Pretomanid
FDA Drug Information • Also known as: Pretomanid
- Brand Names
- Pretomanid
- Drug Class
- Antimycobacterial [EPC]
- Route
- ORAL
- Dosage Form
- TABLET
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION Pretomanid is an oral nitroimidazooxazine antimycobacterial drug. Pretomanid is a white to off-white to yellow-colored powder. The chemical name for pretomanid is (6 S )-2-Nitro-6-{[4-(trifluoromethoxy)phenyl]methoxy}-6,7-dihydro-5 H -imidazo[2,1- b ][1,3]oxazine. The molecular formula for pretomanid is C 14 H 12 F 3 N 3 O 5 , and the molecular weight is 359.26. The structural formula of pretomanid is as follows: Each Pretomanid Tablet contains 200 mg of pretomanid. The inactive ingredients are colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and sodium starch glycolate. Pretomanid Structural Formula
What Is Pretomanid Used For?
1 INDICATIONS AND USAGE Limited Population: Pretomanid Tablet is indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary tuberculosis (TB) resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. 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. Limitations of Use:
Pretomanid Tablets are not indicated in patients with: o Drug-sensitive (DS) TB o Latent infection due to Mycobacterium tuberculosis o Extra-pulmonary infection due to Mycobacterium tuberculosis o TB resistant to isoniazid and rifampin who are responsive to standard therapy and not treatment-intolerant o TB with known resistance to any component of the combination Safety and effectiveness of Pretomanid Tablets have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen [see Dosage and Administration (2.2) ] . Limited Population: Pretomanid Tablet is an antimycobacterial indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary tuberculosis (TB) that is resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. 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. ( 1 ) Limitations of Use: ( 1 ) 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 TB resistant to isoniazid and rifampin, who are responsive to standard therapy and not treatment-intolerant TB with known resistance to any component of the combination Safety and effectiveness of Pretomanid Tablets have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen.Dosage and Administration
2 DOSAGE AND ADMINISTRATION Important Administration Instructions: ( 2.1 )
Pretomanid Tablets must be administered only in combination with bedaquiline and linezolid as part of the recommended dosage regimen. Administer the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid by directly observed therapy (DOT). Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food. Doses of the combination regimen missed for safety reasons can be made up at the end of treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up. Administer Pretomanid Tablets in combination with bedaquiline and linezolid as follows: ( 2.2 ) Pretomanid Tablets: Pretomanid Tablet 200 mg orally once daily for 26 weeks. Administer Pretomanid Tablets whole with water. For patients with swallowing difficulties see the full prescribing information for crushing or soaking followed by crushing instructions of the Pretomanid Tablets. Bedaquiline : 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. Bedaquiline 200 mg orally once daily for 8 weeks followed by 100 mg once daily for 18 weeks, for a total of 26 weeks. Linezolid : Linezolid Preferred: 600 mg orally once daily for 26 weeks. Alternative: 1,200 mg orally once daily for 26 weeks. If myelosuppression, peripheral neuropathy, or optic neuropathy occurs, reduce or interrupt linezolid dosing as necessary. 2.1 Important Administration Instructions Pretomanid Tablets must be administered only in combination with bedaquiline and linezolid as part of the recommended dosage regimen [see Dosage and Administration (2.2) ] . Administer the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid by directly observed therapy (DOT). Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food [see Clinical Pharmacology (12.3) ] . Emphasize the need for compliance with the full course of therapy to patients [see Patient Counseling Information (17) ] . 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 [see Dosage and Administration (2.4) ] . Dosing of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be extended beyond 26 weeks, if necessary [see Clinical Studies (14) ] . 2.2 Recommended Dosage Pretomanid Tablets must be administered in combination with bedaquiline and linezolid with food [see Clinical Pharmacology (12.3) ] . The recommended dosage and duration for Pretomanid Tablets, bedaquiline and linezolid when administered in the combination regimen are as follows: Pretomanid Tablets: Administer...Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following serious adverse reactions are discussed here and elsewhere in the labeling:
Hepatotoxicity [see Warnings and Precautions (5.2) ] Myelosuppression [see Warnings and Precautions (5.3) ] Peripheral and Optic Neuropathy [see Warnings and Precautions (5.4) ] QT Prolongation [see Warnings and Precautions (5.5) ] Reproductive Effects [see Warnings and Precautions (5.7) ] Lactic Acidosis [see Warnings and Precautions (5.8) ] Most common adverse reactions (≥ 10%) are peripheral neuropathy, anemia, nausea, acne, vomiting, increased transaminases, headache, musculoskeletal pain, dyspepsia, rash, pruritus, decreased appetite, abdominal pain, pleuritic pain, increased gamma-glutamyltransferase, hemoptysis and hyperamylasemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, refer to the prescribing information for the respective drugs for a description of the adverse reactions associated with their use. Approximately 3100 subjects have been exposed to Pretomanid Tablets, either alone or as part of a combination therapy in clinical trials. The registrational trial, Trial 1 (NCT02333799), was a single-arm, open-label trial conducted in three sites in South Africa in which adult patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug or pulmonary TB resistant to isoniazid and rifampin, who were treatment-intolerant or non-responsive to standard therapy received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months (extendable to 9 months) with 24 months of follow-up. One hundred and nine patients were treated; 76% were black, and 23% were of mixed race. Their ages ranged from 17 years to 60 years (mean 36 years), and all patients were from South Africa. Fifty-six (51%) patients were HIV-positive. There were 8 deaths. Six patients died while receiving treatment; all surviving patients, excluding one patient who withdrew consent, completed treatment. Two patients died during follow-up at Day 369 and Day 486, respectively. Trial 2 (NCT03086486) was a phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid in combination with Pretomanid Tablets plus bedaquiline in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug, or pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug, or pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy. A total of 181 patients were randomized to one of the 4 treatment arms, Pretomanid Tablets plus bedaquiline plus either 1,200 mg or 600 mg of linezolid for 26 weeks or for 9 weeks (not an approved dosing regimen), followed by a linezolid placebo for 17 weeks. Males represented 67% of the patients in the trial and the median age of all patients was 36 years. 64% of patients were White and the remaining patients were Black (36%). The treatment groups were comparable with respect to demographic characteristics. Most patients (93%) completed treatment. One patient died in the linezolid 1,200 mg for 9 weeks (not an approved dosing regimen) arm. Common Adverse Reactions Reported in Trials 1 and 2 Table 1 summarizes the incidence of select adverse reactions occurring in ≥ 5% of patients treated for 26 weeks in Trials 1 and...Drug Interactions
7 DRUG INTERACTIONS
Strong or moderate CYP3A4 inducers such as rifampin or efavirenz: Avoid co-administration. ( 5.6 , 7.1 ) Organic anion transporter-3 (OAT3) substrates: Monitor for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. ( 7.2 ) 7.1 Effect of Other Drugs on Pretomanid CYP3A4 Inducers Co-administration of pretomanid with rifampin and efavirenz resulted in a decrease in pretomanid plasma concentrations [see Clinical Pharmacology (12.3) ] . 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. Lopinavir/Ritonavir Co-administration of pretomanid with lopinavir/ritonavir did not affect the plasma concentrations of pretomanid [see Clinical Pharmacology (12.3) ] . Lopinavir/ritonavir can be co-administered with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. 7.2 Effect of Pretomanid on Other Drugs Midazolam Co-administration of pretomanid with the CYP3A4 substrate, midazolam, resulted in no clinically significant effect on the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy-midazolam [see Clinical Pharmacology (12.3) ] . The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be administered with CYP3A4 substrate drugs. Organic Anion Transporter-3 (OAT3), BCRP, OATP1B3 and P-gp Substrates The effect of co-administration of pretomanid on the pharmacokinetics of OAT3 substrates in humans is unknown. However, in vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter [see Clinical Pharmacology (12.3) ] , which could result in increased concentrations of OAT3 substrate drugs clinically and may increase the risk of adverse reactions associated with these drugs. If pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate, indomethacin, ciprofloxacin), increase monitoring 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. In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of BCRP, OATP1B3 and P-gp [see Clinical Pharmacology (12.3) ] . No clinical studies have been performed to investigate these interactions. Therefore, it cannot be excluded that co-administration of pretomanid with sensitive OATP1B3 substrates (e.g., valsartan, statins), BCRP substrates (e.g., rosuvastatin, prazosin, glyburide, sulfasalazine) and P-gp substrates (e.g., digoxin, dabigatran etexilate, verapamil) may increase their exposure. If pretomanid is co-administered with substrates of OATP1B3, BCRP, or P-gp, increased monitoring for drug-related adverse reactions to the...Contraindications
4 CONTRAINDICATIONS 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.
Pretomanid Tablets used in combination with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid is contraindicated. ( 4 )Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary There are no studies or available data on pretomanid use in pregnant women to inform any drug-associated risks. There are risks associated with active tuberculosis during pregnancy (see Clinical Considerations ). When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, the pregnancy information for bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolid prescribing information for more information on bedaquiline and linezolid associated risks of use during pregnancy. In animal reproduction studies, there was increased post-implantation loss in the presence of maternal toxicity (reduced bodyweight and feed consumption) with oral administration of pretomanid during organogenesis in rats at doses about 4 times the exposure at the recommended dose in humans. There were no adverse embryo fetal effects in rats or rabbits dosed with oral pretomanid during organogenesis at doses up to approximately 2 times the exposure in humans. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Active tuberculosis in pregnancy is associated with adverse maternal and neonatal outcomes including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death. Data Animal Data In animal reproduction studies, pregnant rats were dosed orally with pretomanid at 10, 30, and 100 mg/kg/day during organogenesis (gestational Days 7 through 17). Rats showed increased post-implantation loss in the presence of maternal toxicity (including...
Overdosage
10 OVERDOSAGE There is no experience with the treatment of acute overdose with pretomanid. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Pretomanid Tablet 200 mg is packaged in either white, round, high-density polyethylene bottles with polypropylene child-resistant closure or child-resistant blister packages comprised of a polyvinylchloride film with foil and paper backing. Pretomanid Tablet 200 mg is a white to off-white, oval tablet debossed with M on one side and P200 on the other side. NDC Number Size 49502-476-26 Bottle of 26 49502-476-14 Unit dose blister pack of 14 (1 strip of 14 tablets) 49502-476-29 Unit dose blister pack of 100 (10 strips of 10 tablets) 49502-476-72 Bottle of 182 Store below 30°C (86°F). Dispense only in original container and keep container tightly closed.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.