Raxtemy^® (Tablets) Instructions for Use

Marketing Authorization Holder

Mylan Laboratories, Limited (India)

Manufactured By

Rottapharm, Ltd. (Ireland)

ATC Code

J04AK08 (Pretomanid)

Active Substance

Pretomanid (Rec.INN registered by WHO)

Dosage Form

Raxtemy®

Tablets 200 mg: 70 pcs.

Dosage Form, Packaging, and Composition

Tablets are white or almost white, oval, uncoated, with an imprinted inscription “M” on one side and “P200” on the other side.

Excipients: lactose monohydrate, microcrystalline cellulose (type 102), sodium starch glycolate (type A), povidone K30, sodium lauryl sulfate, colloidal anhydrous silica, magnesium stearate.

14 pcs. – blisters (5) – cardboard packs.

The cardboard pack may have a first-opening control (in the form of a sticker).

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Agents active against mycobacteria; antituberculosis agents; other antituberculosis agents

Pharmacological Action

The mechanism of action of pretomanid is believed to involve inhibition of mycobacterial cell wall lipid synthesis under aerobic conditions and generation of reactive nitrogen species under anaerobic conditions.

Reductive activation of pretomanid by the mycobacterial deazaflavin (F420)-dependent nitroreductase is required for activity under both aerobic and anaerobic conditions.

Pharmacokinetics

The absolute bioavailability of pretomanid has not been established. Two mass balance studies showed that the absolute bioavailability exceeded 53% and 64%, respectively. Mean T_max values ranged from 4 to 5 hours. Administration of 200 mg pretomanid with a high-fat, high-calorie meal increased the mean C_max by 76% and the mean AUC_0-inf by 88% compared to administration under fasting conditions. The plasma protein binding of pretomanid is 86.4%, so the unbound fraction is 13.6%. The binding of pretomanid to human serum albumin was similar (82.7%), indicating that albumin binding accounts for the plasma protein binding of pretomanid. The mean apparent V_d after a single 200 mg dose under fed conditions was 97 L for a mean body weight of 72 kg. The metabolic profile of pretomanid has not been fully established. Pretomanid is extensively metabolized, forming more than 19 metabolites identified via multiple metabolic pathways. In a mass balance study, Pretomanid had a T_1/2 of 16 hours, while the total radioactivity period was 18 days, indicating the presence of partially unidentified long-lived metabolites. In vitro, Pretomanid was moderately metabolized by the CYP3A4 isoenzyme. Nitroreduction in Mycobacterium tuberculosis and possibly in the gastrointestinal flora is also involved in the metabolism of pretomanid. After a single dose of 14C-pretomanid, excretion was approximately 90%, with about 53-65% excreted renally and 26-38% excreted via the intestine. The apparent clearance after a single dose was 7.6 and 3.9 L/h under fasting and fed conditions, respectively. T_1/2 was 17 hours.

Indications

In combination with bedaquiline and linezolid in adults for the treatment of pulmonary extensively drug-resistant tuberculosis, intolerance to drug therapy, or non-susceptibility to multi-drug therapy.

ICD codes

Dosage Regimen

Use Raxtemy^® only in a combination regimen with bedaquiline and linezolid.

Administer the regimen under directly observed therapy (DOT) as per local practice.

The recommended oral dose is 200 mg once daily for 26 weeks.

Take tablets with food to enhance absorption.

If a dose is missed, administer it as soon as possible. If it is near the time for the next dose, skip the missed dose and continue the regular schedule. Do not double the dose.

Extend combination therapy beyond 26 weeks on an individual basis if clinically necessary.

Monitor liver function tests, ECG, and complete blood count before and during therapy as specified in the full prescribing information.

Discontinue the entire regimen if clinically significant ventricular arrhythmia or QTcF interval >500 ms occurs.

Adverse Reactions

Infections and infestations oral candidiasis.

Blood and lymphatic system disorders anemia, leukopenia, neutropenia, thrombocytopenia, lymphopenia, pancytopenia.

Metabolism and nutrition disorders hypoglycemia, lactic acidosis, hypomagnesemia, dehydration, hypocalcemia, hypovolemia.

Psychiatric disorders insomnia, anxiety, depression.

Nervous system disorders peripheral neuropathy, dysgeusia, dizziness, headache.

Eye disorders vision blurred, eye irritation, eye pain, optic neuropathy, dry eye, lenticular abnormality, eye pruritus, eye swelling, papilloedema, presbyopia.

Ear and labyrinth disorders deafness.

Cardiac disorders palpitations, sinus tachycardia, hypotension.

Respiratory, thoracic and mediastinal disorders cough, epistaxis.

Gastrointestinal disorders intestinal obstruction, nausea, vomiting, dyspepsia, gastritis, diarrhea, constipation, GERD, pancreatitis, abdominal pain, abdominal distension, glossodynia, hematemesis.

Hepatobiliary disorders increased hepatic transaminases, hyperbilirubinemia, hepatomegaly, jaundice.

Skin and subcutaneous tissue disorders acne, dry skin, alopecia, pruritus, rash, allergic dermatitis, skin hyperpigmentation.

Musculoskeletal and connective tissue disorders musculoskeletal pain, muscle spasms.

Reproductive system and breast disorders erectile dysfunction, metrorrhagia.

General disorders and administration site conditions fatigue, malaise.

Investigations increased GGT, QT prolonged on ECG, increased alkaline phosphatase, increased CPK, increased blood urea, increased lipase, increased amylase, increased blood creatinine; infrequently – albumin urine present, increased CPK, increased blood uric acid, renal creatinine clearance decreased.

Contraindications

Hypersensitivity to pretomanid, other nitroimidazoles, pregnancy, breastfeeding period, children and adolescents under 18 years of age.

Use in Pregnancy and Lactation

Pretomanid should be used during pregnancy only if the benefit to the patient outweighs the potential risk to the fetus.

It is not known whether Pretomanid or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data from animal studies indicate excretion of pretomanid in milk. A risk to the breastfed infant cannot be excluded. The decision to discontinue breastfeeding or discontinue pretomanid therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Use in Hepatic Impairment

The safety and efficacy of pretomanid in patients with hepatic impairment have not been established.

Use in Renal Impairment

The safety and efficacy of pretomanid in patients with renal impairment have not been established due to lack of data. Use in patients with renal impairment is not recommended.

Pediatric Use

Safety and efficacy in children from 0 to 18 years of age have not been established.

Geriatric Use

There are limited clinical data on the use of pretomanid in elderly patients. Safety and efficacy have not been established.

Special Precautions

Liver function parameters should be monitored during treatment. Consumption of alcohol and hepatotoxic drugs (including herbal supplements), except those indicated for use, should be avoided, especially in patients with impaired liver function.

Symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) should be managed throughout the treatment course. Laboratory tests (ALT, AST, alkaline phosphatase activity, and bilirubin concentration) should be performed at the start of treatment and at least once weekly for the first month of treatment, once every 2 weeks for the second month, and then monthly during treatment and as needed. If signs of new or worsening liver dysfunction appear, testing for viral hepatitis should be performed and other hepatotoxic drugs should be discontinued.

The entire treatment regimen should be discontinued if increased aminotransferase activity is accompanied by an increase in total bilirubin more than 2 times the upper limit of normal (ULN); increased aminotransferase activity more than 8 times ULN; increased aminotransferase activity more than 5 times ULN and persists for more than 2 weeks. Upon normalization of liver enzyme levels and clinical symptoms, treatment may be resumed under close monitoring.

Complete blood count results should be monitored at least at the start of treatment, after 2 weeks, and then monthly in patients receiving linezolid as part of the combination therapy regimen. Hematology results fluctuate from measurement to measurement, and their decrease should be assessed in the context of the patient’s overall health.

ECG should be performed before starting treatment and at least once a month during the use of the combination therapy regimen including Pretomanid, bedaquiline, and linezolid.

Serum potassium, calcium, and magnesium levels should be determined at baseline and corrected if abnormal.

If QT interval prolongation is detected, subsequent monitoring of electrolyte levels should be performed.

The following factors may increase the risk of QT interval prolongation: history of polymorphic ventricular tachycardia of the ‘torsades de pointes’ type, personal or family history of congenital long QT syndrome, history of or persistent hypothyroidism, persistent bradyarrhythmia, heart failure, or known structural heart disease, Fridericia-corrected QT interval (QTcF) > 450 ms (confirmed by repeat ECG), or serum calcium, magnesium, or potassium levels below the lower limit of normal.

The pretomanid, bedaquiline, and linezolid regimen should be completely discontinued if the patient develops clinically significant ventricular arrhythmia or a QTcF interval exceeding 500 ms (confirmed by repeat ECG). In case of syncope, an ECG should be performed to detect QT interval prolongation. The risk of QT interval prolongation for the combination therapy has not been established at exposures exceeding the therapeutic level. The risk may be increased with increased systemic exposure to pretomanid.

Effect 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 disturbances. This should be considered when assessing a patient’s ability to drive vehicles or operate machinery.

Drug Interactions

Pretomanid is partially metabolized by the CYP3A4 isoenzyme. Consequently, exposure to pretomanid may be reduced when co-administered with inducers of the CYP3A4 isoenzyme. In drug interaction studies of multiple doses of pretomanid with multiple doses of rifampicin or efavirenz, the AUC_{0-24 h} of pretomanid was reduced by 66% or 35%, respectively. Due to the potential for reduced therapeutic effect of pretomanid due to decreased systemic exposure, co-administration of pretomanid with moderate and strong systemically administered inducers of the CYP3A4 isoenzyme (e.g., efavirenz, etravirine, rifamycins including rifampicin, rifapentine and rifabutin, carbamazepine, phenytoin, preparations of St. John’s wort (Hypericum perforatum)) should be avoided.

In a drug interaction study of multiple doses of pretomanid with multiple doses of ritonavir-boosted lopinavir, the AUC_0-24h of pretomanid was reduced by 17%.

In vitro studies indicate that Pretomanid is an inducer of the CYP2C8 isoenzyme, while these studies do not allow a definitive conclusion regarding the ability of pretomanid to induce CYP2C9 and 2C19 isoenzymes. In vivo induction cannot be excluded, as clinical studies have not been conducted. When pretomanid is co-administered with substrates of CYP2C8, 2C9, and 2C19 isoenzymes, e.g., paclitaxel, warfarin, mephenytoin, physicians and their patients should consider the possibility of reduced efficacy of these substrates.

Pretomanid is an inhibitor of the OAT3 transporter in vitro, which may lead to a clinical increase in the concentration of OAT3 substrate drugs and may increase the risk of adverse reactions of these drugs. When pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate, benzylpenicillin, indomethacin, ciprofloxacin), adverse reactions caused by OAT3 substrate drugs should be monitored, and consideration should be given to reducing the dose of the OAT3 substrate drug if necessary.

In vitro studies indicate that Pretomanid is an inhibitor of BCRP, OATP1B3, and P-gp. It cannot be excluded that co-administration of pretomanid with sensitive OATP1B3 substrates (e.g., valsartan, statins), BCRP substrates (e.g., rosuvastatin, prazosin, glibenclamide, sulfasalazine), and P-gp substrates (e.g., digoxin, dabigatran etexilate, verapamil) may increase their exposure. When pretomanid is co-administered with OATP1B3, BCRP, or P-gp substrates, adverse reactions to the co-administered drug should be monitored.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.