Class: Antituberculosis Agents
Chemical Name: (6S)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
Molecular Formula: C14H12F3N3O5
CAS Number: 187235-37-6
Pretomanid is an antituberculosis agent.
Uses for Pretomanid
Pretomanid has the following uses:
Limited Population: Pretomanid is an antimycobacterial indicated 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 has the following limitations of use:
Pretomanid is not indicated for patients with: drug-sensitive (DS) tuberculosis, latent infection due to Mycobacterium tuberculosis, extrapulmonary infection due to M. tuberculosis, or MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy.
Safety and effectiveness of pretomanid have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen.
Pretomanid Dosage and Administration
Pretomanid is available in the following dosage form(s) and strength(s):
Tablets: 200 mg
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Dosage and Administration
Pretomanid must be administered only as part of a regimen in combination with bedaquiline and linezolid.
Administer pretomanid in combination with bedaquiline and linezolid by directly observed therapy (DOT).
Administer pretomanid in combination with bedaquiline and linezolid as follows:
Pretomanid: 200 mg orally 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: 1,200 mg daily orally for up to 26 weeks, with dose adjustments for known linezolid toxicities.
Take the combination regimen with food.
Doses of the 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.
Cautions for Pretomanid
Pretomanid used in combination with bedaquiline and linezolid is contraindicated in patients for whom bedaquiline and/or linezolid is contraindicated.
Risks Associated With the Combination Treatment Regimen
Pretomanid is indicated for use as part of a regimen in combination with bedaquiline and linezolid. Refer to the prescribing information for bedaquiline and linezolid for additional risk information. Warnings and precautions related to bedaquiline and linezolid also apply to their use in the combination regimen with pretomanid.
Hepatic adverse reactions were reported with the combination regimen of pretomanid, bedaquiline, and linezolid. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid while on pretomanid, especially in patients with impaired hepatic function.
Monitor symptoms and signs (such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, and hepatomegaly) and laboratory tests (ALT, AST, alkaline phosphatase, and bilirubin) at a minimum at baseline, at two weeks, and then monthly while on treatment and as needed. If evidence of new or worsening liver dysfunction occurs, test for viral hepatitides and discontinue other hepatotoxic medications. Interrupt treatment with the entire regimen if:
Aminotransferase elevations are accompanied by total bilirubin elevation greater than 2 times the upper limit 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 beyond 2 weeks.
Myelosuppression (including anemia, leukopenia, thrombocytopenia, and pancytopenia) was reported with the combination regimen of pretomanid, bedaquiline, and linezolid. Myelosuppression is a known adverse reaction of linezolid. Anemia can be life threatening. When linezolid dosing, as part of the combination regimen of pretomanid, bedaquiline, and linezolid, was reduced, interrupted, or discontinued, the observed hematologic abnormalities were reversible. Complete blood counts should be monitored at a minimum at baseline, at two weeks, and then monthly in patients receiving linezolid as part of the combination regimen of pretomanid, bedaquiline, and linezolid, and decreasing or interrupting linezolid dosing should be considered in patients who develop or have worsening myelosuppression.
Peripheral and Optic Neuropathy
Peripheral neuropathy and optic neuropathy were reported with the combination regimen of pretomanid, bedaquiline, and linezolid. Neuropathy is a known adverse reaction of long-term linezolid use. Neuropathy associated with linezolid is generally reversible or improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid dosing. Monitor visual function in all patients receiving the combination regimen of pretomanid, bedaquiline, and linezolid; if a patient experiences symptoms of visual impairment, interrupt linezolid dosing and obtain prompt ophthalmologic evaluation.
QT prolongation was reported with the combination regimen of pretomanid, bedaquiline, and linezolid. QT prolongation is a known adverse reaction of bedaquiline. Obtain an ECG before initiation of treatment, and at least 2, 12, and 24 weeks after starting treatment with the combination regimen of pretomanid, bedaquiline, and linezolid. Obtain serum potassium, calcium, and magnesium at baseline and correct if abnormal. Monitor these electrolytes if QT prolongation is detected.
The following may increase the risk for QT prolongation when patients are receiving bedaquiline as part of the combination regimen of pretomanid, bedaquiline, and linezolid: a history of torsades de pointes, congenital long QT syndrome, ongoing hypothyroidism, ongoing bradyarrhythmia, uncompensated heart failure, 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 assessment and with frequent ECG monitoring.
Discontinue the combination regimen of pretomanid, bedaquiline, and linezolid if the patient develops clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms (confirmed by repeat ECG). If syncope occurs, obtain an ECG to detect QT prolongation.
Pretomanid may be in part metabolized by CYP3A4. Avoid co-administration of strong or moderate CYP3A4 inducers, such as rifampin or efavirenz, during treatment with pretomanid.
Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated.
Lactic acidosis was reported with the combination regimen of pretomanid, bedaquiline, and linezolid. Lactic acidosis is a known adverse reaction of 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 combination regimen of pretomanid, bedaquiline, and linezolid should be considered.
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 When pretomanid is 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 embryofetal 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.
Disease-Associated Maternal and/or Embryofetal 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.
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 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 adverse embryofetal effects in rats dosed with oral pretomanid during organogenesis at doses up to approximately 2 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 outcomes was observed when oral doses of pretomanid were administered to dams during organogenesis (gestational Days 7 to 19) at doses up to 60 mg/kg/day (approximately 2 times the exposure in humans for a 200 mg dose on an AUC basis).
In a pre- and postnatal development study, there were no adverse developmental effects in pups of pregnant rats orally dosed with up to 20 mg/kg/day from gestational Day 6 through lactation Day 20. Pups of pregnant females 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 maternally toxic dose (based on maternal weight loss and reduced food consumption).
Risk Summary: There is no information regarding the presence of pretomanid in human milk, or its effects on milk production or the breastfed infant. Pretomanid was detected in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for adverse reactions in nursing infants, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pretomanid and any potential adverse effects on the breastfed infant from pretomanid or from the underlying maternal condition. When pretomanid are administered in combination with bedaquiline and linezolid, information on lactation for bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolid prescribing information for more information on their use during lactation.
Animal Data: In a pre- and postnatal development study in rats treated with pretomanid at doses 0.5 and 2 times the human exposure for a 200 mg dose (AUC) from gestational day 7 through lactation day 20, concentrations in milk on lactation 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 of pretomanid in human milk.
Females and Males of Reproductive Potential
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 serum follicle stimulating hormone and luteinizing hormone in rodents.
Reduced fertility and testicular toxicity cannot be definitively ruled out in male human subjects at this time.
Safety and effectiveness of pretomanid in pediatric patients have not been established.
Clinical studies of the combination regimen of pretomanid, bedaquiline, and linezolid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
The effect of hepatic impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known.
The effect of renal impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known.
Common Adverse Effects
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.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Strong or moderate CYP3A4 inducers such as rifampin or efavirenz: Avoid co-administration.
Organic anion transporter-3 (OAT3) substrates (e.g., methotrexate): Monitor for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed.
Actions and Spectrum
Mechanism of Action
Pretomanid is a nitroimidazooxazine antimycobacterial drug. Pretomanid kills actively replicating M. tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production. Under anaerobic conditions, against non-replicating bacteria, pretomanid acts as a respiratory poison following nitric oxide release. All of these activities require nitro-reduction of pretomanid within the mycobacterial cell by the deazaflavin-dependent nitroreductase, Ddn, which is dependent on the reduced form of the cofactor F420. Reduction of F420 is accomplished by the F420-dependent glucose-6-phosphate dehydrogenase, Fgd1.
Pretomanid has demonstrated in vitro activity against the M. tuberculosis complex. Pretomanid has also demonstrated anti-M. tuberculosis activity in animal models of tuberculosis.
In murine tuberculosis models, the 3-drug combination of pretomanid, bedaquiline, and linezolid reduced bacterial counts in the lungs to a greater extent and resulted in fewer relapses at 2 and 3 months post-therapy compared to 2-drug combinations of pretomanid, bedaquiline, and linezolid.
In clinical Study 1, the pretomanid MIC was determined using the Mycobacterial Growth Indicator Tube (MGIT). The baseline pretomanid MIC for M. tuberculosis isolates in the study ranged from 0.06 to 1 mcg/mL.
Mutations in five M. tuberculosis genes (ddn, fgd1, fbiA, fbiB, and fbiC) have been associated with pretomanid resistance. The products of these genes are involved in bioreductive activation of pretomanid within the bacterial 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 of resistance 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.
Advice to Patients
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Important Information on Co-administration of Pretomanid in Combination with Bedaquiline and Linezolid
Advise patients or their caregiver that the combination regimen of pretomanid, bedaquiline, and linezolid is for patients with XDR-TB or treatment-intolerant or nonresponsive MDR-TB.
Instruct the patient or caregiver that the combination regimen of pretomanid, bedaquiline, and linezolid must be administered by directly observed therapy (DOT).
Inform patients of safety concerns associated with linezolid and bedaquiline and advise the patient or their caregiver to read the Medication Guide for bedaquiline.
Inform the patient or caregiver that pretomanid administered as a combination regimen with bedaquiline and linezolid would be useful only in adult patients with XDR-TB or treatment-intolerant or nonresponsive MDR-TB. This regimen is not indicated for treatment of latent infection or extra-pulmonary infection due to M. tuberculosis, drug-sensitive tuberculosis, or MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy.
Advise patients that the following serious adverse reactions can occur with the combination regimen of pretomanid, bedaquiline, and linezolid: liver enzyme abnormalities, myelosuppression including anemia, 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 ophthalmologic evaluation if the patient experiences symptoms of visual impairment.
Additional serious adverse reactions can occur with the use of linezolid, including serotonin syndrome, lactic acidosis, and convulsions. Refer to the prescribing information for linezolid for additional counseling information 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 known linezolid adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy.
Compliance with Treatment
Inform patients that pretomanid must be taken as part of a combination regimen with bedaquiline and linezolid. Compliance with the full course of therapy must be emphasized. Advise patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed for the full prescribed duration of dosing. Skipping doses other than as directed by a physician or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that their Mycobacterium may develop resistance and the disease will not be treatable by the regimen or other antibacterial drugs in the future.
Inform patients to take the regimen with food. Doses of the combination regimen of pretomanid, bedaquiline, and linezolid 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. If bedaquiline and/or pretomanid are permanently discontinued, the entire combination regimen of pretomanid, bedaquiline, and linezolid should 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 and effectiveness of the combination regimen of pretomanid, bedaquiline, and linezolid in populations with hepatic 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 medical conditions before starting treatment with pretomanid.
Advise patients to abstain from alcohol, hepatotoxic medications, and herbal products.
Advise patients to store pretomanid, bedaquiline, and linezolid at room temperature below 86°F (30°C).
AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
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AHFS Drug Information. © Copyright 2021, Selected Revisions September 16, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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