Pretomanid Tablets (Pretomanid Tablets): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Pretomanid Tablets

Pretomanid is an oral nitroimidazooxazine antimycobacterial drug.

Pretomanid is a white to off-white to yellow-colored powder. The chemical name for pretomanid is (6S)-2- Nitro-6-{[4-(trifluoromethoxy)phenyl]methoxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine. The molecular formula for pretomanid is C₁₄H₁₂F₃N₃O₅, 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.

Uses for Pretomanid Tablets

Limited Population: Pretomanid Tablet is indicated, as part of a combination regimen with bedaquiline andlinezolid for the treatment of adults with pulmonary tuberculosis (TB) resistant to isoniazid, rifamycins, afluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant toisoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. Approval of thisindication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited andspecific population of patients.

Limitations Of Use

• Take 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 withdrugs other than bedaquiline and linezolid as part of the recommended dosing regimen [see DOSAGE AND ADMINISTRATION].

Dosage for Pretomanid Tablets

Important Administration Instructions

• Pretomanid Tablets must be used only in combination with bedaquiline and linezolid as part of therecommended dosing regimen [see Recommended Dosage].
• Emphasize the need for compliance with the full course of therapy to patients [see PATIENT INFORMATION].
• Administer the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid by directlyobserved therapy (DOT).

Recommended Dosage

Pretomanid Tablets must be administered in combination with bedaquiline and linezolid. The recommendeddosage and duration for bedaquiline and linezolid when used in the combination regimen with PretomanidTablet are as follows:

• Pretomanid Tablet 200 mg orally (1 tablet of 200 mg), once daily, for 26 weeks. Swallow PretomanidTablets whole with water.
• Bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least48 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 andfurther reduction to 300 mg daily or interruption of dosing as necessary for known linezolid adversereactions of myelosuppression, peripheral neuropathy, and optic neuropathy [see Discontinuation Of Dosing and WARNINGS AND PRECAUTIONS].
• Take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with food [see CLINICAL PHARMACOLOGY].
• If the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid is interrupted by ahealthcare provider for safety reasons, missed doses can be made up at the end of the treatment; doses oflinezolid 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 extendedbeyond 26 weeks, if necessary [see Clinical Studies ].

Assessments 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], aspartateaminotransferase [AST], alkaline phosphatase, and bilirubin) [see WARNINGS AND PRECAUTIONS].
• Obtain complete blood count [see WARNINGS AND PRECAUTIONS]. Obtain serum potassium, calcium,and magnesium and correct if abnormal [see WARNINGS AND PRECAUTIONS]. Obtain an ECG beforeinitiation of treatment [see WARNINGS AND PRECAUTIONS].

Discontinuation Of Dosing

If either bedaquiline or Pretomanid Tablets are discontinued, the entire combination regimen should also bediscontinued.

If linezolid is permanently discontinued during the initial four consecutive weeks of treatment, bedaquiline andPretomanid Tablets should also be discontinued. If linezolid is discontinued after the initial four weeks ofconsecutive treatment, continue administering bedaquiline and Pretomanid Tablets [see Recommended Dosage].

HOW SUPPLIED

Dosage Forms And Strengths

Pretomanid Tablets, 200 mg, are white to off-white oval tablets debossed with M on one side and P200 on theother side.

Storage And Handling

Pretomanid Tablet 200 mg is packaged in either white, round, high-density polyethylene bottles withpolypropylene child-resistant closure or child-resistant blister packages comprised of a polyvinylchloride filmwith foil and paper backing.

Pretomanid Tablet 200 mg is a white to off-white, oval-shaped tablet debossed with M on one side and P200 onthe other side.

Store below 30 °C (86 °F).

Dispense only in original container and keep container tightly closed.

Manufactured by: Mylan Laboratories Limited, Hyderabad, 500 096, India. Revised: Dec 2022

Side Effects for Pretomanid Tablets

The following serious adverse reactions are discussed here and elsewhere in the labeling:

• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Myelosuppression [see WARNINGS AND PRECAUTIONS]
• Peripheral and Optic Neuropathy [see WARNINGS AND PRECAUTIONS]
• QT Prolongation [see WARNINGS AND PRECAUTIONS]
• Reproductive Effects [see WARNINGS AND PRECAUTIONS]
• Lactic Acidosis [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in theclinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and maynot reflect the rates observed in clinical practice.

When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, refer to theprescribing information for the respective drugs for a description of the adverse reactions associated with theiruse.

More than 1691 subjects, at least 1348 patients with tuberculosis and 343 healthy volunteers, have been exposedto Pretomanid Tablets, either alone or as part of a combination therapy in 24 trials.

The registrational trial, Trial 1 (NCT02333799), was a single-arm, open-label trial conducted in three sites inSouth Africa in which adult patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinoloneand a second line injectable antibacterial drug or pulmonary TB resistant to isoniazid and rifampin, who weretreatment intolerant or non-responsive to standard therapy received the combination regimen of PretomanidTablets, bedaquiline, and linezolid for 6 months (extendable to 9 months) with 24 months of follow up. Onehundred and nine subjects were treated; 76% were black, and 23% were of mixed race. Their ages ranged from17 years to 60 years (mean 36 years), and all patients were from South Africa. Fifty-six (51%) patients wereHIV-positive. There were 8 deaths. Six patients died while receiving treatment; all surviving patients, excludingone patient who withdrew consent, completed treatment. Two patients died during follow-up at Day 369 andDay 486, respectively.

Common Adverse Reactions Reported In Trial 1

Table 1 summarizes the incidence of select adverse reactions occurring in ≥5% of patients in Trial 1.

Table 1: Select Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving the CombinationRegimen of Pretomanid Tablets, Bedaquiline, and Linezolid in Trail 1

The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid at a rate of less than 5% in Trail 1:

Gastrointestinal Disorders: pancreatitis, dysgeusia

Laboratory Investigations: blood creatine phosphokinase increase, blood creatinine increase, blood alkalinephosphatase increase

Blood and Lymphatic System Disorders: leukopenia

Metabolism and Nutrition Disorders: hypomagnesemia, hyperglycemia, hypokalemia, hyperkalemia,hyponatremia

Nervous System Disorders: dizziness, seizure

Laboratory Abnormalities Reported In Trail 1

Table 2 summarizes select laboratory abnormalities.

Table 2: Select Laboratory Abnormalities in Trail 1

In Trail 1, 28% of patients experienced increased transaminases. Except for one patient who died due topneumonia and sepsis, all patients who experienced increased transaminases were able to continue therapy and complete the full course of treatment.

Myelosuppression is a known adverse reaction of linezolid. The most common hematopoietic cytopenia wasanemia (37%). The majority of cytopenias began after 2 weeks of treatment. Three patients experienced cytopenias that were considered serious: neutropenia in 1 patient and anemia in 2 patients. All 3 serious adversereactions resulted in interruption of linezolid or all components of the combination regimen of PretomanidTablets, bedaquiline, and linezolid, and all resolved.

Peripheral And Optic Neuropathy

Peripheral neuropathy is a known adverse reaction of linezolid. In Trial 1, peripheral neuropathy was reported in81% of patients. Most of these adverse reactions (64%) occurred after 8 weeks of treatment and resulted indosing interruption, dose reduction, or discontinuation of linezolid. Severe, moderate, and mild peripheralneuropathy occurred in 22%, 32%, and 26% of patients, respectively. No adverse reaction related to peripheralneuropathy led to a discontinuation of the entire study regimen.

Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%) in Trial 1 developed opticneuropathy after 16 weeks of treatment. Both were serious, confirmed on retinal examination as opticneuropathy/neuritis, and resulted in discontinuation of linezolid; both adverse reactions resolved.

Overall, patients administered a linezolid dose of 600 mg twice daily had a similar safety profile to thoseadministered a dose of 1,200 mg once daily.

Drug Interactions for Pretomanid Tablets

Effect Of Other Drugs On Pretomanid

CYP3A4 Inducers

Co-administration of pretomanid with rifampin and efavirenz resulted in a decrease in pretomanid plasmaconcentrations [see CLINICAL PHARMACOLOGY]. Avoid co-administration of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with rifampin, efavirenz, or other strong or moderate CYP3A4inducers. Refer to the prescribing information for bedaquiline for additional information about drug interactionswith CYP3A4.

Lopinavir/Ritonavir

Co-administration of pretomanid with lopinavir/ritonavir did not affect the plasma concentrations of pretomanid [see CLINICAL PHARMACOLOGY]. Lopinavir/ritonavir can be co-administered with the combination regimenof Pretomanid Tablets, bedaquiline, and linezolid.

Effect Of Pretomanid On Other Drugs

Midazolam

Co-administration of pretomanid with the CYP3A4 substrate, midazolam, resulted in no clinically significanteffect on the pharmaco*kinetics of midazolam or its major metabolite, 1-hydroxy-midazolam [see CLINICAL PHARMACOLOGY] . The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can beadministered with CYP3A4 substrate drugs.

Organic Anion Transporter-3 (OAT3), BCRP, OATP1B3 And P-gp Substrates

The effect of co-administration of pretomanid on the pharmaco*kinetics of OAT3 substrates in humans isunknown. However, in vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter [see CLINICAL PHARMACOLOGY] , which could result in increased concentrations of OAT3 substrate drugsclinically 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 OAT3substrate drugs, if needed. Refer to the prescribing information of the co-administered drug for dosage reductioninformation.

In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of BCRP, OATP1B3 and P-gp [see CLINICAL PHARMACOLOGY]. 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-administeredwith substrates of OATP1B3, BCRP, or P-gp, increased monitoring for drug-related adverse reactions to the co-administered medicinal product should be performed.

Warnings for Pretomanid Tablets

Included as part of the "PRECAUTIONS" Section

Precautions for Pretomanid Tablets

Risks Associated With The Combination Treatment Regimen

Pretomanid Tablet is indicated for use as part of a regimen in combination with bedaquiline and linezolid. Referto the prescribing information for bedaquiline and linezolid for additional risk information. Warnings andPrecautions related to bedaquiline and linezolid also apply to their use in the combination regimen withPretomanid Tablets.

Hepatotoxicity

Hepatic adverse reactions were reported with the combination regimen of Pretomanid Tablets, bedaquiline, andlinezolid [see Risks Associated With The Combination Treatment Regimen, and ADVERSE REACTIONS]. Avoid alcohol and hepatotoxicagents, including herbal supplements and drugs other than bedaquiline and linezolid [see INDICATIONS] while on Pretomanid Tablets, especially in patients with impaired hepatic function.

Monitor symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, andhepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at a minimum at baseline, attwo weeks, and then monthly while on treatment and as needed. If evidence of new or worsening liverdysfunction occurs, test for viral hepatitides and discontinue other hepatotoxic medications. Interrupt treatmentwith the entire regimen if:

• Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upperlimit of normal.
• Aminotransferase elevations are greater than 8 times the upper limit of normal.
• Aminotransferase elevations are greater than 5 times the upper limit of normal and persist beyond2 weeks.

Myelosuppression

Myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) was reported with thecombination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Myelosuppression is a known adversereaction of linezolid. Anemia can be life threatening [see Risks Associated With The Combination Treatment Regimen, and ADVERSE REACTIONS]. When linezolid dosing, as part of the combination regimen of Pretomanid Tablets, bedaquiline,and linezolid, was reduced, interrupted, or discontinued, the observed hematologic abnormalities werereversible. Complete blood counts should be monitored at a minimum at baseline, at two weeks, and thenmonthly in patients receiving linezolid as part of the combination regimen of Pretomanid Tablets, bedaquiline,and linezolid, and decreasing or interrupting linezolid dosing should be considered in patients who develop orhave worsening myelosuppression [see DOSAGE AND ADMINISTRATION].

Peripheral And Optic Neuropathy

Peripheral neuropathy and optic neuropathy were reported with the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid [see Risks Associated With The Combination Treatment Regimen, and ADVERSE REACTIONS]. Neuropathy is aknown adverse reaction of long-term linezolid use. Neuropathy associated with linezolid is generally reversibleor improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezoliddosing. Monitor visual function in all patients receiving the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid; if a patient experiences symptoms of visual impairment, interrupt linezolid dosingand obtain prompt ophthalmologic evaluation.

QT Prolongation

QT prolongation was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Risks Associated With The Combination Treatment Regimen, ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY]. QTprolongation is a known adverse reaction of bedaquiline. Obtain an ECG before initiation of treatment, and atleast 2, 12, and 24 weeks after starting treatment with the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid. Obtain serum potassium, calcium, and magnesium at baseline and correct ifabnormal. Monitor these electrolytes if QT prolongation is detected [see ADVERSE REACTIONS].

The following may increase the risk for QT prolongation when patients are receiving bedaquiline as part of thecombination regimen of Pretomanid Tablets, bedaquiline, and linezolid: a history of Torsade de Pointes,congenital long QT syndrome, ongoing hypothyroidism, ongoing bradyarrhythmia, uncompensated heartfailure, or serum calcium, magnesium, or potassium levels below the lower limits of normal. If necessary,bedaquiline treatment initiation could be considered in these patients after a favorable benefit-risk assessmentand with frequent ECG monitoring.

Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if the patient developsclinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeatECG). If syncope occurs, obtain an ECG to detect QT prolongation.

Drug Interactions

CYP3A4 Inducers

Pretomanid may be in part metabolized by CYP3A4 [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY]. Avoid co-administration of strong or moderate CYP3A4 inducers, such as rifampin or efavirenz, duringtreatment with pretomanid.

Reproductive Effects

Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductivetoxicities seen in animal studies and that the potential effects on human male fertility have not been adequatelyevaluated [see Use In Specific Populations and Nonclinical Toxicology].

Lactic Acidosis

Lactic acidosis was reported with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid [see Risks Associated With The Combination Treatment Regimen and ADVERSE REACTIONS]. Lactic acidosis is a known adverse reactionof linezolid. Patients who develop recurrent nausea or vomiting should receive immediate medical evaluation,including evaluation of bicarbonate and lactic acid levels, and interruption of linezolid or the entire combinationregimen of Pretomanid Tablets, bedaquiline, and linezolid should be considered.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Important Information On Co-Administration Of Pretomanid Tablets In Combination With Bedaquiline And Linezolid

• Inform the patient or caregiver that Pretomanid Tablets administered as a combination regimen withbedaquiline and linezolid would be useful only in adult patients with TB resistant to isoniazid, rifamycins,a fluoroquinolone and a second line injectable antibacterial drug or TB resistant to isoniazid and rifampin,who are treatment-intolerant or nonresponsive to standard therapy. This regimen is not indicated fortreatment in patients with latent infection or extra-pulmonary infection due to M. tuberculosis , drug-sensitive TB, TB resistant to isoniazid and rifampin who are responsive to standard therapy and nottreatment-intolerant, or who have TB with known resistance to any component of the regimen(Pretomanid Tablets, bedaquiline, or linezolid).
• Instruct the patient or caregiver that the combination regimen of Pretomanid Tablets, bedaquiline, andlinezolid must be administered by directly observed therapy (DOT).
• Inform patients of safety concerns associated with linezolid and bedaquiline and advise the patient or theircaregiver to read the Medication Guide for bedaquiline.

Adverse Reactions

Advise patients that the following serious adverse reactions can occur with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid: liver enzyme abnormalities, myelosuppression includinganemia, peripheral and optic neuropathy, and cardiac rhythm abnormalities.

Peripheral And Optic Neuropathy

Advise patients to promptly inform their physician if they experience changes in vision during linezolid therapy.Monitor visual function in all patients receiving linezolid. Counsel patients to obtain prompt ophthalmologicalevaluation if the patient experiences symptoms of visual impairment.

Additional serious adverse reactions can occur with the use of linezolid, including serotonin syndrome, lacticacidosis, and convulsions. Refer to the prescribing information for linezolid for additional counselinginformation for these serious adverse reactions.

Interruption Of Linezolid Dosing To Manage Linezolid Adverse Reactions

Counsel patients that linezolid dosing may be modified or interrupted during the therapy to manage the knownlinezolid adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy.

Compliance With Treatment

Inform patients that Pretomanid Tablets must be taken as part of a combination regimen with bedaquiline andlinezolid. Compliance with the full course of therapy must be emphasized. Advise patients that although it iscommon to feel better early in the course of therapy, the medication should be taken exactly as directed for thefull prescribed duration of dosing. Skipping doses other than as directed by a physician or not completing thefull course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase thelikelihood that their Mycobacterium may develop resistance and the disease will not be treatable by the regimenor other antibacterial drugs in the future.

Administration Instructions

Inform patients to take the regimen with food. Doses of the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid missed for safety reasons can be made up at the end of treatment; doses of linezolidalone missed due to linezolid adverse reactions should not be made up. If bedaquiline and/or Pretomanid Tabletsare permanently discontinued, the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolidshould be discontinued.

Use In Patients With Hepatic Or Renal Impairment

Advise patients to inform their physician if they have a history of liver or kidney problems. The safety andeffectiveness of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid in populations withhepatic or renal impairment have not been established.

Use With Alcohol And Other Medications

Advise patients to discuss with their physician the other medications they are taking and other medicalconditions before starting treatment with Pretomanid Tablets.

Advise patients to abstain from alcohol, hepatotoxic medications, and herbal products.

Storage Instructions

Advise patients to store Pretomanid Tablets, bedaquiline, and linezolid at room temperaturebelow 86°F (30°C).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No mutagenic or clastogenic effects were detected in conventional genotoxicity studies with pretomanid. Acirculating metabolite of pretomanid, M50, was mutagenic in a bacterial reverse mutation assay. Nocarcinogenic potential was revealed in a 6-month study in transgenic mice where this metabolite was produced.In a 2-year study in rats, there was no evidence of carcinogenic risk.

Mutagenesis

No mutagenic or clastogenic effects were detected in both an in vitro bacterial reverse mutation assay and an invitro mammalian chromosome aberrations assay using a Chinese hamster ovary cell line. Pretomanid wasnegative for clastogenicity in a mouse bone marrow micronucleus assay.

A metabolite of pretomanid was mutagenic in a bacterial reverse mutation assay. This metabolite representsapproximately 6% of the human exposure (AUC) to pretomanid at the MRHD.

Fertility

In a fertility and general reproduction study in rats, male rats treated orally with pretomanid for 13 to 14 weekshad reduced fertility at 30 mg/kg/day and complete infertility at 100 mg/kg/day (approximately 1 and 2-timesthe human exposure for a 200 mg dose, respectively). At 100 mg/kg/day, males had testicular atrophy includinghypospermia in the epididymal tubules and focal epithelial hyperplasia of the epididymal tubular epithelium.Following a 10-week treatment-free period, these effects were partially reversed in male rats given pretomanidat 30 mg/kg/day but not at 100 mg/kg/day. These effects were associated with increased serum follicle-stimulating hormone and decreased serum inhibin B concentrations. There were no effects of pretomanid inmale rats treated for 13 weeks at 10 mg/kg/day (approximately half of the human exposure for a 200 mg dose).Pretomanid did not affect mating behavior in female rats given oral pretomanid at 100 mg/kg/day for two weeks(approximately twice the human exposure).

Testicular toxicity was present in male mice treated orally for 13 weeks at 20 mg/kg/day [approximately equalto the human exposure (AUC) for a 200 mg dose]. There were no adverse testicular effects observed in micegiven pretomanid at 6 mg/kg/day (0.2-times the human exposure for a 200 mg dose).

Testicular toxicity was observed in male rats following 7 or 14 days of dosing with oral pretomanid at100 mg/kg/day (approximately 2-times the human exposure for a 200 mg dose). The effects were partiallyreversible during a 6-month post treatment recovery period in rats treated with pretomanid for 7 days, but not14 days.

In a 3-month study, decreased sperm motility and total sperm count, and increased abnormal sperm ratio werenoted in sexually mature monkeys given ≥150 mg/kg/day (approximately 3 times the human exposure for a200 mg dose).

Use In Specific Populations

Pregnancy

Risk Summary

There are no studies or available data on pretomanid use in pregnant women to inform any drug-associatedrisks. There are risks associated with active tuberculosis during pregnancy (see Clinical Considerations). WhenPretomanid Tablets are administered in combination with bedaquiline and linezolid, the pregnancy informationfor bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolidprescribing information for more information on bedaquiline and linezolid associated risks of use duringpregnancy.

In animal reproduction studies, there was increased post-implantation loss in the presence ofmaternal toxicity (reduced bodyweight and feed consumption) with oral administration of pretomanid duringorganogenesis in rats at doses about 4 times the exposure at the recommended dose in humans. There were noadverse embryo fetal effects in rats or rabbits dosed with oral pretomanid during organogenesis at doses up toapproximately 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 Statesgeneral population, the estimated background risks of major birth defects and miscarriage in clinicallyrecognized 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 maternalanemia, 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/dayduring organogenesis (gestational Days 7 through 17). Rats showed increased post-implantation loss in thepresence of maternal toxicity (including reduced body weight and feed consumption) at 100 mg/kg/day,approximately 4 times the exposure in humans for a 200 mg dose on an AUC basis. There were no adverseembryofetal effects in rats dosed with oral pretomanid during organogenesis at doses up to approximately2 times the exposure in humans. Pregnant rabbits were dosed orally with pretomanid during organogenesis(gestational Days 7 through 19) at 10, 30, and 60 mg/kg/day. No evidence of adverse developmental outcomeswas observed when oral doses of pretomanid were administered to dams during organogenesis (gestationalDays 7 to 19) at doses up to 60 mg/kg/day (approximately 2 times the exposure in humans for a 200 mg dose onan AUC basis).

In a pre- and postnatal development study, there were no adverse developmental effects in pups of pregnant ratsorally dosed with up to 20 mg/kg/day from gestational Day 6 through lactation Day 20. Pups of pregnantfemales dosed at 60 mg/kg/day (about 2 times the exposure for the 200 mg dose) had lower body weights and a slight delay in the age at which the air-drop righting reflex developed. These effects occurred at a maternallytoxic dose (based on maternal weight loss and reduced food consumption).

Lactation

Risk Summary

There is no information regarding the presence of pretomanid in human milk, or its effects on milk productionor the breastfed infant. Pretomanid was detected in rat milk (see Data). When a drug is present in animal milk, itis likely that the drug will be present in human milk. Because of the potential for adverse reactions in nursinginfants, the developmental and health benefits of breastfeeding should be considered along with the mother’sclinical need for Pretomanid Tablets and any potential adverse effects on the breastfed infant from PretomanidTablets or from the underlying maternal condition. When Pretomanid Tablets are administered in combinationwith bedaquiline and linezolid, information on lactation for bedaquiline and linezolid also applies to thiscombination regimen. Refer to the bedaquiline and linezolid prescribing information for more information ontheir use during lactation.

Data

Animal Data

In a pre- and postnatal development study in rats treated with pretomanid at doses 0.5 and 2 times the humanexposure for a 200 mg dose (AUC) from gestational day 7 through lactation day 20, concentrations in milk onlactation day 14 were 1.4 and 1.6 times higher than the maximum concentration observed in maternal plasma,respectively. The concentration of pretomanid in rat milk does not necessarily predict the concentration ofpretomanid in human milk.

Females And Males Of Reproductive Potential

Infertility

Males

Reduced fertility and/or testicular toxicity were observed in male rats and mice treated with oral pretomanid.These effects were associated with hormonal changes including decreased serum inhibin B and increased serumfollicle stimulating hormone and luteinizing hormone in rodents [see Nonclinical Toxicology].

Reduced fertility and testicular toxicity cannot be definitively ruled out in male human subjects at this time.

Pediatric Use

Safety and effectiveness of Pretomanid Tablets in pediatric patients have not been established.

Geriatric Use

Clinical studies of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid did not includesufficient numbers of subjects aged 65 and over to determine whether they respond differently from youngersubjects.

Hepatic Impairment

The effect of hepatic impairment on the safety, effectiveness, and pharmaco*kinetics of pretomanid is not known.

Renal Impairment

The effect of renal impairment on the safety, effectiveness, and pharmaco*kinetics of pretomanid is not known.

Overdose Information for Pretomanid Tablets

There is no experience with the treatment of acute overdose with pretomanid. Take general measures to supportbasic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate oraccidental overdose.

Contraindications for Pretomanid Tablets

Pretomanid Tablets used in the combination regimen with bedaquiline and linezolid are contraindicated inpatients for whom bedaquiline and/or linezolid are contraindicated. Refer to the bedaquiline and linezolidprescribing information.

Clinical Pharmacology for Pretomanid Tablets

Mechanism Of Action

Pretomanid is a nitroimidazooxazine antimycobacterial drug [see Microbiology].

Pharmacodynamics

Cardiac Electrophysiology

A randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg), crossover, thorough QTstudy of pretomanid was performed in 74 healthy adult subjects. At 400 mg (2 times the approvedrecommended dosage) and 1,000 mg (5 times the approved recommended dosage) single doses of pretomanid,no significant QT prolongation effect was detected.

In Trial 1, patients received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for6 months. No patient had QTcF intervals greater than 480 msec, and 1 subject had a post-baseline increase ofQTcF of greater than 60 msec.

Pharmaco*kinetics

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 dosesgreater than 200 mg and up to 1,000 mg (5 times the approved recommended dosage), AUC and Cmax increasedin a less than dose proportional manner. Steady-state pretomanid plasma concentrations were achievedapproximately 4 to 6 days following multiple dose administration of 200 mg, and the accumulation ratio was approximately 2. Pharmaco*kinetic parameters following single and multiple 200 mg doses of pretomanid inhealthy adult subjects are summarized in Table 3.

Table 3: Mean (SD) Pretomanid Pharmaco*kinetic Parameters in Healthy Adult Subjects Under Fastedand Fed Conditions

Absorption

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% andmean AUCinf by 88% as compared with the fasted state (see also Table 3 above).

Distribution

The plasma protein binding of pretomanid is approximately 86.4%.

Elimination

See Table 3 above for estimates of apparent oral clearance and half-life of pretomanid.

Metabolism

Pretomanid is metabolized by multiple reductive and oxidative pathways, with no single pathway considered asmajor. In vitro studies using recombinant CYP3A4 demonstrated that this enzyme is responsible for up toapproximately 20% of the metabolism of pretomanid.

Excretion

In healthy adult males receiving 1,100 mg oral ¹⁴C-radiolabeled pretomanid, a mean (SD) of 53% (3.4%) of aradioactive dose was excreted in urine and 38% (2.7%) in feces, primarily as metabolites; approximately 1% ofthe radioactive dose was excreted in the urine as unchanged pretomanid.

Specific Populations

No clinically significant differences in the pharmaco*kinetics of pretomanid were observed based on sex, bodyweight, race (Black, White, or other), pulmonary TB status (resistant to isoniazid, rifamycins, a fluoroquinoloneand a second line injectable antibacterial drug OR resistant to isoniazid and rifampin and treatment intolerant or non-responsive to standard therapy), or HIV status. The effect of renal or hepatic impairment on thepharmaco*kinetics of pretomanid is unknown.

Drug Interaction Studies

Clinical Studies

Efavirenz

Co-administration of 200 mg QD of pretomanid with efavirenz 600 mg QD for 7 days resulted in adecrease of pretomanid mean AUC by 35% and Cmax by 28%. Mean AUC and Cmax of efavirenz were notaffected when given with pretomanid.

Lopinavir/ritonavir

Co-administration of 200 mg QD pretomanid with lopinavir/ritonavir 400/100 mg BID for7 days resulted in a decrease of pretomanid mean AUC by 17% and Cmax by 13%. Mean AUC and Cmax oflopinavir were decreased by 14% and 17%, respectively, when given with pretomanid.

Rifampin

Co-administration of 200 mg QD pretomanid with rifampin 600 mg QD for 7 days resulted in adecrease of pretomanid mean AUC by 66% and Cmax by 53%.

Midazolam

Co-administration of 400 mg (twice the approved recommended dosage) QD pretomanid for14 days and a single 2 mg oral dose of midazolam on Day 14 resulted in a decrease in midazolam mean AUC by15% and Cmax by 16%, and an increase in 1-hydroxy midazolam mean AUC by 14% and Cmax by 5%.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

Cytochrome P450 (CYP) Enzymes

CYP3A4 plays a role in the metabolism of pretomanid, i.e., up to 20%.Pretomanid is not a substrate of CYP2C9, CYP2C19, and CYP2D6. Pretomanid is not an inhibitor of CYP1A2,CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations based on in vitro studies.Pretomanid is not an inducer of CYP3A4.

Transporter Systems

Pretomanid is an inhibitor of the OAT3 transporter in vitro, which could result inincreased concentrations of OAT3 substrate medicinal products clinically and may increase the risk of adversereactions associated with these medicines. No clinical drug-drug interaction studies have been conducted withOAT3 substrates [see DRUG INTERACTIONS].

In vitro studies cannot exclude the possibility that pretomanid is an inhibitor of BCRP, OATP1B3, and P-gptransporters. The effect of co-administration of pretomanid on the pharmaco*kinetics of BCRP, OATP1B3 and P-gp substrates in humans is unknown [see DRUG INTERACTIONS].

In vitro studies indicated that pretomanid does not inhibit human OAT1, OCT1, OCT2, OAT1B1, BSEP,MATE1, and/or MATE2-K mediated transport at clinically relevant concentrations of pretomanid. Pretomanid isnot a substrate of OAT1, OAT3, OCT2, OAT1B1, OATP1B3, MATE1, MATE2-K, BCRP, and/or P-gptransporters.

Microbiology

Mechanism Of Action

Pretomanid Tablet is a nitroimidazooxazine antimycobacterial drug. Pretomanid kills actively replicating M. tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Under anaerobicconditions, against non-replicating bacteria, pretomanid acts as a respiratory poison following nitric oxiderelease. All of these activities require nitro-reduction of pretomanid within the mycobacterial cell by thedeazaflavin-dependent nitroreductase, Ddn, which is dependent on the reduced form of the cofactor F₄₂₀. Reduction of F₄₂₀ is accomplished by the F-dependent glucose-6-phosphate dehydrogenase, Fgd1.

Resistance

Mutations in five M. tuberculosis genes (ddn, fgd1, fbiA,fbiB, and fbiC) have been associated with pretomanidresistance. The products of these genes are involved in bioreductive activation of pretomanid within thebacterial cell. Not all isolates with increased minimum inhibitory concentrations (MICs) have mutations in these genes, suggesting the existence of at least one other mechanism of resistance. The in vitro frequency ofresistance development to pretomanid ranged from 10^-7 to 10^-5 at 2 to 6 times the pretomanid MICs. Cross-resistance of pretomanid with other compounds in the same class has been observed.

Antimicrobial Activity

Pretomanid has demonstrated in vitro activity against the M. tuberculosis complex. Pretomanid has alsodemonstrated anti-M. tuberculosis activity in animal models of tuberculosis [see INDICATIONS].

In murine tuberculosis models, the 3-drug combination of pretomanid, bedaquiline, and linezolid reducedbacterial counts in the lungs to a greater extent and resulted in fewer relapses at 2 and 3 months post-therapycompared to 2-drug combinations of pretomanid, bedaquiline, and linezolid.

In Trial 1, the pretomanid MIC was determined using the Mycobacterial Growth Indicator Tube (MGIT). Thebaseline pretomanid MIC for M. tuberculosis isolates in the trial ranged from 0.06 to 1 mcg/mL.

Susceptibility Test Methods

For specific information regarding susceptibility test criteria and associated test methods and quality controlstandards recognized by FDA for this drug, please see: www.fda.gov/STIC.

Animal Toxicology And/Or Pharmacology

Cataracts were observed in rats treated with pretomanid at doses of 300 mg/kg/day for 13 weeks or100 mg/kg/day for 26 weeks. There were no cataracts observed in rats given oral pretomanid at 30 mg/kg/day(approximately 2 times the human exposure for a 200 mg dose) for 26 weeks.

In monkeys given oral pretomanid at 450 mg/kg/day for 4 weeks and 300 mg/kg/day for 12 more weeks,cataracts were not present at the end of dosing but developed during the 13-week post treatment recoveryperiod. In a subsequent study, cataracts were not observed following 13 weeks treatment with up to300 mg/kg/day oral pretomanid or during the 20-week post treatment recovery period. Further, no cataractswere observed in monkeys given oral pretomanid at 100 mg/kg/day for 39 weeks with a 12-week post treatmentrecovery. This is approximately 1- to 2-times the human exposure for a 200 mg dose (AUC).

Clinical Studies

Trial 1 (NCT02333799) was an open-label trial conducted in three centers in South Africa in patients withpulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterialdrug (Population 1), or pulmonary TB resistant to isoniazid and rifampin, who were treatment intolerant or non-responsive to standard therapy (Population 2). Fifty-six (51%) patients were HIV-positive. The patients receiveda combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months (extended to 9 months in2 patients) with 24 months of follow-up; linezolid starting dose was either 600 mg twice daily or 1200 mg oncedaily. One hundred seven of the 109 patients enrolled were assessable for the primary efficacy analyses withtwo patients remaining in follow up for the primary outcome assessment.

Treatment failure was defined as the incidence of bacteriologic failure (reinfection – culture conversion topositive status with a different M. tuberculosis strain), bacteriological relapse (culture conversion to positivestatus with the same M. tuberculosis strain), or clinical failure (an unfavorable status at, or before, end oftreatment (EOT) or failing to attain culture negativity, or if the patient was withdrawn at or before EOT forclinical reasons including retreatment or changing treatment) through follow-up until 6 months after the EOT.Results are presented in Table 4. Of the 107 patients assessed, outcomes were classified as success for 95 (89%)patients and failure for 12 (11%) patients. The success rate significantly exceeded the historical success rates forTB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug based ona literature review. The outcomes were similar in both HIV negative and HIV positive patients.

Table 4: Outcomes Six Months After the End of Treatment

Patient Information for Pretomanid Tablets

Pretomanid Tablets
(Pre-TOH-mah-nid)

What is the most important information I should know about the combination regimen of PretomanidTablets, bedaquiline, and linezolid?

Pretomanid Tablets are for use only as part of a combination antibiotic regimen that includesPretomanid Tablets, bedaquiline, and linezolid.

Treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can causeserious side effects. See “What are the possible side effects of the combination regimen of PretomanidTablets, bedaquiline, and linezolid?”

Read the Medication Guide that comes with bedaquiline. Ask your healthcare provider for information aboutlinezolid. The serious side effects that can happen when taking bedaquiline and linezolid can also happen whentaken in the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

What is the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?

Pretomanid Tablets are a prescription medicine used as part of a combination regimen with bedaquiline andlinezolid. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid includes threeprescription antibiotics that are used together in adults to treat tuberculosis (TB) of the lungs that is resistant toother classes of antibiotics (isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibiotic) orin adults who cannot tolerate or do not respond to treatment for TB that is resistant to two specific antibiotics(isoniazid and rifampin).

Pretomanid Tablets are not for use in people who have:

• TB that is not resistant to antibiotics.
• an inactive (latent) TB infection.
• a type of TB other than TB of the lungs.
• TB resistant to isoniazid and rifampin who can tolerate or who respond to medicines usually used to treatthis type of TB.
• TB that is known to be resistant to Pretomanid Tablets, bedaquiline, or linezolid.

It is not known if Pretomanid Tablets are safe and effective for use except in combination with bedaquiline andlinezolid as part of the recommended dosing regimen.

It is not known if Pretomanid Tablets are safe and effective in children.

Pretomanid Tablets were approved by FDA using the Limited Population pathway. This means FDA hasapproved this drug for a limited and specific patient population, and studies on the drug may have onlyanswered focused questions about its safety and effectiveness.

Do not take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if:

• you have been told by your healthcare provider not to take bedaquiline or linezolid.

Before you take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, tell yourhealthcare provider about all of your medical conditions, including if you:

• have liver problems. See “What are the possible side effects of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?”
• have kidney problems.
• have or have had an abnormal heart rhythm (ECG) or other heart problems, including heart failure.
• have a family history of a heart problem called “congenital long QT syndrome.”
• have decreased thyroid gland function (hypothyroidism).
• have HIV infection.
• have been told that you have low levels of calcium, magnesium or potassium in your blood.
• have ever had a seizure.
• are pregnant or plan to become pregnant. It is not known if pretomanid will harm your unborn baby. Talkto your healthcare provider about the possible risks to your baby if you take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid while you are pregnant.
• are breastfeeding or plan to breastfeed. It is not known if pretomanid passes into your breast milk. Talk toyour healthcare provider about the best way to feed your baby if you take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-countermedicines, vitamins, and herbal supplements. You should not take herbal products or medicines that can harmyour liver during treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid regimen may affect how othermedicines work, and other medicines may affect how the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid works.

Especially tell your healthcare provider if you take:

• a type of medicine called a CYP3A4 inducer, such as efavirenz or rifampin. Ask your healthcare providerif you are not sure.

How should I take the combination regimen of Pretomanid Tablets, bedaquiline and linezolid?

• Pretomanid Tablets must only be taken with bedaquiline and linezolid as part of the dosing regimenprescribed by your healthcare provider.
• Take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid exactly as yourhealthcare provider tells you to take it.
• It is important that you complete the full course of treatment with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, and not miss any doses, even if you feel better before youhave completed the full course of treatment. Missing doses may decrease the effectiveness of thetreatment and increase the chance that your TB will not be treatable by the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid or other medicines.
• Take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for a total of 26 weeks.
  • Your healthcare provider will tell you if you should take the combination regimen of PretomanidTablets, bedaquiline, and linezolid for longer than 26 weeks.
  • Your healthcare provider will tell you if you should stop taking linezolid before you have taken itfor 26 weeks or if you should reduce your dose of linezolid due to side effects.
• Your healthcare provider or caregiver will watch you take your doses of Pretomanid Tablets, bedaquiline,and linezolid.
• Pretomanid Tablets, bedaquiline, and linezolid can be taken together.
• Swallow Pretomanid Tablets whole with water.
• Take Pretomanid Tablets, bedaquiline, and linezolid with food.
• Week 1 and Week 2:
  • Take 200 mg of Pretomanid Tablets (1 tablet), 400 mg of bedaquiline, and 1,200 mg of linezolid 1time each day.
• Week 3 to Week 26:
  • Take 200 mg of Pretomanid Tablets (1 tablet) and 1,200 mg of linezolid 1 time each day.
  • Take 200 mg of bedaquiline 3 times a week.
    • Take your doses of bedaquiline at least 48 hours apart. For example, you may takebedaquiline on Monday, Wednesday, and Friday every week from Week 3 to Week 26.
• You may need to take the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid forlonger than 26 weeks. Talk with your healthcare provider.
• Do not miss a dose of Pretomanid Tablets, bedaquiline, or linezolid unless instructed to do so byyour healthcare provider. If you miss doses or do not complete the total 26 weeks of treatment, yourtreatment may not work as well, and your TB may be harder to treat.
• If your healthcare provider tells you to stop taking the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid for a period of time, follow the instructions given to you by your healthcareprovider for taking the missed doses at the end of your treatment. You should not make up any misseddoses of linezolid alone that your healthcare provider told you not to take due to side effects.
• If you miss a dose of Pretomanid Tablets, bedaquiline, or linezolid and you are not sure what to do,talk to your healthcare provider as soon as possible.
• If you take too much Pretomanid Tablets, go to the nearest hospital emergency room right away.

Do not stop taking Pretomanid Tablets, bedaquiline, or linezolid without first talking to your healthcareprovider.

What should I avoid when taking the combination regimen of Pretomanid Tablets, bedaquiline, andlinezolid?

• You should not drink alcohol while taking the combination regimen of Pretomanid Tablets, bedaquiline,and linezolid.

What are the possible side effects of the combination regimen of Pretomanid Tablets, bedaquiline, andlinezolid?

The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid may cause serious sideeffects including:

• See“What is the most important information I should know about the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?”
• Liver problems. Your healthcare provider should do blood tests to check your liver at least before youstart taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, 2 weeks afterstarting treatment, and then monthly during treatment. Tell your healthcare provider right away if youhave symptoms of liver problems, such as:
  • unusual tiredness
  • loss of appetite
  • nausea
  • yellowing of your skin or the whites of your eyes
  • dark (tea-colored) urine
  • tenderness in the upper right side of yourstomach-area (abdomen)

See “What should I avoid when taking the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid?”

Vision problems. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can causenerve problems in your eyes (optic neuropathy). Nerve problems in your eyes can cause problems withyour vision. Tell your healthcare provider right away if you have symptoms of nerve problems in youreyes, such as changes in vision.

Nerve problems in your arms, hands, legs, feet, and eyes are common side effects of long-term use oflinezolid, but can be serious. Nerve problems caused by linezolid were generally reversible or improvedwhen symptoms of nerve problems were monitored by the healthcare provider and linezolid treatmentwas reduced, stopped for a period of time, or stopped permanently.

• Low blood cell counts. The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid cancause low red blood cell counts (anemia), low white blood cell counts (leukopenia), low blood plateletcounts (thrombocytopenia) or a combination of low red and white blood cell counts and low bloodplatelet counts (pancytopenia). Low blood cell counts are a side effect of linezolid. Anemia is a commonside effect of linezolid, but can be serious and life-threatening. Low blood cell counts were reversiblewhen linezolid treatment was reduced, stopped for a period of time, or stopped permanently. Yourhealthcare provider should check your blood cell counts at least before you start taking the combinationregimen of Pretomanid Tablets, bedaquiline, and linezolid, 2 weeks after starting treatment, and thenmonthly during treatment.
• Nerve problems in your arms, hands, legs, and feet (peripheral neuropathy). The combinationregimen of Pretomanid Tablets, bedaquiline, and linezolid can cause nerve problems in your arms, hands,legs, and feet. Tell your healthcare provider if you have symptoms of nerve problems in your arms,hands, legs, or feet, including:
  • numbness
  • burning
  • a feeling of “pins and needles”
  • tremors
  • problems with balance
  • weakness
• Heart rhythm problem called QT prolongation. The combination regimen of Pretomanid Tablets,bedaquiline, and linezolid can cause a heart rhythm problem. Heart rhythm problem is a side effect ofbedaquiline. Your healthcare provider should do a test called an electrocardiogram (ECG) to check yourheart before you start taking the combination regimen of Pretomanid Tablets, bedaquiline, and linezolidand at least 2, 12, and 24 weeks after starting treatment. Tell your healthcare provider right away if you:
  • have a change in heartbeat (a fast or irregularheartbeat)
  • feel dizzy or faint.
• Effects on male fertility. It is not known if pretomanid can cause fertility problems in males. This couldaffect your ability to father a child. Talk to your healthcare provider if this is a concern for you.
• Build-up of an acid in your blood (lactic acidosis). The combination regimen of Pretomanid Tablets,bedaquiline, and linezolid can cause a build-up of acid in your blood. A build-up of acid in your blood isa side effect of linezolid. Call your healthcare provider right away if you have nausea and vomitingthat keep coming back.

The most common side effects of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolidinclude:

• acne
• nausea
• vomiting
• muscle and bone pain
• headache
• abnormal blood tests that maybe due to injury to your liver
• heartburn
• decreased appetite
• rash
• itching
• stomach area (abdominal) pain
• chest pain that worsens whenyou breathe or cough
• lower respiratory tract infection
• abnormal blood tests that maybe due to injury to yourpancreas
• coughing up blood
• cough
• low blood sugar
• unusual weight loss
• diarrhea

These are not all the possible side effects of the combination regimen of Pretomanid Tablets, bedaquiline, andlinezolid. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Pretomanid Tablets?

Store Pretomanid Tablets, bedaquiline, and linezolid below 86°F (30°C). Ask your pharmacist if you havequestions about how to store bedaquiline and linezolid.

Keep Pretomanid Tablets in the original container with the container tightly closed.

Keep Pretomanid Tablets and all medicines out of the reach of children.

General information about the safe and effective use of the combination regimen of Pretomanid Tablets,bedaquiline, and linezolid.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not usePretomanid Tablets, bedaquiline, or linezolid for a condition for which it was not prescribed. Do not givePretomanid Tablets, bedaquiline, or linezolid to other people, even if they have the same symptoms that youhave. This may harm them. You can ask your pharmacist or healthcare provider for information aboutPretomanid Tablets, bedaquiline, and linezolid that is written for health professionals.

What are the ingredients in the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid?

Pretomanid Tablets active ingredient: pretomanid

Pretomanid Tablets inactive ingredients: colloidal silicon dioxide, lactose monohydrate, magnesium stearate,microcrystalline cellulose, povidone, sodium lauryl sulfate, and sodium starch glycolate

The ingredients for bedaquiline can be found in the Medication Guide for bedaquiline. The ingredients forlinezolid can be found in the information about linezolid that is written for health professionals.