Version May 2024
Tuberculosis, pulmonary (treatment-intolerant or nonresponsive multidrug-resistant or extensively drug resistant): Oral: 200 mg once daily in combination with bedaquiline and linezolid for 26 weeks, administered by directly observed therapy. Treatment may be extended beyond 26 weeks if necessary (Conradie 2020).
Missed doses: If the combination regimen of pretomanid, bedaquiline, and linezolid is interrupted by a health care provider for safety reasons, missed doses may be made up at the end of the treatment.
Discontinuation of therapy: If pretomanid or bedaquiline is discontinued or if linezolid is permanently discontinued during the initial 4 consecutive weeks of treatment, the entire regimen should be discontinued. If linezolid is discontinued after the initial 4 weeks of consecutive treatment, pretomanid in combination with bedaquiline only may be continued.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported in combination with bedaquiline and linezolid. Also see bedaquiline and linezolid monographs.
>10%:
Central nervous system: Peripheral neuropathy (81%), headache (28%), severe peripheral neuropathy (22%)
Dermatologic: Acne vulgaris (39%), skin rash (21%), pruritus (20%)
Endocrine & metabolic: Increased gamma-glutamyl transferase (17%), hypoglycemia (11%)
Gastrointestinal: Nausea (37%), vomiting (34%), dyspepsia (24%), decreased appetite (22%), abdominal pain (19%), increased serum amylase (14%)
Hematologic & oncologic: Anemia (37%)
Hepatic: Increased serum transaminases (28%), increased serum alanine aminotransferase (11%)
Neuromuscular & skeletal: Musculoskeletal pain (29%)
Ophthalmic: Visual impairment (12%)
Respiratory: Pleuritic chest pain (19%), lower respiratory tract infection (15%), hemoptysis (13%), cough (12%)
1% to 10%:
Cardiovascular: Hypertension (7%), prolonged QT interval on ECG (6%)
Central nervous system: Insomnia (6%), dizziness (<5%), seizure (<5%)
Dermatologic: Xeroderma (7%)
Endocrine & metabolic: Weight loss (10%), hyperglycemia (<5%), hyperkalemia (<5%), hypokalemia (<5%), hypomagnesemia (<5%), hyponatremia (<5%)
Gastrointestinal: Diarrhea (10%), constipation (8%), gastritis (8%), increased serum lipase (5% to 6%), dysgeusia (<5%), pancreatitis (<5%)
Hematologic & oncologic: Neutropenia (8%), thrombocytopenia (6%), leukopenia (<5%)
Hepatic: Increased serum aspartate aminotransferase (8%), increased serum bilirubin (7%), increased serum alkaline phosphatase (<5%)
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (<5%)
Ophthalmic: Optic neuropathy (2%)
Renal: Increased serum creatinine (<5%)
Frequency not defined:
Endocrine & metabolic: Lactic acidosis
Hematologic & oncologic: Pancytopenia
Hepatic: Hepatotoxicity
Use in patients for whom bedaquiline and/or linezolid are contraindicated.
Concerns related to adverse effects:
• Hepatic effects: Hepatic adverse reactions have been reported with pretomanid in combination with bedaquiline and linezolid. Avoid alcohol and hepatotoxic agents, especially in patients with impaired hepatic function. Monitor patients for signs and symptoms of hepatotoxicity (eg, anorexia, dark urine, elevations in liver function tests, fatigue, hepatomegaly, jaundice, liver tenderness, nausea); if new or worsening hepatic 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 >2 times ULN, aminotransferase elevations are >8 times ULN, or aminotransferase elevations are >5 times ULN and persist >2 weeks.
• Lactic acidosis: Lactic acidosis has been reported with pretomanid in combination with bedaquiline and linezolid. Lactic acidosis is a known adverse reaction of linezolid. Immediately evaluate patients who develop recurrent nausea or vomiting, including assessment of bicarbonate and lactic acid levels, and consider interruption of treatment with linezolid or the entire regimen.
• Myelosuppression: Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia, has been reported with pretomanid in combination with bedaquiline and linezolid. Myelosuppression is a known adverse reaction of linezolid. When linezolid dosing, as part of this combination regimen, was reduced, interrupted, or discontinued, the hematologic abnormalities were reversible. Monitor CBC and consider decreasing or interrupting linezolid dosing in patients who develop or have worsening myelosuppression.
• Neuropathy: Peripheral and optic neuropathy have been reported with pretomanid in combination with bedaquiline and linezolid. Neuropathy is a known adverse reaction of long-term linezolid use that is generally reversible or improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid. Monitor visual function in all patients; if a patient experiences symptoms of visual impairment, interrupt linezolid dosing and promptly obtain an ophthalmologic evaluation.
• QT prolongation: QT prolongation was reported with pretomanid in combination with bedaquiline and linezolid. QT prolongation is a known adverse reaction of bedaquiline. Risk may be increased in patients with 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; treatment could be considered in these patients after a favorable risk-benefit assessment and with frequent ECG monitoring. Obtain an ECG prior to initiation of treatment and ≥2, 12, and 24 weeks after starting treatment, or if syncope occurs. Obtain serum calcium, magnesium, and potassium at baseline; correct if abnormal and repeat testing if QT prolongation occurs. Discontinue treatment with the entire regimen if clinically significant ventricular arrhythmia or a QTcF interval >500 msec (confirmed by repeat ECG) occurs.
Pretomanid tablets: FDA approved August 2019; anticipated availability in 2019.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Generic: 200 mg
Yes
Tablets (Pretomanid Oral)
200 mg (per each): $26.64
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Oral: Administer with food. Swallow tablet whole with water.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Pretomanid may cause reproductive toxicity.
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets (NIOSH 2016). Facilities may perform assessment of some (non-antineoplastic) hazardous drugs to determine if appropriate for alternative containment strategies and handling requirements; assess risk to determine appropriate containment strategy (USP-NF 2018).
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212862s000lbl.pdf#page=19, must be dispensed with this medication.
Tuberculosis: Treatment of adults with pulmonary tuberculosis (TB) resistant to isoniazid, rifamycins, a fluoroquinolone, and a second-line injectable antibacterial drug, as part of a combination regimen with bedaquiline and linezolid or adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy.
Limitations of use: Not indicated for patients with drug-sensitive TB, TB infection (latent TB) 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, or TB with known resistance to any component of the combination. Safety and efficacy have not been established for use in combination with drugs other than bedaquiline and linezolid.
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the hepatotoxic effect of Pretomanid. Risk X: Avoid combination
BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Pretomanid may increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Pretomanid. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Pretomanid. Risk X: Avoid combination
OAT1/3 Substrates (Clinically Relevant): Pretomanid may increase the serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor therapy
OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors): Pretomanid may increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Pretomanid may increase the serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Administration with a high-fat, high-calorie meal increased Cmax and AUC. Management: Administer with food.
Evaluate pregnancy status prior to treatment of multidrug-resistant tuberculosis (TB) in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment for multidrug resistant TB (Esmail 2018).
Adverse events were observed in some animal reproduction studies.
Tuberculosis (TB) disease (active TB) is associated with adverse fetal outcomes, including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020), as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020).
Data are limited for use of second line drugs during pregnancy (ie, pretomanid). The treatment of multidrug-resistant TB in pregnant patients should be individualized; evidence to support a specific regimen is not available (ATS/CDC/ERS/IDSA [Nahid 2019]; WHO 2020). However, pretomanid is used in combination with bedaquiline and linezolid. Pregnant women were excluded from the initial studies using this 3-drug combination; therefore, use during pregnancy is not currently recommended (WHO 2020).
It is not known if pretomanid is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Pretomanid is used in combination with bedaquiline and linezolid; refer to the bedaquiline and linezolid monographs for additional information.
Monitor CBC and liver function tests (ALT, AST, alkaline phosphatase, bilirubin) at a minimum at baseline, at 2 weeks, and then monthly while on treatment. If evidence of new or worsening hepatic dysfunction occurs, test for viral hepatitides. Monitor visual function. Obtain an ECG prior to initiation of treatment and ≥2, 12, and 24 weeks after starting treatment. Obtain serum calcium, magnesium, and potassium at baseline; repeat testing if QT prolongation occurs.
Pretomanid is an antimycobacterial drug that kills actively replicating Mycobacterium tuberculosis by inhibiting mycolic acid biosynthesis, blocking cell wall production. Against nonreplicating bacteria, under anaerobic conditions, pretomanid acts as a respiratory poison following nitric oxide release.
Distribution: Vd/F: 97 to 180 L.
Protein binding: ~86.4%.
Metabolism: Multiple reductive and oxidative pathways; CYP3A4 accounts for up to ~20% of metabolism.
Half-life elimination: 16 hours.
Time to peak: 4.5 hours (median).
Excretion: Urine: 53% (primarily metabolites [~1% as unchanged drug]); Feces: 38%.
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