Pretomanid FGK

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pretomanid FGK 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 PARTICULARS 
 
4.1 Therapeutic indications 
 
Pretomanid FGK is indicated in combination with bedaquiline and linezolid, in adults, for the 
treatment of pulmonary extensively drug resistant (XDR), or treatment-intolerant or nonresponsive 
multidrug-resistant (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). 
 

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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 
 

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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 

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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. 
 
The entire regimen of pretomanid, bedaquiline, and linezolid must be discontinued if the patient 
develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms 
(confirmed by repeat ECG). If syncope occurs, an ECG should be obtained to detect QT prolongation. 
 
The QT prolongation risk for the combination regimen has not been established at exposures higher 
than therapeutic levels. The risk may be increased if the systemic exposure of pretomanid is elevated 
(see sections 4.5 and 5.2).  
 
Excipients 
 
Pretomanid FGK contains lactose. Patients with rare hereditary problems such as galactose 
intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. 
Pretomanid FGK 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 inducers 

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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 
 
OAT3 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 medicinal product should be 
considered, if needed (see section 4.4).  
 
Substrates of CYP2C8, CYP2C9 and CYP2C19 
Pretomanid has been shown to inhibit CYP2C8 and CYP2C19 in a time dependent manner in vitro. 
Induction of CYP2C8, CYP2C9 and CYP2C19 by pretomanid has not been studied. Therefore, the net 
effect of pretomanid on CYP2C8 and/or CYP2C19 substrates is unknown. Consequently concomitant 
treatment with substrates of CYP2C8, CYP2C9 and CYP2C19 should be closely monitored. 
 
Substrates of Pgp, OATP1B3, OCT2 and BCRP 
The potential of pretomanid to inhibit Pgp, OATP1B3, OCT2 and BCRP in vivo is unknown. Caution 
is recommended for concomitant treatment with pretomanid and transporter substrates with a narrow 
therapeutic index. 
 
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). 

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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 ∆. 
 
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 ∆ Leukopenia ∆, neutropenia 
∆, thrombocytopenia ∆,  

Lymphopenia ∆, 
pancytopenia ∆ 

Metabolic and 
nutrition 
disorders 

Decreased appetite Hypoglycaemia, lactic 
acidosis ∆  

Acidosis ∆, dehydration, 
hypocalcaemia, 
hypovolaemia, 
hypomagnesaemia 

Psychiatric 
disorders 

 Insomnia Anxiety, depression 

Nervous system 
disorders 

Peripheral 
neuropathy* ∆, 
headache 

Dysgeusia, dizziness   

Eye disorders  Visual impairment*, eye 
irritation, eye pain, optic 
neuropathy*∆ 

Lens disorder, dry eye, 
eye pruritis, eye swelling, 
papilloedema, presbyopia 

Ear and 
labyrinth 
disorder 

  Deafness 

Cardiac disorder   Palpitations, sinus 
tachycardia  

Vascular 
disorders 

  Hypotension 

Respiratory,   Cough, epistaxis 

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System Organ 
Class 

Very Common  

≥1/10 

Common 

≥1/100 to <1/10 

Uncommon 

≥1/1,000 to <1/100 

thoracic and 
mediastinal 
disorders 

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 Gamma-
glutamyltransferase 
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 

 
*Selected terms are collapsed as follows: peripheral neuropathy (burning sensation, hypoesthesia, 
hyporeflexia, neuropathy peripheral, paraesthesia, peripheral motor neuropathy, peripheral 
sensorimotor neuropathy, peripheral sensory neuropathy); gastritis (gastritis, chronic gastritis); acne 
(acne, dermatitis acneiform); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, 
pain in extremity); 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); pruritus (pruritus, pruritus 
generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain 
upper, abdominal tenderness); 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). 
 
Description of selected adverse reactions 
 
Increased transaminases 
In the Nix-TB trial in which 109 patients were treated with pretomanid in combination with 
bedaquiline and linezolid, 21% 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 

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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 PROPERTIES 
 
5.1 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 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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 μg/ml for testing using the MGIT System. Over 99% of clinical isolates surveyed showed MIC 
values at or below 1 μg/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/µl). 
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. 

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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 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. 
 
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 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 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 

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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 anion-
transporting 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). Taken together, these studies suggest that the no-effect level for cataracts was 
30 mg/kg/day observed in rats (26-week study), which is 2-fold the exposure at the MRHD of 
200 mg/day.  
 
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 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 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. 

12 



 
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 μg/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 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 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.  
 
 
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 
 
24 months 
 
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. 
 

13 



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 
 
FGK Representative Service GmbH 
Heimeranstrasse 35 
80339 Munich, Germany 
Phone: +49 (0) 89 893 119-22 
Fax:     +49 (0) 89 893 119-20 
 
 
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 
 
 
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. 

14 

http://www.ema.europa.eu/


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE CONDITIONAL 
MARKETING AUTHORISATION 

15 



A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Mylan Hungary Kft 
Mylan utca 1. 
Komarom 
2900 
Hungary 
 
Generics (UK) Limited 
Station Close 
Potters Bar, EN6 1TL  
United Kingdom 
 
Mylan UK Healthcare Ltd 
Building 20, Station Close 
Potters Bar, EN6 1TL 
United Kingdom 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c (7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

16 



 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE CONDITIONAL MARKETING AUTHORISATION  
 
This being a conditional marketing authorisation and pursuant to Article 14-a of Regulation (EC) No 
726/2004, the MAH shall complete, within the stated timeframe, the following measures: 

 

Description Due date 

 
In order to further evaluate the safety, efficacy and tolerability of linezolid plus 
bedaquiline and pretomanid after 26 weeks of treatment in participants with either 
pulmonary XDR-TB, pre-XDR TB, or treatment intolerant or non-responsive MDR-TB, 
the marketing authorisation holder should complete and submit results from the ongoing 
study ZeNix – A Phase 3 Partially-blinded, Randomized Trial Assessing the Safety and 
Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and 
Pretomanid in Participants With Pulmonary Infection of Either Extensively Drug-resistant 
Tuberculosis (XDR-TB), Pre-XDR-TB or Treatment Intolerant or Non-responsive Multi-
drug Resistant Tuberculosis (MDR-TB) 

 

Annual reports to be 
submitted 
 
Final report by  
Q4 2022 
 

In order to confirm the safety and efficacy of pretomanid the marketing authorisation 
holder should complete and submit results from the ongoing Phase 3 Open-label Trial 
Assessing the Safety and Efficacy of Bedaquiline Plus Pretomanid Plus Linezolid (B-Pa-
L) in Subjects with Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis 
(XDR-TB) or Treatment Intolerant/Non-responsive Multi-Drug Resistant Tuberculosis 
(MDR-TB). (NiX) 

 

Final report by Q2 
2021 
 
 

 

 

17 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

18 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

19 



 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON (BLISTER) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pretomanid FGK 200 mg tablets 
pretomanid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg pretomanid 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Tablet 
 
Blisters: 
14 tablets 
182 tablets 
 
Perforated unit dose blisters: 
14 × 1 tablet 
182 × 1 tablet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 

20 



 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
FGK Representative Service GmbH 
Heimeranstrasse 35 
80339 Munich 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1437/001 
EU/1/20/1437/002 
EU/1/20/1437/004 
EU/1/20/1437/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Pretomanid FGK 200 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 

21 



 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS  
 
BLISTER  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pretomanid FGK 200 mg tablets 
pretomanid 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
FGK Representative Services GmbH 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 

22 



 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON (BOTTLE) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pretomanid FGK 200 mg tablets 
pretomanid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg pretomanid 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
26 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

23 



 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
FGK Representative Service GmbH 
Heimeranstrasse 35 
80339 Munich 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1437/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Pretomanid FGK 200 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  
 
 
 

24 



 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Pretomanid FGK 200 mg tablets 
pretomanid 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg pretomanid. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
26 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

25 



 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
FGK Representative Service GmbH 
Heimeranstrasse 35 
80339 Munich 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1437/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 

26 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

27 



 
Package leaflet: Information for the patient 

 
Pretomanid FGK 200 mg tablets 

pretomanid 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again.  
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Pretomanid FGK is and what it is used for  
2. What you need to know before you take Pretomanid FGK 
3. How to take Pretomanid FGK 
4. Possible side effects  
5. How to store Pretomanid FGK  
6. Contents of the pack and other information 
 
 
1. What Pretomanid FGK is and what it is used for 
 
Pretomanid FGK contains the active substance pretomanid, a type of antibiotic. Antibiotics are 
medicines used to kill bacteria that cause diseases. 
 
Pretomanid FGK is used in combination with two other medicines called linezolid and bedaquiline to 
treat tuberculosis that affects the lungs, when the disease has become resistant to many other 
antibiotics: 
• extensively drug resistant tuberculosis or 
• treatment-intolerant or multidrug-resistant tuberculosis 
It is used in adults 18 years and over. 
 
 
2. What you need to know before you take Pretomanid FGK 
 
Do not take Pretomanid FGK 
 
• if you are allergic to pretomanid, antibiotics of the group called nitroimidazoles, or any of the 

other ingredients of this medicine (listed in section 6) 
 
Since pretomanid must be used in combination with other medicines against tuberculosis – linezolid 
and bedaquiline – please make sure that you read the “Do not take” section of the package leaflets for 
these medicines as well. If you are unsure of any information in the package leaflets, please contact 
your doctor or pharmacist. 
 

28 



Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before taking Pretomanid FGK if you: 
• have reduced liver function  
• drink alcohol on a regular basis 
• have reduced kidney function 
• have or have had disturbances of the heart rhythm, or if someone in your family has a heart 

rhythm problem 
• have heart failure 
• have or have had an underactive thyroid 
• have reduced blood levels of calcium, magnesium or potassium 
 
Liver damage 
There is a risk of liver damage when you are treated with Pretomanid FGK, linezolid and bedaquiline. 
Your doctor will therefore monitor you for signs of liver damage and take blood samples before the 
start of treatment and regularly during treatment. 
Tell your doctor if you experience symptoms such as: 
• fatigue 
• lack or loss of appetite 
• nausea 
• yellowing of the skin and eyes 
• dark urine 
• abdominal pain 
The doctor will adjust your treatment if your liver is affected. 
 
Reduced number of blood cells 
Treatment with Pretomanid FGK, linezolid and bedaquiline can severely reduce the number of blood 
cells, such as blood platelets, red blood cells and white blood cells called neutrophils. Contact your 
doctor immediately about any signs of bruising, bleeding or infections. 
Your doctor will monitor complete blood counts before the start of treatment and regularly during 
treatment. The doctor will adjust your treatment if your blood cell count is reduced. 
 
Nerve disorders in hands, feet or eyes 
Nerve disorders in hands, feet or eyes may occur during treatment. Contact your doctor if you have 
visual problems, or numbness, tingling or burning in your hands or feet during treatment. Your doctor 
will adjust your treatment in these cases. If visual problems occur contact a doctor for a prompt eye 
examination. 
 
Increased blood level of lactic acid 
A disorder of blood over-acidification called lactic acidosis may occur during treatment. Contact your 
doctor if you have recurrent nausea or vomiting. Your doctor may adjust your treatment in these cases. 
 
Heart problems 
A certain heartbeat abnormality known as QT prolongation may occur during treatment. Your doctor 
will therefore perform an ECG before the start of treatment and regularly during treatment. Your 
treatment will be adjusted if heartbeat abnormalities occur. In addition, potassium, calcium and 
magnesium levels will be monitored and corrected if abnormal. 
 
The safety and efficacy of Pretomanid FGK has not been studied in combination with medicines other 
than linezolid and bedaquiline and therefore it should not be used as part of any other treatment 
combination. 
 
Children and adolescents 
 
This medicine is not recommended for children and adolescents under 18 years. This is because it has 
not been studied in this age group. 

29 



 
Other medicines and Pretomanid FGK 
 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines, including herbal therapies. These may affect the way Pretomanid FGK works or increase 
the risk of side effects. 
 
Avoid treatment with Pretomanid FGK and any of the following medicines at the same time. These 
may lower the effect of Pretomanid FGK so your treatment may not work; therefore, inform your 
doctor immediately about these: 
• rifampicin, rifamycin, rifapentine, rifabutin: other medicines to treat tuberculosis or certain 

other infections 
• efavirenz, etravirine: medicines to treat HIV infection 
• carbamazipine, phenytoin: medicines to treat epilepsy and certain pain conditions 
• St John’s wort: a herbal medicine to treat depression and anxiety 
 
You should also avoid the use of medicines that may have a damaging effect on your liver (other than 
bedaquiline and linezolid). Talk to you doctor who will be able to tell you which medicines this 
applies to. 
  
Inform your doctor if you are using: 
• methotrexate: a medicine to treat severe joint inflammation, cancer and the skin disease 

psoriasis 
• benzylpenicillin, ciprofloxacin: medicines to treat bacterial infections 
• indomethacin: a medicine to treat pain and inflammation 
• ritonavir: a medicine to treat HIV infection 
 
Pretomanid FGK with alcohol 
 
Avoid drinking alcohol while being treated with Pretomanid FGK since this increases the risk of 
serious liver damage. 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
• Pregnancy 

Very limited knowledge exists about the use of Pretomanid FGK during pregnancy. Therefore, 
Pretomanid FGK is used during pregnancy only if the benefit to the patient outweighs the 
potential risk to the foetus. Your doctor will decide whether you should be treated with 
Pretomanid FGK. 

• Breast-feeding 
It is not known if pretomanid is passed into human milk. Your doctor has to decide if you 
should discontinue breast-feeding or avoid treatment with Pretomanid FGK.  

 
Driving and using machines 
 
You may feel dizzy after taking Pretomanid FGK or you may experience problems with your vision. 
Do not drive or operate machinery if this happens. 
 

30 



Pretomanid FGK contains lactose and sodium 
 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-
free’. 
 
 
3. How to take Pretomanid FGK 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
Pretomanid FGK is used in combination with linezolid and bedaquiline. Please also read the package 
leaflets from these medicines. If you have any questions ask your doctor or pharmacist. 
 
The recommended dose is  
• Pretomanid FGK: 1 tablet once daily 
• linezolid: 1,200 mg daily 
• bedaquiline: 400 mg once daily for 2 weeks, followed by 200 mg 3 times per week (with at least 

48 hours between doses). For example you may take bedaquiline on Monday, Wednesday and 
Friday every week from week 3 onwards. 

 
Method of use 
Take Pretomanid FGK at the same time as linezolid and bedaquiline. Swallow the tablets with a glass 
of water and take them with food. 
The tablets are taken under direct observation of a healthcare professional or in accordance with local 
practice.  
 
Duration of use 
The duration of treatment with the combination Pretomanid FGK, linezolid and bedaquiline is 
26 weeks. Your doctor may decide to expand this period or to interrupt dosing to ensure that the 
treatment is safe and effective for you. 
 
If you take more Pretomanid FGK than you should 
 
Contact your doctor straight away and take the medicine pack with you. 
 
If you forget to take Pretomanid FGK 
 
Do not take a double dose to make up for a forgotten dose. 
 
Any missed dose of pretomanid and bedaquiline is recommended to be made up at the end of 
treatment. Doses of linezolid missed due to linezolid adverse reactions are not recommended to be 
made up. Talk to your doctor or pharmacist if you have missed a dose and you are not sure what to do. 
 
If you stop taking Pretomanid FGK 
 
Do not stop taking Pretomanid FGK or its combination medicines linezolid or bedaquiline without 
your doctor’s permission. Skipping doses or not completing the full course of therapy may make 
treatment ineffective and your tuberculosis could get worse. In addition, this would increase the chance 
that bacteria become resistant to these medicines. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 

31 



4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
When Pretomanid FGK is used together with linezolid and bedaquiline the following side effects have 
been reported: 
 
Contact your doctor immediately if you experience any of the following: 
Very common (may affect more than 1 in 10 people) 
• reduced number of red blood cells 

Possible signs are feeling tired, weakness, shortness of breath, loss of consciousness and 
increased thirst. 

• increased blood levels of liver enzymes called 
- gamma GT (indicating how well your liver is working) 
- transaminase such as ALT, AST 
Tell your doctor if you experience symptoms such as fatigue, lack or loss of appetite, nausea, 
yellowing of the skin and eyes, dark urine or abdominal pain. 

 
Common (may affect up to 1 in 10 people) 
• reduced number of white blood cells or platelets 

Possible signs are bruising, bleeding or infections. 
• increased blood level of lactic acid 

Contact your doctor if you have recurrent nausea or vomiting. 
 
Other side effects may occur with following frequencies: 
Very common (may affect more than 1 in 10 people) 
• headache 
• nausea, vomiting, indigestion 
• abdominal pain 
• acne, itching skin, rash 
• decreased appetite 
• nerve problems in the hands or feet, such as pain, burning, abnormal sensation or numbness 
• muscle and skeleton pain, such as joint pain, back pain, muscle pain 
• increased blood levels: 

- amylase 
- a liver enzyme called gamma GT (indicating how well your liver is working) 
- liver enzymes called transaminase such as ALT, AST 

 
Common (may affect up to 1 in 10 people) 
• sleeping difficulties 
• weakness, fatigue 
• taste disturbance 
• dizziness 
• muscle spasm 
• diarrhoea, constipation 
• inflammation of stomach lining, pancreas inflammation 
• reflux of stomach juices in the oesophagus 
• hair loss, dry skin 
• irritation or pain of the eye, vision problems 
• optic nerve damage and/or inflammation with swellings and visual disturbances 
• abnormal electrical activity of the heart (prolonged electrocardiogram QT interval) 
• increased blood levels: 

- bilirubin, which is the yellow breakdown substance of the blood pigment 
- lipase 
- alkaline phosphatase 
- creatine phosphokinase 

32 



- urea 
• decreased blood sugar level 
 
Uncommon (may affect up to 1 in 100 people) 
• fungal (including candida yeast fungi) infection in the mouth or throat, which appears as white 

patches 
• fungal infection 
• too much fluid loss, reduced body fluid volume 
• anxiety, depression 
• enlarged liver 
• yellowing of the skin, internal organs and/or the whites of the eyes (jaundice) 
• eye lens disorder, dry eye 
• worsening ability to focus clearly on close objects  
• eye itching, eye swelling 
• optic disc swelling (leading to loss of vision) 
• deafness 
• feeling of increased heartbeat 
• increased heartbeat 
• low blood pressure 
• cough, nosebleed 
• feeling bloated 
• burning tongue, enlargement of the small, nipple-like structures on the upper surface of the 

tongue 
• eczema, excessive skin pigmentation 
• muscles and skeleton stiffness 
• inability to have or maintain an erection 
• womb bleeding at irregular intervals, particularly between the expected menstrual periods 
• feeling unwell 
• abnormal presence of the protein albumin in the urine 
• vomiting blood 
• acidity of the blood 
• decreased elimination of the muscle tissue breakdown product creatinine through kidneys 
• lack of white and red blood cells, and blood platelets 
• decreased blood levels: 

- calcium 
- magnesium 

• increased blood levels: 
- creatinine and creatine phosphokinase 
- uric acid 

 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Pretomanid FGK 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton, bottle or blister after 
“EXP”. The expiry date refers to the last day of that month. 
 

33 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


This medicine does not require any special temperature storage conditions. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
6. Contents of the pack and other information 
 
What Pretomanid FGK contains 
 
• The active substance is pretomanid. Each tablet contains 200 mg pretomanid. 
• The other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch 

glycolate, magnesium stearate, silica colloidal, sodium lauryl sulphate, povidone. 
 
What Pretomanid FGK looks like and contents of the pack 
 
Pretomanid FGK is a white to off-white oval tablet with “M” debossed on one side and “P200” on the 
other side. Tablet dimensions: 18 × 9 mm. 
 
The tablets are provided in: 
Blister packs containing 14, 14 × 1, 182 or 182 × 1 tablets 
Plastic bottles containing 26 tablets 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
 
FGK Representative Service GmbH 
Heimeranstrasse 35 
80339 Munich 
Germany 
 
Manufacturer 
 
Mylan Hungary Kft.  
H-2900, Komárom 
Mylan utca 1 
Hungary 
 
Generics [UK] Limited 
Station Close, Potters Bar 
Hertfordshire, EN6 1TL 
United Kingdom 
 
Mylan UK Healthcare Ltd 
Building 20, Station Close 
Potters Bar, EN6 1TL 
United Kingdom 
 
This leaflet was last revised in {MM/YYYY} 
 
This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 
 

34 



Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu  

35 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex IV 

 
Conclusions on the granting of the conditional marketing authorisation presented by the 

European Medicines Agency 
 

 

36 



Conclusions presented by the European Medicines Agency on: 
 
• Conditional marketing authorisation 
 
The CHMP having considered the application is of the opinion that the risk-benefit balance is 
favourable to recommend the granting of the conditional marketing authorisation as further 
explained in the European Public Assessment Report. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET
	Conclusions on the granting of the conditional marketing authorisation presented by the European Medicines Agency