20 week post treatment recovery period. Additionally, no cataracts were observed inrepeat-dose toxicity studies of up to 9 months in monkeys (approximately 2-3-fold of MRHDexposure). In addition, in a 2-year carcinogenicity study in rats, pretomanid resulted in an increasedincidence of cataracts at 10 mg/kg/day, resulting in an exposure in the same range as at the MRHD.
The clinical relevance of this finding is unknown.
In repeat dose studies in rats, convulsions were observed at systemic exposures 4- to 10-fold higherthan the clinical exposure at the MHRD of 200 mg/day (Cmax = 3.1 µg/ml and AUC0-24 = 57 h×µg/ml).
In repeat dose studies in monkeys, convulsions were seen at exposures 2- to 8-fold higher thanexposure at the MHRD. In both species, convulsions were observed at lower exposures during thelonger duration studies (6-month rat and 9-month monkey). The mechanism of convulsions innonclinical studies with pretomanid is unknown. The clinical relevance of this finding is unknown.
Pretomanid has the potential to affect cardiac repolarisation via blockade of hERG potassium channelsand/or other cardiac ion channels including Nav1.5 and KCNQ1/minK.
Testicular toxicity was observed in rats and mice without exposure margin to the MRHD. Decreasedfertility to complete infertility was observed in male rats treated with oral pretomanid. There were nodirect effects of pretomanid on reproductive organs in monkeys given oral pretomanid for 3-monthsand 9-months. Decreased sperm motility, total sperm count and increased abnormal sperm ratio wereobserved in monkeys. Based upon the preclinical data, rodents are susceptible to pretomanid-inducedtesticular injury. Serum levels of the male reproductive hormones are biomarkers that are altered inassociation with this injury. In the preclinical study of primates, no pretomanid-related alterations intestis or male reproductive hormones were observed.
Non-clinical data reveal no special hazard for humans based on conventional studies of embryo-foetaldevelopment and peri-postnatal development.
Transfer of pretomanid from dam to pup via breast milk was studied in rats. After 14 days dosing of20 mg/kg/day, the mean maternal plasma concentration 6 hours post dose was 2.84 μg/ml, which issimilar to the mean steady state Cmax for 200 mg pretomanid in humans. At the same time, the meanconcentration in milk was 4.07 μg/ml, and the mean plasma concentration in rat pups was 0.119 μg/ml.
The concentration of pretomanid in rat milk does not necessarily predict the concentration ofpretomanid in human milk.
No mutagenic or clastogenic effects were detected in conventional genotoxicity studies withpretomanid. A circulating metabolite of pretomanid, M50, was mutagenic in a bacterial reversemutation assay. No carcinogenic potential was revealed in a 6-month study in transgenic mice wherethis metabolite is produced. In a 2-year study in rats, an increased incidence of Leydig cell adenomaswas observed at a dose of 10 mg/kg/day. The observation is likely of limited relevance to humans.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate
Microcrystalline cellulose
Sodium starch glycolate
Magnesium stearate
Silica, colloidal
Sodium lauryl sulphate
Povidone
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
6.5 Nature and contents of container
High-density polyethylene (HDPE) bottles with polypropylene screw cap with a pulp liner and anabsorbent cotton or an ullage filler.
Pack size: 26 tablets.
PVC/PVdC-Aluminium foil blisters packs.
Pack sizes: 14, 14 × 1 (unit dose), 182, 182 × 1 (unit dose) tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.