FDA Approves Pretomanid Tablets for use as Part of a Combination Regimen with Bedaquiline and Linezolid for the Treatment of Adults with Pulmonary Extensively Drug Resistant, Treatment-Intolerant or Nonresponsive Multidrug-Resistant Tuberculosis

FDA Approves Pretomanid Tablets for use as Part of a Combination Regimen with Bedaquiline and Linezolid for the Treatment of Adults with Pulmonary Extensively Drug Resistant, Treatment-Intolerant or Nonresponsive Multidrug-Resistant Tuberculosis

On August 14, 2019, the U.S. Food and Drug Administration (FDA) approved Pretomanid Tablets for use as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary extensively drug resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients. Pretomanid Tablets are not indicated in patients with drug-sensitive (DS) TB, latent infection due to Mycobacterium tuberculosis, extra-pulmonary infection due to Mycobacterium tuberculosis, or MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy. Pretomanid Tablets must be used only in combination with bedaquiline and linezolid as part of the recommended dosing regimen. The approved recommended dosage and duration for bedaquiline and linezolid when used in the combination regimen with Pretomanid Tablet are as follows: Pretomanid Tablet 200 mg orally (1 tablet of 200 mg), once daily, for 26 weeks. Swallow Pretomanid Tablets whole with water. Bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least 48 hours between doses, for 24 weeks for a total of 26 weeks. Linezolid starting at 1,200 mg orally per day for 26 weeks, with dose adjustments to 600 mg daily and further reduction to 300 mg daily or interruption of dosing as necessary for known linezolid adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy. Take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with food. If the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid is interrupted by a healthcare provider for safety reasons, missed doses can be made up at the end of the treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up. Dosing of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be extended beyond 26 weeks, if necessary. Pretomanid Tablets used in the combination regimen with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated. Refer to the bedaquiline and linezolid prescribing information. Prior to initiating the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, assess for symptoms and signs of liver disease (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly). Obtain laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and bilirubin). Obtain complete blood count, serum potassium, calcium, and magnesium and correct if abnormal. Obtain an ECG before initiation of treatment. Additional information regarding dosage and administration as well as important warnings and precautions about hepatotoxicity, myelosuppression, peripheral neuropathy and optic neuropathy, QT prolongation, reproductive effects, and lactic acidosis can be found in the full prescribing information linked below.  Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD) MOA: Pretomanid is a nitroimidazooxazine antimycobacterial drug. General PK: Pretomanid AUC and Cmax were approximately dose proportional over a range of single oral doses from 50 mg (0.25 times the approved recommended dosage) to 200 mg (approved recommended dosage); at single doses greater than 200 mg and up to 1,000 mg (5 times the approved recommended dosage), AUC and Cmax increased in a less than dose proportional manner. Steady-state pretomanid plasma concentrations were achieved approximately 4 to 6 days following multiple dose administration of 200 mg, and the accumulation ratio was approximately 2. Absorption: The median (minimum, maximum) Tmax of pretomanid single dose under fasted conditions was 4.0 hours (2.0 hours, 6.0 hours). Effect of Food: Administration of an oral tablet dose of pretomanid with a high-fat, high-calorie meal (approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) increased mean Cmax by 76% and mean AUCinf by 88% as compared with the fasted state. Distribution: The plasma protein binding of pretomanid is approximately 86.4%. Elimination: The mean (SD) t½ of pretomanid single dose under fasted conditions was 16.9 hours (3.1 hours). Metabolism: Pretomanid is metabolized by multiple reductive and oxidative pathways, with no single pathway considered as major. CYP3A4 is responsible for up to approximately 20% of the metabolism of pretomanid, in vitro. Excretion: In healthy adult males receiving 1,100 mg oral radiolabeled pretomanid, a mean (SD) of 53% (3.4%) of a radioactive dose was excreted in urine and 38% (2.7%) in feces, primarily as metabolites; approximately 1% of the radioactive dose was excreted in the urine as unchanged pretomanid. Cardiac Electrophysiology: At 400 mg (2 times the approved recommended dosage) and 1,000 mg (5 times the approved recommended dosage) single doses of pretomanid, no significant QT prolongation effect was detected. In the open-label clinical trial, patients received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months. No patient had QTcF intervals greater than 480 msec, and 1 subject had a post-baseline increase of QTcF of greater than 60 msec. Drug Interactions CYP3A4 Inducers: Co-administration of pretomanid with rifampin and efavirenz decreased pretomanid plasma concentrations. Avoid co-administration of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with rifampin, efavirenz, or other strong or moderate CYP3A4 inducers. Refer to the prescribing information for bedaquiline for additional information about drug interactions with CYP3A4. Organic Anion Transporter-3 (OAT3) Substrates: Pretomanid may increase concentrations of OAT3 substrate drugs, which may increase the risk of adverse reactions with these drugs. If pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate), monitor for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. Refer to the prescribing information of the co-administered drug for dosage reduction information. Use in Specific Populations No clinically significant differences in the pharmacokinetics of pretomanid were observed based on sex, body weight, race (Black, White, or other), pulmonary TB status (XDR, treatment intolerant or non-responsive MDR), or HIV status. The effect of renal or hepatic impairment on the pharmacokinetics of pretomanid is unknown. Efficacy and Safety Efficacy of Pretomanid Tablets used in the combination regimen with bedaquiline and linezolid was demonstrated in an open-label study conducted in three centers in South Africa in patients with XDR, treatment-intolerant MDR, or non-responsive MDR pulmonary TB. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below. The most common adverse reactions (≥ 10%) are peripheral neuropathy, acne, anemia, nausea, vomiting, headache, increased transaminases, dyspepsia, decreased appetite, rash, pruritus, abdominal pain, pleuritic pain, increased gamma-glutamyltransferase, lower respiratory tract infection, hyperamylasemia, hemoptysis, back pain, cough, visual impairment, hypoglycemia, abnormal loss of weight, and diarrhea.

Full prescribing information is available at https://go.usa.gov/xVC5S. Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at https://updates.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs. We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.