Dovprela (previously Pretomanid FGK) - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Dovprela 200 mg tablet

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 200 mg pretomanid.

Excipient with known effect

Each 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 PARTICULARS4.1 Therapeutic indications

Dovprela is indicated in combination with bedaquiline and linezolid, in adults, for the treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive multidrugresistant (MDR) tuberculosis (TB), see sections 4.2, 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 the management of multidrug-resistant tuberculosis.

Pretomanid should be administered by directly observed therapy (DOT) or in accordance with local practice.

Posology

The recommended dosage is 200 mg (one tablet) pretomanid once daily, for 26 weeks.

A longer duration of therapy may be considered in patients who have not responded adequately to treatment at 26 weeks on a case by case basis (see section 5.1).

Pretomanid should be administered only in combination with bedaquiline (400 mg once daily for 2 weeks followed by 200 mg 3 times per week [with at least 48 hours between doses] orally for a total of 26 weeks) and linezolid (1,200 mg daily orally for up to 26 weeks).

The product information for bedaquiline and linezolid should be consulted for additional information on the use of these medicinal products.

In addition, see section 4.4 for information on the dose modification of linezolid that was applied during the Nix-TB clinical study and see section 5.1 for details of the study.

Discontinuation of the pretomanid-bedaquiline-linezolid treatment regimen (see also sections 4.4, 4.8 and 5.1)

• • If either bedaquiline or pretomanid is discontinued for any reason, the entire combination regimen should be discontinued.
• • If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, the entire combination regimen should be discontinued.
• • If linezolid is discontinued after the initial four weeks of consecutive treatment, the regimen may be continued with only bedaquiline and pretomanid.

Missed doses

Any missed doses of pretomanid and bedaquiline should be made up at the end of treatment. Doses of linezolid that are missed due to linezolid adverse reactions should not be made up at the end of treatment.

Refer to the product information of bedaquiline and linezolid for additional information on these medicinal products.

Treatment duration

The total duration of treatment with pretomanid in combination with bedaquiline and linezolid is 26 weeks. Data on longer treatment duration is limited. A longer duration of therapy may be considered in patients who have not responded adequately to treatment at 26 weeks on a case by case basis (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 and efficacy of pretomanid in elderly patients have not been established.

Hepatic impairment

The safety and efficacy of pretomanid in populations with hepatic impairment have not been established (see section 4.4).

Renal impairment

The 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 population

The safety and efficacy of pretomanid in children and adolescents have not yet been established.

No data are available.

Method of administration

For oral use.

Pretomanid should be taken with food (see section 5.2).

Tablets should be swallowed with water.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Safety and effectiveness of pretomanid have not been established for its use in combination with medicinal products other than bedaquiline and linezolid as part of the recommended dosing regimen, and thus pretomanid should not be used as part of any other regimen.

Hepatotoxicity

Hepatotoxicity may occur with use of the regimen consisting of pretomanid, bedaquiline and linezolid. Liver-related laboratory tests should be monitored. Alcohol and hepatotoxic medicinal products (including herbal supplements), other than those specified in the indication statement (see section 4.1), should be avoided while on the regimen, especially in patients with impaired hepatic function. Symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) should be addressed throughout treatment. Laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) should be monitored at initiation of treatment, and at a minimum once every week during the first month of treatment, every other week during month 2, and monthly thereafter while on treatment, and as needed. If evidence of new or worsening liver dysfunction occurs, a test for viral hepatitis should be performed and other hepatotoxic medicinal products should be discontinued. Treatment with the entire regimen should be interrupted if:

• • Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit of normal.
• • Aminotransferase elevations are greater than 8 times the upper limit of normal.
• • Aminotransferase elevations are greater than 5 times the upper limit of normal and persist

beyond 2 weeks.

Treatment may be re-initiated under close surveillance when hepatic enzymes and clinical symptoms normalize.

Modification/in­terruption due to linezolid adverse reactions

Modification or interruption of linezolid dosing may be needed during the course of therapy to manage the known linezolid toxicities. The recommendations below reflect the procedures used in the Nix-TB study (section 5.1).

Myelosuppression

Complete blood counts should be monitored at a minimum at start of treatment, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen. Haematologic parameters are variable from measurement to measurement, and decreases should be evaluated in the context of the patient’s overall medical condition. Guidelines below may be considered when it is likely that linezolid has caused the decrease in blood count. Consider pausing or reducing the dose of linezolid in the following situations.

• • Anaemia – if haemoglobin falls below 80 g/l or more than 25% below the start of treatment.
• • Leukopenia – if the Absolute Neutrophil Count (ANC) falls below 0.75 × 109/l or significantly

below baseline. Confirm with a repeat test before making further decisions as ANCs can have diurnal and other variability.

• • Thrombocytopenia – if platelets fall below 50 × 109/l or significantly below baseline. Ideally confirm with a repeat test before making further decisions.

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

Peripheral neuropathy and optic neuropathy

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

Lactic acidosis

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

QT prolongation

QT prolongation was reported with the combination regimen of pretomanid, bedaquiline, and linezolid. QT prolongation is a known adverse reaction of bedaquiline. Bedaquiline in combination with pretomanid appears to result in a higher QT prolongation than expected with bedaquiline alone. However, the impact of pretomanid has not been fully characterized.

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

The following may increase the risk for QT prolongation:

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

4.5 Interaction with other medicinal products and other forms of interaction

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 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 coadministered medicinal product should be performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are very limited amount of data from the use of pretomanid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryo-fetal 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).

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 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).

4.8 Undesirable effects

The most frequent adverse drug reactions during treatment with pretomanid in combination with bedaquiline and linezolid were nausea (36%), vomiting (28%) and transaminases increased (21%). 81% and 37% of patients experienced peripheral neuropathy and anaemia, which are known adverse reactions to linezolid, respectively. Nausea, vomiting and transaminases increased are possible adverse reactions to all three medicinal products in the regimen. Refer to the Summary of Product Characteristics of bedaquiline and linezolid for more information on adverse reactions caused by these two medicinal products.

Tabulated list of adverse reactions

Adverse drug reactions (ADRs) reported from the uncontrolled phase 3 trial in 109 patients treated with pretomanid in combination with bedaquiline and linezolid are summarized in the table below by system organ class and frequency. ADRs considered attributed to linezolid are marked with A.

System Organ Class	Very Common >1/10	Common >1/100 to <1/10	Uncommon >1/1,000 to <1/100
Infections and infestations			Fungal infection, oral candidiasis, oral fungal infection
Blood and lymphatic system disorder	Anaemia A	Leukopenia A, neutropenia A, thrombocytopenia A,	Lymphopenia A, pancytopenia A
Metabolic and nutrition disorders	Decreased appetite	Hypoglycaemia, lactic acidosis A	Acidosis A, dehydration, hypocalcaemia, hypovolaemia, hypomagnesaemia
Psychiatric disorders		Insomnia	Anxiety, depression
Nervous system disorders	Peripheral neuropathy* A, headache	Dysgeusia, dizziness
Eye disorders		Visual impairment*, eye irritation, eye pain, optic neuropathy*A	Lens disorder, dry eye, eye pruritis, eye swelling, papilloedema, presbyopia
Ear and labyrinth disorder			Deafness
Cardiac disorder			Palpitations, sinus tachycardia
Vascular disorders			Hypotension

System Organ Class	Very Common >1/10	Common >1/100 to <1/10	Uncommon >1/1,000 to <1/100
Respiratory, thoracic and mediastinal disorders			Cough, epistaxis
Gastrointestinal disorders	Nausea, vomiting, dyspepsia, abdominal pain	Gastritis, diarrhoea, constipation, gastrooesophageal reflux disease, pancreatitis	Abdominal distension, glossodynia, haematemesis
Hepatobiliary disorders	Transaminase increased	Hyperbilirubinaemia	Hepatomegaly, jaundice
Skin and subcutaneous tissue disorder	Acne, pruritus, rash	Dry skin, alopecia	Dermatitis allergic, skin hyperpigmentation
Musculoskeletal and connective tissue disorders	Musculoskeletal pain	Muscle spasms	Musculoskeletal stiffness
Reproductive system and breast disorder			Erectile dysfunction, metrorrhagia
General disorders and administration site conditions		Fatigue, asthenia	Malaise
Investigations	Gammaglutamyl­transferase increased; amylase increased	Electrocardiogram QT prolonged, blood alkaline phosphatase increased, blood creatine phosphokinase increased, blood urea increased, lipase increased	Albumin urine present, blood creatinine increased, blood creatine phosphokinase MB increased, blood uric acid increased, creatinine renal clearance decreased

increased transaminases were able to continue or resume therapy after interruption, and complete the full course of treatment.

ECG QT interval prolongation

QT prolongation is a known adverse reaction of bedaquiline. Bedaquiline in combination with pretomanid appears to result in a higher QT prolongation than expected with bedaquiline alone. However, the impact of pretomanid has not been fully characterised. In the Nix-TB trial, 6 patients (5.5%, common) experienced QT prolongation. In the entire Nix-TB trial, no subject was reported to have a treatment emergent QTcF exceeding 480 ms. One subject was reported to have a change from baseline of QTcF exceeding 60 ms.

Myelosuppression

Myelosuppression is a known adverse reaction of linezolid. In the Nix-TB trial, 37% (very common) of patients experienced anaemia, as the most common ADR of hematopoietic cytopenia attributed to linezolid. The majority of cytopenias began after 2 weeks of treatment. Overall, three patients experienced cytopenias that were considered serious: neutropenia in 1 patient and anaemia in 2 patients. All 3 serious adverse events resulted either in interruption of linezolid or in interruption of pretomanid, bedaquiline, and linezolid, and all resolved.

Peripheral neuropathy

Peripheral neuropathy is a known ADR of linezolid. In the Nix-TB trial, 81% (very common) of patients experienced peripheral neuropathy. Most of these adverse reactions occurred after 8 weeks of treatment and resulted in dosing interruption, dose reduction, or discontinuation of linezolid. No adverse reactions related to peripheral neuropathy led to a discontinuation of the entire study regimen.

Optic neuropathy

Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%, common) in the Nix-TB trial developed optic neuropathy, both after 16 weeks of treatment. Both were serious, confirmed on retinal examination as optic neuropathy/ne­uritis, and resulted in discontinuation of linezolid; both adverse reactions resolved.

Reporting of suspected adverse reactions

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

4.9 Overdose

There is no experience of acute overdose with pretomanid. General measures should be taken to support basic vital functions including monitoring of vital signs and ECG in case of deliberate or accidental overdose.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycobacterials, drugs for treatment of tuberculosis, ATC code: not yet assigned.

Mechanism of action

The mechanism of action of pretomanid is thought to involve inhibition of the synthesis of cell wall lipids under aerobic conditions and generation of reactive nitrogen species under anaerobic conditions. Reductive activation of pretomanid by a mycobacterial deazaflavin (F420)-dependent nitro-reductase is required for activity under both aerobic and anaerobic conditions (see also mechanism of resistance, below).

Resistance

The activation of pretomanid, which takes place within the bacterial cell, is dependent on enzymes encoded by 5 genes: a co-factor F420-dependent nitroreductase named Ddn; a glucose-6-phosphate dehydrogenase 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 been associated with high level pretomanid resistance in vitro.

Not all isolates with increased minimum inhibitory concentrations (MICs) have mutations in these genes, 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 for delamanid where cross-resistance has been demonstrated in vitro. This is likely to be due to pretomanid and delamanid being activated via the same pathway, see above. Only one case of acquisition of pretomanid resistance has been observed thus far in trials sponsored by TB Alliance.

Susceptibility testing breakpoint

Based on the limited information available, a critical concentration for pretomanid is provisionally set at 1 p.g/ml for testing using the MGIT System. Over 99% of clinical isolates surveyed showed MIC values at or below 1 p,g/ml. Conversely, all Mycobacterium tuberculosis isolates with known mechanisms of resistance to pretomanid had MIC values above this concentration

Clinical efficacy and safety

Pretomanid was evaluated in a multicenter, open-label study conducted in subjects with XDR, treatment-intolerant MDR or non-responsive MDR pulmonary tuberculosis. The subjects 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 twice daily or 1200 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 of bacteriologic failure, bacteriological relapse (culture conversion to positive status after completion of therapy with same Mycobacterium tuberculosis strain, after conversion to negative during therapy), or clinical failure through follow-up until 6 months after the End of Treatment. Subjects considered treatment 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 mean duration since initial TB diagnosis was 24 months. 47%/38% of patients had unilateral/bi­lateral cavities and 51% of patients were HIV-positive (with a mean CD4 cell count of 396 cells/gl). Outcome of the primary efficacy analysis is presented in the table below.

	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: extensively drug resistant

TI/NR MDR: treatment-intolerant or nonresponsive multidrug-resistant

The outcomes were similar in both HIV negative and HIV positive subjects. Of the 9 unfavourable outcomes, 6 were deaths while receiving treatment. Two additional subjects relapsed in follow-up after the End of Treatment; one of those subjects later died.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with pretomanid in one or more subsets of the paediatric population in treatment of multi-drug-resistant tuberculosis (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary

5.2 Pharmacokinetic properties

The pharmacokinetic properties of pretomanid are similar in adult healthy subjects and in adult tuberculosis-infected patients.

Absorption

The absolute bioavailability of pretomanid has not been established. Two mass balance studies have indicated that the absolute bioavailability is greater than 53% and 64%.

The median t max 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.

Distribution

The 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 responsible for 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 was

97 L when the mean weight was 72 kg.

Biotransformation

The metabolic profile of pretomanid has not been completely elucidated. Pretomanid is extensively metabolised with over 19 metabolites identified through multiple metabolic pathways. In the massbalance 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 further supported by a clinical drug interaction study with CYP3A4 inducers. Nitro-reduction within Mycobacterium tuberculosis and potentially in gastrointestinal microflora is also involved in the metabolism of pretomanid.

Pretomanid is not a substrate of cytochrome P450 (CYP) 2C9, 2C19 or 2D6 in vitro.

Elimination

The 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, bile salt export pump (BSEP), multidrug and toxin extrusion protein (MATE)1, MATE2-K, organic anion transporter (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 aniontransporting polypeptide (OATP)1B3. The potential of pretomanid to inhibit P gp, OATP1B3, OCT2 and 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), with absorption saturation above 1000 mg. In the fed state, there were no significant changes in bioavailability across doses of 50 mg through 200 mg.

Special populations

Hepatic impairment

The pharmacokinetics of pretomanid has not been established in patients with impaired hepatic function.

Renal impairment

The pharmacokinetics of pretomanid has not been established in patients with impaired renal function.

Paediatric population

The pharmacokinetics of pretomanid have not been established in the paediatric population.

Elderly

There is limited clinical data (n=5) on the use of pretomanid in elderly subjects (>65 years).

Race

There were no clinically meaningful differences in the pharmacokinetics of pretomanid between Black and Caucasian subjects. The pharmacokinetics of pretomanid have not been established in other racial populations.

5.3 Preclinical safety data

Cataracts developed in rats given pretomanid at 300 mg/kg/day for 13 weeks with 7-fold the maximum recommended human dose (MRHD) exposure and at 100 mg/kg/day for 26 weeks with 3–4-fold MRHD exposure. The cataracts were not present at the end of dosing in monkeys given oral pretomanid 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-week post treatment recovery period. In a subsequent study in monkeys, cataracts were not observed following 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 in repeat-dose toxicity studies of up to 9 months in monkeys (approximately 2–3-fold of MRHD exposure). In addition, in a 2-year carcinogenicity study in rats, pretomanid resulted in an increased incidence 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 higher than the clinical exposure at the MHRD of 200 mg/day (Cmax = 3.1 gg/ml and AUC0–24 = 57 h^gg/ml). In repeat dose studies in monkeys, convulsions were seen at exposures 2– to 8-fold higher than exposure at the MHRD. In both species, convulsions were observed at lower exposures during the longer duration studies (6-month rat and 9-month monkey). The mechanism of convulsions in nonclinical 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 channels and/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. Decreased fertility to complete infertility was observed in male rats treated with oral pretomanid. There were no direct effects of pretomanid on reproductive organs in monkeys given oral pretomanid for 3-months and 9-months. Decreased sperm motility, total sperm count and increased abnormal sperm ratio were observed in monkeys. Based upon the preclinical data, rodents are susceptible to pretomanid-induced testicular injury. Serum levels of the male reproductive hormones are biomarkers that are altered in association with this injury. In the preclinical study of primates, no pretomanid-related alterations in testis or male reproductive hormones were observed.

Non-clinical data reveal no special hazard for humans based on conventional studies of embryo-foetal development and peri-postnatal development.

Transfer of pretomanid from dam to pup via breast milk was studied in rats. After 14 days dosing of 20 mg/kg/day, the mean maternal plasma concentration 6 hours post dose was 2.84 gg/ml. which is similar to the mean steady state Cmax for 200 mg pretomanid in humans. At the same time, the mean concentration in milk was 4.07 gg/ml. and the mean plasma concentration in rat pups was 0.119 gg/ml. The concentration of pretomanid in rat milk does not necessarily predict the concentration of pretomanid in human milk.

No mutagenic or clastogenic effects were detected in conventional genotoxicity studies with pretomanid. A circulating metabolite of pretomanid. M50. was mutagenic in a bacterial reverse mutation assay. No carcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite is produced. In a 2-year study in rats. an increased incidence of Leydig cell adenomas was observed at a dose of 10 mg/kg/day. The observation is likely of limited relevance to humans.

6. PHARMACEUTICAL PARTICULARS6.1 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

3 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 an absorbent cotton.

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

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited

Unit 35/36 Grange Parade

Baldoyle Industrial Estate

Dublin 13

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/20/1437/001

EU/1/20/1437/002

EU/1/20/1437/003

EU/1/20/1437/004

EU/1/20/1437/005

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 31 July 2020

Date of latest renewal: 17 June 2021