Pretomanid macleods

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRETOMANID MACLEODS

Composition:

Active substance: pretomanid;

One tablet contains 200 mg of pretomanid;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); povidone; sodium lauryl sulfate; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: oval-shaped tablets, white to almost white, biconvex, uncoated, with "K31" embossed on one side and smooth on the other.

Pharmacotherapeutic group. Antimycobacterial agents for systemic use. Other drugs for the treatment of tuberculosis. Pretomanid. ATC code J04AK08.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Pretomanid is a nitroimidazooxazine antimycobacterial agent. Pretomanid kills actively replicating M. tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking bacterial cell wall formation. Under anaerobic conditions, pretomanid acts against non-replicating bacteria as a respiratory poison following the release of nitric oxide. All these actions require nitroreduction of pretomanid within the mycobacterial cell by deazaflavin-dependent nitroreductase Ddn, which depends on the reduced form of the cofactor F420. Reduction of F420 is mediated by F420-dependent glucose-6-phosphate dehydrogenase, Fgd1.

Resistance

Mutations in five M. tuberculosis genes (ddn, fgd1, fbiA, fbiB, and fbiC) are associated with resistance to pretomanid. The products of these genes are involved in the bioreductive activation of pretomanid within the bacterial cell. Not all isolates with elevated minimum inhibitory concentration (MIC) have mutations in these genes, suggesting the existence of at least one additional resistance mechanism. The frequency of development of resistance to pretomanid in vitro ranged from 10⁻⁷ to 10⁻⁵ at 2- to 6-fold exceedance of pretomanid MIC. Cross-resistance between pretomanid and other compounds of the same class has been observed.

Antimicrobial Activity

Pretomanid demonstrated in vitro activity against M. tuberculosis strains. Pretomanid also showed activity against M. tuberculosis in animal models of tuberculosis. In murine models of tuberculosis, the combination of three drugs—pretomanid, bedaquiline, and linezolid—resulted in a significant reduction in bacterial load in the lungs and a lower relapse rate at 2 and 3 months after treatment, compared to combinations of two of these agents.

In clinical trial 1, the MIC of pretomanid was determined using the Mycobacteria Growth Indicator Tube (MGIT) system. The baseline MIC of pretomanid for M. tuberculosis isolates in the trial ranged from 0.06 to 1 µg/mL.

Pharmacokinetics

The area under the plasma concentration-time curve (AUC) and maximum concentration (C_max) of pretomanid were approximately dose-proportional over the range of single oral doses from 50 mg (0.25 times the approved recommended dose) to 200 mg (the approved recommended dose). At single doses above 200 mg up to 1000 mg (5 times the approved recommended dose), AUC and C_max increased less than proportionally with dose. Steady-state plasma concentrations of pretomanid were reached approximately 4–6 days after multiple dosing of 200 mg, with an accumulation ratio of approximately 2. Pharmacokinetic parameters after single and multiple doses of 200 mg pretomanid in healthy adult volunteers are presented in Table 1.

Table 1

Mean pharmacokinetic parameters of pretomanid in healthy adult volunteers under fasting and fed conditions

Pharmacokinetic parameter	Single 200 mg dose administered fasting	Single 200 mg dose administered after food intake	Steady-state 200 mg once daily administered fasting
Cmax (μg/mL)	1.1 (0.2)	2.0 (0.3)	1.7 (0.3)
AUCt (μg•h/mL)	† 28.1 (8.0)	† 51.6 (10.1)	§30.2 (3.7)
AUCinf (μg•h/mL)	28.8 (8.3)	53.0 (10.6)	NR
*Tmax (h)	4.0 (2.0, 6.0)	5.0 (3.0, 8.1)	4.5 (2.0, 8.0)
Vd/F (L)	180 (51.3)	97.0 (17.2)	NR
CL/F (L/h)	7.6 (2.5)	3.9 (0.8)	NR
t½ (h)	16.9 (3.1)	17.4 (2.8)	16.0 (1.6)

* Median (minimum, maximum); † AUC96 h; § AUC24 h; NR – not reported.

Absorption

Administration of a dose of pretomanid tablets for oral use with a high-calorie, high-fat meal (approximately 150, 250, and 500–600 calories from protein, carbohydrates, and fat, respectively) increased mean Cmax by 76% and mean AUCinf by 88% compared to fasting conditions.

Distribution

Plasma protein binding of pretomanid is approximately 86.4%.

Metabolism

Pretomanid is metabolized via several reductive and oxidative pathways, with no single pathway considered predominant. In vitro studies using recombinant CYP3A4 have shown that this enzyme accounts for approximately 20% of pretomanid metabolism.

Elimination

Table 1 presents calculated values of apparent oral clearance and elimination half-life of pretomanid.

In healthy adult males who received a single oral dose of 1100 mg radiolabeled 14C-pretomanid, on average, 53% (3.4%) of the radioactive dose was excreted in urine and 38% (2.7%) in feces, predominantly as metabolites, with approximately 1% of the radioactive dose excreted unchanged in urine.

Special Populations

No clinically significant differences in pretomanid pharmacokinetics were observed based on sex, body weight, race (non-Black, White, Asian), pulmonary tuberculosis status (resistant to isoniazid, rifamycins, fluoroquinolones, and second-line injectable antibacterial agents, or resistant to isoniazid and rifampicin with intolerance or non-responsiveness to standard therapy), or HIV status. The effect of renal or hepatic impairment on pretomanid pharmacokinetics is unknown.

Clinical trials of combination therapy with pretomanid tablets, bedaquiline, and linezolid did not include a sufficient number of patients aged 65 years and older to determine whether their response to treatment differs from younger patients.

Drug Interaction Studies

Efavirenz. Concomitant administration of 200 mg pretomanid once daily and 600 mg efavirenz once daily for 7 days resulted in a 35% decrease in mean AUC and a 28% decrease in Cmax of pretomanid. Mean AUC and Cmax values of efavirenz remained unchanged when coadministered with pretomanid.

Lopinavir/ritonavir. Concomitant administration of 200 mg pretomanid once daily and 400/100 mg lopinavir/ritonavir twice daily for 7 days resulted in a 17% decrease in mean AUC and a 13% decrease in Cmax of pretomanid. Mean AUC and Cmax values of lopinavir decreased by 14% and 17%, respectively, when administered with pretomanid.

Rifampin. Concomitant administration of 200 mg pretomanid once daily and 600 mg rifampin once daily for 7 days resulted in a 66% decrease in mean AUC and a 53% decrease in Cmax of pretomanid.

Midazolam. Concomitant administration of 400 mg pretomanid once daily (twice the approved recommended dose) for 14 days and a single 2 mg oral dose of midazolam on day 14 resulted in a 15% decrease in midazolam AUC and a 16% decrease in Cmax, and a 14% increase in AUC and a 5% increase in Cmax of 1-hydroxymidazolam.

In vitro studies without additional clinical evaluation of potential drug interactions

Cytochrome P450 (CYP) enzymes. CYP3A4 is involved in pretomanid metabolism (up to 20%). Pretomanid is not a substrate of CYP2C9, CYP2C19, or CYP2D6. Pretomanid is not an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations based on in vitro data. Pretomanid is not an inducer of CYP2C9 or CYP3A4.

Transporters. In vitro studies have shown that pretomanid strongly inhibits the drug transporter OAT3, which may lead to increased concentrations of drugs that are OAT3 substrates at clinically relevant concentrations of pretomanid. Drug interaction studies with OAT3 substrates have not been conducted.

In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of transporters BCRP, OATP1B3, and P-gp. The effect of concomitant administration of pretomanid on the pharmacokinetics of BCRP, OATP1B3, and P-gp substrates in humans is unknown.

In vitro studies have shown that pretomanid does not inhibit OAT1, OCT1, OCT2, OAT1B1, OATP1B3, BCRP, BSEP, P-gp, MATE1, and/or MATE2-K-mediated transport in humans at clinically relevant concentrations of pretomanid. Pretomanid is not a substrate of OAT1, OAT3, OCT2, OAT1B1, OATP1B3, MATE1, MATE2-K, BCRP, and/or P-gp transporters.

Clinical characteristics.

Indications.

The medicinal product Pretomanid Macleods is indicated in combination with bedaquiline and linezolid for the treatment of adult patients with pulmonary tuberculosis resistant to isoniazid, rifamycins, fluoroquinolones, and injectable second-line antibacterial agents, or adult patients with pulmonary tuberculosis resistant to isoniazid and rifampicin, in whom standard therapy is not tolerated or has proven ineffective.

Limitations of use

Pretomanid is not indicated for patients with the following conditions:

• Drug-susceptible (DS) tuberculosis;
• Latent infection caused by Mycobacterium tuberculosis;
• Extrapulmonary infection caused by Mycobacterium tuberculosis;
• Tuberculosis resistant to isoniazid and rifampicin without documented intolerance or ineffectiveness of standard therapy;
• Tuberculosis with known resistance to any component of the combination regimen.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Contraindications associated with the use of bedaquiline and linezolid (see prescribing information for bedaquiline and linezolid), since pretomanid is administered only in combination with these medicinal products.

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on pretomanid

Inducers of CYP3A4

Pretomanid is partially metabolized by CYP3A4. Consequently, pretomanid exposure may be reduced when co-administered with CYP3A4 inducers. In multiple-dose interaction studies, co-administration of pretomanid with multiple doses of rifampicin or efavirenz resulted in a 66% or 35% reduction in pretomanid AUC0–24 h, respectively. Due to the potential for reduced therapeutic effect of pretomanid resulting from decreased systemic exposure, concomitant use of pretomanid with moderate or strong CYP3A4 inducers (e.g., efavirenz, etravirine, rifamycins including rifampicin, rifapentine, and rifabutin, carbamazepine, phenytoin, systemic St John’s wort (Hypericum perforatum)) should be avoided (see section "Special precautions for use").

In a multiple-dose interaction study of pretomanid and lopinavir boosted with ritonavir, pretomanid AUC0–24 h decreased by 17%.

Concomitant use of bedaquiline with moderate or strong CYP3A4 inhibitors may increase systemic exposure to bedaquiline, potentially increasing the risk of adverse reactions. Therefore, the combination of bedaquiline with moderate or strong CYP3A4 inhibitors for systemic use should be avoided for more than 14 consecutive days. If concomitant use is required, more frequent ECG monitoring and liver transaminase monitoring are recommended.

Lopinavir/ritonavir

Concomitant administration of pretomanid with lopinavir/ritonavir did not affect plasma concentrations of pretomanid. Lopinavir/ritonavir may be co-administered in a combination regimen with pretomanid, bedaquiline, and linezolid.

Effect of pretomanid on other medicinal products

Midazolam

Concomitant administration of pretomanid with midazolam, a CYP3A4 substrate, did not result in a clinically significant effect on the pharmacokinetics of midazolam or its main metabolite, 1-hydroxymidazolam. Combination therapy with pretomanid, bedaquiline, and linezolid may be administered concomitantly with medicinal products that are CYP3A4 substrates.

Organic anion transporter-3 (OAT3), BCRP, OATP1B3, and P-gp substrates

The effect of concomitant pretomanid administration on the pharmacokinetics of OAT3 substrates in humans is unknown. However, in vitro studies have shown that pretomanid strongly inhibits the drug transporter OAT3, which may lead to increased clinical concentrations of medicinal products that are OAT3 substrates and may increase the risk of adverse reactions to these medicinal products. When Pretomanid Macleods is used concomitantly with medicinal products that are OAT3 substrates (e.g., methotrexate, benzylpenicillin, indomethacin, ciprofloxacin), adverse reactions associated with OAT3 substrate drugs should be monitored, and dosage reduction of such agents should be considered if necessary.

In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of BCRP, OATP1B3, and P-gp. Clinical studies on these interactions have not been conducted. Therefore, it cannot be excluded that concomitant administration of pretomanid with sensitive OATP1B3 substrates (e.g., valsartan, statins), BCRP substrates (e.g., rosuvastatin, prazosin, glyburide, sulfasalazine), or P-gp substrates (e.g., digoxin, dabigatran etexilate, verapamil) may increase their effects. Enhanced monitoring for adverse reactions associated with the co-administered medicinal product is recommended when pretomanid is used concomitantly with OATP1B3, BCRP, or P-gp substrates.

CYP2C8, CYP2C9, and CYP2C19 substrates

In vitro studies indicate that pretomanid is an inducer of CYP2C8, while studies on the potential of pretomanid to induce CYP2C9 and CYP2C19 are inconclusive. In vivo induction cannot be excluded, as clinical studies have not been performed. If pretomanid is administered concomitantly with substrates of CYP2C8, CYP2C9, and CYP2C19, such as paclitaxel, warfarin, mephenytoin, physicians and their patients should monitor for potential reduction in efficacy of these substrates.

Special precautions for use.

Risks associated with the combination treatment regimen

Pretomanid Macleods is indicated for use as part of a combination regimen with bedaquiline and linezolid. Refer to the prescribing information for bedaquiline and linezolid for additional information on risks. Warnings and precautions associated with bedaquiline and linezolid also apply to their use in combination with Pretomanid Macleods.

Hepatotoxicity

Hepatic adverse reactions have been reported during combination treatment with pretomanid, bedaquiline, and linezolid. Alcohol consumption and the use of hepatotoxic agents, including herbal supplements and other medicinal products, should be avoided during treatment with Pretomanid Macleods, especially in patients with hepatic impairment. Monitor for symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, hepatic tenderness, and hepatomegaly) and laboratory parameters (ALT, AST, alkaline phosphatase, and bilirubin) at least at baseline, after two weeks, and then monthly during treatment, and as clinically indicated. If signs of developing or worsening hepatic dysfunction occur, investigate for viral hepatitis and discontinue other hepatotoxic medications.

Treatment with the entire combination regimen should be interrupted if:

• elevation of aminotransferase is accompanied by an increase in total bilirubin more than twice the upper limit of normal (ULN);
• aminotransferase levels exceed 8 times the ULN;
• aminotransferase levels exceed 5 times the UL, persisting for more than 2 weeks.

Treatment may be resumed under close monitoring once liver enzymes and clinical symptoms have normalized.

Modification/interruption due to linezolid-related adverse reactions

Modification or interruption of linezolid may be necessary during the course of therapy to manage known linezolid toxicity. The recommendations below reflect procedures used in the Nix-TB study.

Myelosuppression

Myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) has been reported during combination treatment with pretomanid, bedaquiline, and linezolid. Myelosuppression is a known adverse reaction of linezolid. Anemia may be life-threatening. Hematological abnormalities observed during combination treatment with pretomanid, bedaquiline, and linezolid were reversible upon dose reduction, interruption, or permanent discontinuation of linezolid. Complete blood counts should be monitored at baseline, after two weeks, and then monthly in patients receiving linezolid as part of the combination regimen of pretomanid, bedaquiline, and linezolid. Consideration should be given to reducing or discontinuing linezolid in patients who develop or experience worsening myelosuppression (see section "Dosage and administration").

Peripheral and optic neuropathy

Peripheral neuropathy and optic neuropathy have been reported during combination treatment with pretomanid, bedaquiline, and linezolid. Neuropathy is a known adverse reaction associated with prolonged use of linezolid. Neuropathy related to linezolid is usually reversible or improves with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid. Visual function should be monitored in all patients receiving the combination regimen of pretomanid, bedaquiline, and linezolid. If visual disturbances occur, linezolid should be discontinued and an urgent ophthalmological evaluation performed to assess for signs of optic neuropathy.

QT interval prolongation

QT interval prolongation has been reported during combination treatment with pretomanid, bedaquiline, and linezolid. QT prolongation is a known adverse reaction of bedaquiline. The combination of bedaquiline with pretomanid has been shown to result in greater QT prolongation than expected with bedaquiline alone. However, the contribution of pretomanid to this effect has not been fully characterized.

An ECG should be performed before starting treatment and at least monthly during combination treatment with pretomanid, bedaquiline, and linezolid. Baseline serum potassium, calcium, and magnesium levels should be checked and corrected if outside the normal range. If QT prolongation is detected, ongoing electrolyte monitoring is required. The following conditions may increase the risk of QT prolongation:

• history of torsade de pointes ventricular tachycardia;
• personal or family history of congenital long QT syndrome;
• history of or current hypothyroidism;
• existing bradyarrhythmia;
• heart failure or structural heart disease;
• QT interval corrected by Fridericia’s formula (QTcF) > 450 ms (confirmed by repeat ECG);
• serum calcium, magnesium, or potassium levels below the lower limit of normal.

The combination regimen of pretomanid, bedaquiline, and linezolid should be discontinued if the patient develops a clinically significant ventricular arrhythmia or if the QTcF interval exceeds 500 ms (confirmed by repeat ECG). If syncope occurs, an ECG should be performed to assess for QT prolongation.

The risk of QT prolongation with the combination regimen has not been established at exposures higher than therapeutic levels. The risk may increase if systemic exposure to pretomanid is elevated.

CYP3A4 inducers

Pretomanid may be partially metabolized by CYP3A4 (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of strong or moderate CYP3A4 inducers such as rifampicin or efavirenz should be avoided during treatment with Pretomanid Macleods.

Effect on reproductive function

Pretomanid caused testicular atrophy and impaired fertility in male rats. Patients should be informed about the reproductive toxicity observed in animal studies and that the potential impact on male fertility has not been adequately evaluated.

Lactic acidosis

Lactic acidosis has been reported during combination treatment with pretomanid, bedaquiline, and linezolid. Lactic acidosis is a known adverse reaction of linezolid. Patients who develop recurrent nausea or vomiting should undergo immediate medical evaluation, including measurement of bicarbonate and lactate levels, and consideration should be given to interrupting linezolid or the entire combination regimen. Linezolid may be restarted at a lower dose under close monitoring once signs and symptoms of lactic acidosis have resolved.

Excipients

Pretomanid Macleods contains lactose. Patients with known sugar intolerances should consult their physician before taking this medicinal product.

Pretomanid Macleods contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of pretomanid, bedaquiline, and linezolid in pregnant women are very limited. Animal studies with pretomanid and bedaquiline did not reveal direct or indirect harmful effects on embryofetal development. Animal studies with linezolid demonstrated reproductive toxicity. A potential risk to humans exists.

Pretomanid in combination with bedaquiline and linezolid may be used during pregnancy only if the expected benefit to the patient outweighs the potential risk to the fetus.

Breastfeeding

There is no information on the presence of pretomanid in human milk or its effects on milk production or the breastfed infant. Pretomanid has been detected in the milk of lactating rats. If the drug is present in animal milk, it is highly likely to be present in human milk.

Animal studies with linezolid have shown that linezolid and its metabolites may be excreted into breast milk.

It is unknown whether bedaquiline or its metabolites pass into human breast milk.

A risk to breastfed infants cannot be excluded. A decision on whether to discontinue breastfeeding or to discontinue pretomanid therapy should be made, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

Reduced fertility and/or testicular toxicity were observed in male rats and mice administered pretomanid orally. These effects were associated with hormonal changes, including decreased serum inhibin levels and increased serum follicle-stimulating and luteinizing hormone levels in rodents.

At present, the possibility of reduced fertility and testicular toxicity in men cannot be definitively excluded.

Ability to influence the ability to drive and use machines

No studies on the effects of the medicinal product on the ability to drive and operate machinery have been conducted.

Pretomanid may have a minor influence on the ability to drive a car or operate machinery. Dizziness has been reported in some patients treated with Pretomanid Macleods, and visual disturbances have been observed in some patients. This should be taken into account when assessing a patient's ability to drive or operate machinery.

Method of Administration and Dosage

Treatment with pretomanid should be initiated and supervised by a physician experienced in the management of tuberculosis.

The medicinal product Pretomanid Macleods should be administered in combination with bedaquiline and linezolid. Patients must be advised of the importance of completing the full course of treatment.

The combination regimen of pretomanid, bedaquiline, and linezolid should be administered as Directly Observed Therapy (DOT).

The recommended dosage and duration of bedaquiline and linezolid when used in combination with pretomanid are as follows:

• Pretomanid: 200 mg orally (1 tablet of 200 mg) once daily for 26 weeks; the tablet should be swallowed whole with water;
• Bedaquiline: 400 mg orally once daily for 2 weeks, followed by 200 mg three times per week with at least 48 hours between doses for 24 weeks, for a total duration of 26 weeks;
• Linezolid: initiate at a dose of 1200 mg orally daily for 26 weeks, followed by dose reduction to 600 mg daily, and further reduction to 300 mg daily or discontinuation as needed in the event of known linezolid adverse reactions—myelosuppression, peripheral neuropathy, and optic neuropathy (see section "Special Warnings and Precautions for Use").

The combination treatment regimen should be taken with food.

If the physician interrupts the combination regimen for safety reasons, missed doses may be made up at the end of the treatment period; however, doses of linezolid missed due to adverse reactions to linezolid should not be compensated.

The combination of pretomanid, bedaquiline, and linezolid may be extended beyond 26 weeks if clinically indicated.

Pre-treatment Evaluation before Starting Combination Therapy with Pretomanid, Bedaquiline, and Linezolid

Assess symptoms and signs of liver disease (such as fatigue, anorexia, nausea, jaundice, dark urine, hepatic tenderness, and hepatomegaly). Laboratory tests should be performed (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin).

A complete blood count should also be performed. Serum potassium, calcium, and magnesium levels should be determined and corrected if outside the normal range. An ECG should be performed prior to initiating treatment.

Discontinuation of Treatment

If administration of bedaquiline or Pretomanid Macleods is discontinued, the entire combination regimen should be stopped.

If linezolid is permanently discontinued during the first four consecutive weeks of treatment, bedaquiline and pretomanid should also be discontinued. If linezolid is discontinued after completion of the first four weeks of continuous treatment, bedaquiline and Pretomanid Macleods should be continued.

Elderly Patients

Clinical trials of the combination regimen of pretomanid, bedaquiline, and linezolid did not include a sufficient number of patients aged 65 years and older to determine whether they respond differently from younger patients.

Hepatic Impairment

The effect of hepatic impairment on the safety, efficacy, and pharmacokinetics of pretomanid is unknown (see section "Special Warnings and Precautions for Use").

Renal Impairment

The effect of renal impairment on the safety, efficacy, and pharmacokinetics of pretomanid is unknown. Use in patients with renal function impairment is not recommended.

Children

The safety and efficacy of Pretomanid Macleods tablets in children have not been established.

Overdose

There is no experience with the treatment of acute pretomanid overdose. In case of accidental or intentional overdose, general supportive measures should be implemented to maintain vital functions, including monitoring of vital signs and ECG (QT interval).

Adverse reactions

The most common adverse reactions during treatment with pretomanid in combination with bedaquiline and linezolid were nausea (36%), vomiting (28%), and increased transaminase levels (21%).

Peripheral neuropathy and anemia were observed in 81% and 37% of patients, respectively, which are known adverse reactions associated with linezolid. Nausea, vomiting, and elevated transaminase levels are potential adverse reactions to all three medicinal products included in the treatment regimen. Refer to the prescribing information for bedaquiline and linezolid for detailed information on adverse reactions associated with these two medicinal products.

Adverse drug reactions reported in an uncontrolled Phase III trial involving 109 patients receiving pretomanid in combination with bedaquiline and linezolid are summarized in Table 2 by system organ class and frequency of occurrence. Adverse reactions considered related to linezolid are marked with Δ.

Table 2

Adverse reactions of pretomanid when administered in combination with bedaquiline and linezolid

System organ class	Very common (≥ 1/10)	Common (≥ 1/100 – < 1/10)	Uncommon (≥ 1/1000 – < 1/100)
Infections and infestations			Fungal infection, oral candidiasis, fungal infection of oral cavity
Blood and lymphatic system disorders	Anaemia Δ	Leukopenia Δ, neutropenia Δ, thrombocytopenia Δ	Lymphocytopenia Δ, pancytopenia Δ
Metabolism and nutrition disorders	Decreased appetite	Hypoglycaemia, lactic acidosis Δ	Acidosis Δ, dehydration, hypocalcaemia, hypovolemia, hypomagnesaemia
Psychiatric disorders		Insomnia	Anxiety, depression
Nervous system disorders	Peripheral neuropathy*Δ, headache	Dysgeusia, dizziness
Eye disorders		Visual disturbance*, eye irritation, eye pain, optic neuropathy*Δ	Lens disorders, dry eyes, eye pruritus, eye swelling, optic disc edema, presbyopia
Ear and labyrinth disorders			Deafness
Cardiac disorders			Palpitations, sinus tachycardia
Vascular disorders			Arterial hypotension
Respiratory, thoracic and mediastinal disorders			Cough, nosebleeds
Gastrointestinal disorders	Nausea, vomiting, dyspepsia, abdominal pain	Gastritis*, diarrhoea, constipation, gastroesophageal reflux disease, pancreatitis*	Flatulence, glossodynia, vomiting of blood
Hepatobiliary disorders	Increased transaminase levels*	Hyperbilirubinaemia	Hepatomegaly, jaundice
Skin and subcutaneous tissue disorders	Acne*, pruritus*, rash*	Skin dryness, alopecia	Allergic dermatitis, skin hyperpigmentation
Musculoskeletal and connective tissue disorders	Musculoskeletal pain	Muscle spasms	Musculoskeletal stiffness
Reproductive system and breast disorders			Erectile dysfunction, metrorrhagia
General disorders and administration site conditions		Fatigue, asthenia	Malaise
Investigations	Increased gamma-glutamyltransferase levels, increased amylase levels*	QT interval prolongation on ECG, increased blood alkaline phosphatase levels, increased blood creatine phosphokinase levels, increased blood urea levels, increased lipase levels*	Presence of albumin in urine, increased blood creatinine levels, increased MB fraction of creatine phosphokinase in blood, increased blood uric acid levels, decreased creatinine renal clearance

* Selected terms are grouped as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, peripheral neuropathy, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy); gastritis (gastritis, chronic gastritis); acne (acne, acne dermatitis); anemia (anemia); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity); increased transaminases (increased ALT, increased AST, drug-induced liver injury, increased liver enzyme levels, liver function disorder, increased liver function parameters, increased transaminases); rash (rash, erythematous rash, maculopapular rash, papular rash, vesicular rash); pruritus (pruritus, generalized pruritus, pruritic rash); abdominal pain (abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness); lower respiratory tract infections (bronchitis, influenza, lower respiratory tract infections, pneumonia); hyperamylasemia (increased amylase level, hyperamylasemia); cough (cough, productive cough); visual disturbance (blurred vision, decreased visual acuity, visual disturbance); neutropenia (neutropenia); hypertension (increased blood pressure, hypertension); hyperlipasemia (hyperlipasemia, increased lipase level); thrombocytopenia (thrombocytopenia); optic neuropathy (optic neuropathy, optic neuritis); pancreatitis (pancreatitis, hemorrhagic pancreatitis).

Table 3

Laboratory abnormalities

Exceeding the upper limit of normal (ULN) (ULN)	Combination treatment with pretomanid, bedaquiline, and linezolid (N = 109) n (%)
Transaminases and bilirubin
Alanine aminotransferase (ALT)
3 to ≤ 5 × ULN	6 (6)
5 to ≤ 8 × ULN	5 (5)
8 × ULN	1 (1)
Aspartate aminotransferase (AST)
3 to ≤ 5 × ULN	7 (6)
5 to ≤ 8 × ULN	2 (2)
8 × ULN	1 (1)
Total bilirubin
1 × ULN to ≤ 2 × ULN	6 (6)
2 × ULN	2 (2)
Complete blood count
Hemoglobin
≤ 79 g/L	6 (6)
Absolute neutrophil count
≤ 0.749×10⁹/L	5 (5)
Platelets
≤ 49×10⁹/L	2 (2)
Serum biochemistry
Lipase
2 × ULN	5 (5)

ULN – upper limit of normal.

Description of individual adverse reactions

Elevated transaminase levels

In the Nix-TB study, in which 109 patients received treatment with pretomanid in combination with bedaquiline and linezolid, 21% of patients experienced elevated transaminase levels (very common). Except for one patient who died from pneumonia and sepsis, all patients who developed elevated transaminase levels were able to continue or resume therapy after interruption and completed the full course of treatment.

QT interval prolongation on ECG

QT interval prolongation is a known adverse reaction associated with bedaquiline. It has been established that bedaquiline in combination with pretomanid leads to a greater QT interval prolongation than expected with bedaquiline alone.

However, the impact of pretomanid is not fully characterized. In the Nix-TB study, QT prolongation was observed in 6 patients (5.5%, common). Throughout the Nix-TB study, no patient had a QTcF interval exceeding 480 ms during treatment. One patient experienced a change in QTcF from baseline exceeding 60 ms.

Myelosuppression

Myelosuppression is a known adverse reaction of linezolid. The most common hematopoietic cytopenia was anemia (37%). Most cytopenias began within 2 weeks of treatment. Three patients experienced cytopenia considered serious: neutropenia in 1 patient and anemia in 2 patients. All 3 serious adverse reactions led to discontinuation of linezolid or all components of the combination regimen (pretomanid, bedaquiline, and linezolid), and all adverse reactions resolved.

Peripheral neuropathy

Peripheral neuropathy is a known adverse reaction of linezolid. In the Nix-TB study, peripheral neuropathy was reported in 81% of patients. Most of these adverse reactions (64%) occurred after 8 weeks of treatment and led to interruption, dose reduction, or discontinuation of linezolid therapy. Peripheral neuropathy of severe, moderate, and mild severity was observed in 22%, 32%, and 26% of patients, respectively. An adverse reaction related to peripheral neuropathy did not lead to discontinuation of the entire investigational regimen.

Optic neuropathy

Optic neuropathy is a known adverse reaction of linezolid. In two patients (2%) in the Nix-TB study, optic neuropathy developed after 16 weeks of treatment. Both cases were serious, confirmed by retinal examination as optic neuropathy/neuritis, and led to discontinuation of linezolid; both adverse reactions resolved.

Reporting suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions

Store at temperatures not exceeding 30 °C in a light-protected place.

Keep out of reach of children.

Packaging.

10 tablets per blister, 19 blisters per cardboard package.

14 tablets per blister, 13 blisters per cardboard package.

Prescription category.

Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and location of operations.

Plot No. M-50 to M-54-A, Indore Special Economic Zone, Phase II, Pitampura, Dhar, Madhya Pradesh, 454774, India (IND).