Dovprela

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DOVPRELA (DOVPRELA)

Composition:

Active substance: pretomanid;

1 tablet contains pretomanid 200 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); magnesium stearate; colloidal anhydrous silicon dioxide; sodium lauryl sulfate; povidone (PVP K30).

Pharmaceutical form. Tablets.

Main physicochemical characteristics: oval, uncoated tablets, white to almost white in color, with an embossing M on one side and P200 on the other side of the tablet.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Other medicinal products for the treatment of tuberculosis. Pretomanid.

ATC code J04A K08.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Dovprela, tablets, is an antimycobacterial agent belonging to the nitroimidazooxazine class. The active substance of the medicinal product, pretomanid, kills actively replicating M. tuberculosis by inhibiting the biosynthesis of mycolic acid, thereby blocking bacterial cell wall formation. Under anaerobic conditions, pretomanid acts against non-replicating bacteria as a respiratory poison by releasing nitric oxide. These effects require nitroreduction of pretomanid within the mycobacterial cell mediated by deazaflavin-dependent nitroreductase Ddn, which depends on the reduced form of the cofactor F420. The conversion of F420 is facilitated by F420-dependent glucose-6-phosphate dehydrogenase, Fgd1.

Resistance

Mutations in five M. tuberculosis genes (ddn, fgd1, fbiA, fbiB, and fbiC) are associated with insensitivity to pretomanid. The proteins encoded by these genes are involved in the bioreductive activation of pretomanid within the bacterial cell. Not all isolates with elevated minimum inhibitory concentrations (MICs) carry mutations in these genes, indicating the presence 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 pretomanid MICs 2–6 times higher. Cross-resistance to pretomanid has been observed with other compounds belonging to the same class.

Antimicrobial activity

In vitro, pretomanid has demonstrated activity against the M. tuberculosis complex. Pretomanid also showed activity against M. tuberculosis in animal models of tuberculosis.

In mouse models of tuberculosis, the combination of three medicinal products—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 (NCT02333799), the MIC of pretomanid was determined using the MGIT (Mycobacterial Growth Indicator Tube) assay. The baseline MIC of pretomanid for M. tuberculosis isolates in the study ranged from 0.06 to 1 µg/mL.

Clinical efficacy

Study 1 (NCT02333799) was an open-label study conducted at three research centers in South Africa, enrolling patients with pulmonary tuberculosis resistant to isoniazid, rifamycins, fluoroquinolones, and second-line injectable antibacterial agents (population 1), or with pulmonary tuberculosis resistant to isoniazid and rifampicin, with intolerance or non-response to standard treatment (population 2). Fifty-six (51%) patients were HIV-positive. Patients received combination treatment with pretomanid tablets, bedaquiline, and linezolid for 6 months (extended to 9 months in 2 patients), followed by 24 months of post-treatment follow-up. The initial dose of linezolid was 600 mg twice daily or 1200 mg once daily. One hundred seven of the 109 study participants were evaluable for the primary efficacy analyses; the remaining two patients remained under follow-up for assessment of the primary outcome.

Treatment failure was defined as the rate of bacteriological failure (reversion to culture-positive status with the same M. tuberculosis strain), bacteriological relapse (reversion to culture-positive status with the same M. tuberculosis strain), or clinical failure (unfavorable status during or prior to end of treatment, or lack of negative culture conversion, or if the patient was withdrawn during or prior to end of treatment for clinical reasons, including retreatment or change in therapy) during the 6-month post-treatment follow-up period. Results are presented in Table 1. Among the 107 evaluable patients, outcomes were classified as success in 95 (89%) patients and as failure in 12 (11%) patients. The success rate was statistically significantly higher than the historical success rate for tuberculosis resistant to isoniazid, rifamycins, fluoroquinolones, and second-line injectable antibacterial agents, based on a review of published literature. Results were similar in both HIV-negative and HIV-positive patients.

Table 1

Outcomes at six months after completion of treatment

Population 1 – tuberculosis resistant to isoniazid, rifamycins, fluoroquinolones, and second-line injectable antibacterial agents.

Population 2 – tuberculosis resistant to isoniazid and rifampicin, with intolerance to or non-response to standard treatment.

* Patient died on day 486.

Cardiac electrophysiology

In study 1 (NCT02333799), patients received combination treatment with pretomanid tablets, bedaquiline, and linezolid for 6 months. In none of the participants did the QTcF interval duration exceed 480 ms, and in one participant, QTcF prolongation of more than 60 ms from baseline was observed.

Pharmacokinetics.

AUC and Cmax of pretomanid were approximately dose-proportional over the single oral dose range of 50 mg (one-quarter of the approved recommended dose) to 200 mg (approved recommended dose); after single doses above 200 mg up to 1000 mg (five times the approved recommended dose), AUC and Cmax increased less than dose-proportionally. Steady-state plasma concentrations of pretomanid were reached approximately within 4–6 days after multiple dosing of 200 mg, and the accumulation ratio was approximately 2. Pharmacokinetic parameters after single and multiple doses of pretomanid 200 mg in healthy adult volunteers are presented in Table 2.

Table 2

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

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

Absorption

Effect of food

Oral administration of pretomanid tablets with a high-calorie, high-fat meal (approximately 150, 250, and 500–600 kilocalories from protein, carbohydrates, and fat, respectively) resulted in an increase of 76% in mean Cmax and 88% in mean AUCinf compared to administration under fasting conditions (see also Table 2 above).

Distribution

Pretomanid binding to plasma proteins is approximately 86.4%.

Metabolism

Pretomanid is metabolized via multiple reductive and oxidative metabolic pathways, none of which is considered predominant. In vitro studies using recombinant CYP3A4 demonstrated that this enzyme is responsible for approximately 20% of pretomanid metabolism.

Elimination

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

Special populations

No clinically significant differences in the pharmacokinetics of pretomanid were observed based on sex, body weight, race (Black, White, or other races), status of pulmonary tuberculosis (resistant to isoniazid, rifamycins, fluoroquinolones, and second-line injectable antibacterials, or resistant to isoniazid and rifampicin with intolerance or non-responsiveness to standard therapy), or HIV status of the patient.

The effect of renal or hepatic impairment on the pharmacokinetics of pretomanid has not been studied. Clinical trials of combination treatment with pretomanid tablets, bedaquiline, and linezolid did not include sufficient numbers of patients aged 65 years and over 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 the mean AUC of pretomanid and a 28% decrease in Cmax. The mean AUC and Cmax of efavirenz remained unchanged when administered 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 the mean AUC of pretomanid and a 13% decrease in Cmax. The mean AUC and Cmax of lopinavir decreased by 14% and 17%, respectively, when administered with pretomanid.

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

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 the mean AUC of midazolam and a 16% decrease in Cmax, and a 14% increase in the mean AUC of 1-hydroxymidazolam and a 5% increase in Cmax.

In vitro studies without additional clinical evaluation of potential drug interactions

Cytochrome P450 (CYP) enzymes. CYP3A4 is involved in the metabolism of pretomanid (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 CYP3A4.

Transporters.

Pretomanid is an in vitro inhibitor of the OAT3 transporter, which may clinically lead to increased concentrations of OAT3 substrate drugs and may increase the risk of adverse reactions associated with these drugs. Clinical drug interaction studies with OAT3 substrates have not been conducted.

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

In vitro studies showed 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 Dovprela is used 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 in adults with pulmonary tuberculosis resistant to isoniazid and rifampicin when standard therapy is not tolerated or ineffective.

Limitations of use

Pretomanid is not indicated for patients with:

• Drug-susceptible (DS) tuberculosis.
• Latent infection caused by Mycobacterium tuberculosis.
• Extrapulmonary infection caused by Mycobacterium tuberculosis.
• Tuberculosis resistant to isoniazid and rifampicin that is not associated with intolerance or ineffectiveness of standard therapy.
• Tuberculosis with known resistance to any component of the combination regimen.

Contraindications.

Hypersensitivity to the active substance, other nitroimidazoles, bedaquiline, linezolid, or to any excipient contained in the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on pretomanid

Inducers of CYP3A4

Pretomanid is partially metabolized via CYP3A4. Consequently, pretomanid exposure may be reduced when co-administered with CYP3A4 inducers. In multiple-dose interaction studies, pretomanid AUC0-24 hr was reduced by 66 % or 35 % when co-administered with multiple doses of rifampicin or efavirenz, 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 hr was reduced 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, 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 transaminase level monitoring are recommended.

Lopinavir/ritonavir

Concomitant administration of pretomanid with lopinavir/ritonavir did not affect plasma concentrations of pretomanid. Lopinavir/ritonavir may be administered concurrently 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 have a clinically significant effect on the pharmacokinetics of midazolam or its main metabolite 1-hydroxymidazolam. Combination therapy with pretomanid, bedaquiline, and linezolid may be used concurrently with medicinal products that are CYP3A4 substrates.

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

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 clinically relevant increases in concentrations of medicinal products that are OAT3 substrates, thereby increasing the risk of adverse effects associated with these drugs.

If pretomanid is administered concomitantly with medicinal products that are OAT3 substrates (e.g., methotrexate, benzylpenicillin, indomethacin, ciprofloxacin), enhanced monitoring for adverse reactions associated with these OAT3 substrate drugs should be performed, and dose reduction of such agents may be 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 exposure. When pretomanid is used concomitantly with OATP1B3, BCRP, or P-gp substrates, enhanced monitoring for adverse reactions associated with the co-administered drug is recommended.

Substrates of CYP2C8, CYP2C9, and CYP2C19

In vitro studies indicate that pretomanid is an inducer of CYP2C8, while results regarding pretomanid's potential to induce CYP2C9 and CYP2C19 are inconclusive. In vivo induction cannot be ruled out, as clinical studies have not been conducted. When pretomanid is administered concomitantly with substrates of CYP2C8, CYP2C9, and CYP2C19 (e.g., paclitaxel, warfarin, mephenytoin), physicians and their patients should monitor for potential reduced efficacy of these substrates.

Special precautions for use.

The safety and efficacy of the medicinal product Dovprela, tablets, have not been established when used in combination with other medicinal products, except for bedaquiline and linezolid as part of the recommended treatment regimen (see section "Dosage and administration").

Risks associated with combination therapy

Dovprela is indicated for use in combination with bedaquiline and linezolid. Refer to the product information for bedaquiline and linezolid for additional information on risks. Warnings and precautions related to bedaquiline and linezolid also apply to their use in combination with pretomanid.

Hepatotoxicity

Hepatic adverse reactions have been reported during combination therapy with pretomanid, bedaquiline, and linezolid (see also section "Adverse reactions"). Alcohol consumption and the use of hepatotoxic agents, including herbal supplements and other medicinal products, except bedaquiline and linezolid, should be avoided during treatment with Dovprela, particularly in patients with hepatic impairment.

Symptoms and signs of liver dysfunction (such as increased fatigue, anorexia, nausea, jaundice, dark urine, hepatic tenderness, and hepatomegaly) should be monitored, and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) should be performed at baseline, after two weeks, and then monthly until the end of treatment, as well as when clinically indicated. If signs of developing or worsening liver dysfunction occur, testing for viral hepatitis should be performed and other hepatotoxic medicinal products discontinued. Treatment with the entire combination should be interrupted if:

• aminotransferase levels increase accompanied by total bilirubin levels more than twice the upper limit of normal (ULN);
• aminotransferase levels exceed ULN by more than 8 times;
• aminotransferase levels increase by more than 5 times ULN and persist for more than 2 weeks.

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

Modification/interruption due to linezolid-related adverse reactions

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

Myelosuppression

Cases of myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) have been reported during combination therapy with pretomanid, bedaquiline, and linezolid. Myelosuppression is a known adverse reaction of linezolid. Anemia may be life-threatening (see also section "Adverse reactions"). Hematological abnormalities observed during combination therapy with pretomanid, bedaquiline, and linezolid were reversible upon dose reduction, interruption, or permanent discontinuation of linezolid. A complete blood count should be performed at baseline, after two weeks, and then monthly in patients receiving linezolid as part of the pretomanid, bedaquiline, and linezolid combination. If myelosuppression develops or worsens, consider dose reduction or interruption of linezolid treatment (see section "Dosage and administration").

Peripheral neuropathy and optic nerve neuropathy

Cases of peripheral neuropathy and optic nerve neuropathy have been reported during combination therapy with pretomanid, bedaquiline, and linezolid (see also section "Adverse reactions"). Neuropathy is a known adverse reaction associated with long-term linezolid therapy. Linezolid-associated neuropathy usually resolves or improves with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid. Visual function should be monitored in patients receiving combination therapy with pretomanid, bedaquiline, and linezolid; if a patient develops symptoms of visual deterioration, linezolid should be interrupted and an immediate ophthalmological evaluation performed to assess for signs of optic nerve neuropathy.

QT interval prolongation

Cases of QT interval prolongation have been reported during combination therapy with pretomanid, bedaquiline, and linezolid (see also section "Adverse reactions"). 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 has not been fully characterized.

An ECG should be performed before initiating treatment and at least monthly during combination therapy with pretomanid, bedaquiline, and linezolid. Serum potassium, calcium, and magnesium levels should be measured at baseline and corrected if outside the normal range. If QT prolongation is detected, further electrolyte monitoring should be conducted.

The following conditions may increase the risk of QT prolongation:

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

If a patient develops clinically significant ventricular arrhythmia or QTcF prolongation exceeding 500 ms (confirmed by repeat ECG), combination therapy with pretomanid, bedaquiline, and linezolid should be discontinued. 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.

Interaction with medicinal products

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 pretomanid treatment.

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 sufficiently studied.

Lactic acidosis

Cases of lactic acidosis have been reported during combination therapy with pretomanid, bedaquiline, and linezolid (see also section "Adverse reactions"). 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 interruption of linezolid or the entire combination therapy with pretomanid, bedaquiline, and linezolid should be considered. Linezolid may be reintroduced at a lower dose under close monitoring once signs and symptoms of lactic acidosis have resolved.

Excipients

The medicinal product Dovprela contains lactose. Patients with rare hereditary conditions such as galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

The medicinal product Dovprela contains less than 1 mmol sodium (23 mg) per tablet, i.e., is considered 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 show direct or indirect harmful effects on embryofetal development. Animal studies with linezolid demonstrated reproductive toxicity. There is a potential risk for humans.

During pregnancy, pretomanid in combination with bedaquiline and linezolid should be used only if the benefit to the patient outweighs the potential risk to the fetus.

Breastfeeding

There is no information on the presence of pretomanid in human breast milk or its effects on milk production or on breastfed infants. Pretomanid has been detected in the milk of rats. Since pretomanid is present in animal milk, it is likely that it will also be excreted in human breast milk.

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

It is unknown whether bedaquiline or its metabolites are excreted in human breast milk.

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

Fertility

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

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

Ability to influence the speed of reactions when driving vehicles or operating machinery

Studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have not been conducted.

However, pretomanid may have a minor influence on the ability to drive vehicles or operate machinery. Dizziness and visual disturbances have been reported in some patients receiving pretomanid. This should be taken into account when assessing a patient's ability to drive a car or operate machinery (see section "Adverse reactions").

Method of Administration and Dosage

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

Pretomanid tablets may only be used in combination with bedaquiline and linezolid as part of the recommended treatment regimen.

Patients should 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).

Recommended Dosage

The recommended dosages and duration of treatment are as follows:

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

The combination of drugs should be taken with food.

If the physician interrupts the combination treatment with pretomanid, bedaquiline, and linezolid for safety reasons, the missed doses may be taken at the end of the treatment period; however, if only linezolid doses were missed due to linezolid-related adverse reactions, they should not be made up.

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

Evaluation Prior to Initiation of Combination Treatment with Pretomanid, Bedaquiline, and Linezolid

Symptoms and signs of liver disease (such as increased fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) should be assessed. Laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin) should be performed (see section "Special Warnings and Precautions for Use").

A complete blood count, as well as serum levels of potassium, calcium, and magnesium, should be evaluated and corrected if abnormal. An ECG should also be performed prior to initiating treatment (see section "Special Warnings and Precautions for Use").

Discontinuation of Treatment

If treatment with bedaquiline or pretomanid is discontinued, the entire combination regimen should also be discontinued.

If linezolid is permanently discontinued during the first four weeks of continuous treatment, bedaquiline and pretomanid should also be discontinued.

If linezolid is discontinued after completion of the first four weeks of continuous treatment, treatment with bedaquiline and pretomanid should be continued.

Elderly Patients (≥ 65 years of age)

Clinical data on the use of pretomanid in elderly patients are limited. Therefore, the safety and efficacy of pretomanid in elderly patients have not been established.

Hepatic Impairment

The safety and efficacy of pretomanid in patients with hepatic impairment have not been established (see section "Special Warnings and Precautions for Use").

Renal Impairment

The safety and efficacy of pretomanid in patients with renal impairment have not been established. Data are lacking. Use in patients with renal impairment is not recommended.

Children

The safety and efficacy of Dovprela in children have not been studied.

Overdose

There is no experience with the treatment of acute pretomanid overdose. In the event of intentional or accidental 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 anaemia were observed in 81% and 37% of patients, respectively, which are known adverse reactions associated with linezolid. Nausea, vomiting, and increased transaminase levels are possible adverse reactions to all three medicinal products included in the treatment regimen. Refer to the product information for bedaquiline and linezolid for detailed information on adverse reactions associated with these two medicinal products.

Adverse drug reactions (ADRs) recorded in an uncontrolled Phase III study involving 109 patients receiving pretomanid in combination with bedaquiline and linezolid are summarised in Table 3 by system organ class and frequency of occurrence. ADRs considered related to linezolid are marked with Δ.

Table 3

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

* Selected terms have broad meanings as defined below: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, peripheral neuropathy, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy); gastritis (gastritis, chronic gastritis); acne (acne, acneiform dermatitis); anemia (anemia); muscle, bone and joint pain (arthralgia, back pain, costochondritis, myalgia, limb pain); increased transaminase levels (increased alanine aminotransferase [ALT] levels, increased aspartate aminotransferase [AST] levels, drug-induced liver injury, increased liver enzyme levels, hepatic function abnormality, increased liver function parameters, increased transaminase levels); 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 infection (bronchitis, influenza, lower respiratory tract infection, pneumonia); hyperamylasemia (increased amylase level, hyperamylasemia); cough (cough, productive cough); visual impairment (blurred vision, decreased visual acuity, visual impairment); neutropenia (neutropenia); arterial hypertension (increased blood pressure, arterial hypertension); hyperlipasemia (hyperlipasemia, increased lipase level); thrombocytopenia (thrombocytopenia); optic nerve neuropathy (optic nerve neuropathy, optic neuritis); pancreatitis (pancreatitis, hemorrhagic pancreatitis).

Table 4

Abnormal laboratory findings

ULN – upper limit of normal.

Description of selected adverse reactions

Elevated transaminase levels

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

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 trial, QT interval prolongation was observed in 6 patients (5.5%, common). Throughout the Nix-TB trial, no patient had a QTcF value exceeding 480 ms during treatment. One patient was reported to have a change in QTcF from baseline exceeding 60 ms.

Myelosuppression

Myelosuppression is a known adverse reaction associated with linezolid. In the Nix-TB trial, the most common hematopoietic cytopenia associated with linezolid was anemia (37%, very common). In most cases, cytopenia began after 2 weeks of treatment. Overall, three patients developed cytopenia considered serious: neutropenia in one patient and anemia in two patients. All three serious adverse reactions necessitated interruption of linezolid or all three components of the combination regimen—pretomanid, bedaquiline, and linezolid; all adverse reactions resolved.

Peripheral neuropathy

Peripheral neuropathy is a known adverse reaction associated with linezolid. In the Nix-TB trial, peripheral neuropathy was observed in 81% of patients (very common). In most cases (64%), these adverse reactions occurred after 8 weeks of treatment and led to interruption, dose reduction, or permanent discontinuation of linezolid. Peripheral neuropathy of severe, moderate, and mild severity was observed in 22%, 32%, and 26% of patients, respectively. There were no adverse reactions related to peripheral neuropathy that led to permanent discontinuation of the entire investigational treatment regimen.

Optic nerve neuropathy

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

If you become aware of any adverse reactions related to the use of the company's product, including use during pregnancy or breastfeeding, or those arising from medication errors, incorrect use, abuse, overdose, interactions with other medicinal products or food, off-label use, or due to occupational or non-occupational exposure, suspected transmission of infectious agents, lack of efficacy, or those associated with a quality defect, you must report it to the person responsible for pharmacovigilance at [email protected]

Shelf life.

2 years (182 tablets in a bottle; 1 bottle per cardboard box).

4 years (14 tablets in a blister, 1 or 13 blisters per cardboard box; 26 tablets in a bottle, 1 bottle per cardboard box).

Storage conditions

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of the reach of children.

Packaging

14 tablets in a blister, 1 or 13 blisters per cardboard box.

26 or 182 tablets in a high-density polyethylene white bottle with a polypropylene cap or a child-resistant cap.

1 bottle per cardboard box.

Prescription category

Prescription only.

Manufacturer

Mylan Laboratories Limited.

Manufacturer's address and location of operations

Plot No. H12 & H13 MIDC, Waluj Industrial Estate, Aurangabad, IN-431 136, India.