Pretomanid (pretomanid)

If linezolid is permanently discontinued during the first 4 consecutive weeks of treatment with the 3-drug combination regimen, pretomanid and bedaquiline should also be discontinued. If linezolid is discontinued after the first 4 weeks of consecutive treatment with the combination regimen, pretomanid and bedaquiline may be continued.

If pretomanid or bedaquiline is permanently discontinued, the entire 3-drug combination regimen should be discontinued.

Pretomanid is administered orally with food. The tablets should be swallowed whole with water.

The combination regimen of pretomanid, bedaquiline, and linezolid should be administered using directly observed (supervised) therapy (DOT).

If the combination regimen is interrupted for safety reasons, the missed doses of the drugs may be taken at the end of the treatment; however, if dose(s) of linezolid are missed because of linezolid-associated adverse reactions, the missed dose(s) should not be made up.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Pretomanid/Strong And Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of pretomanid by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and pretomanid may result in decreased levels and clinical effectiveness of pretomanid.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of pretomanid recommends avoiding concurrent use with strong or moderate CYP3A4 inducers during pretomanid therapy.(1) Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and pretomanid should be observed for decreased levels and clinical effectiveness.

DISCUSSION: In a clinical study, concurrent use of pretomanid 200 mg with efavirenz 600 mg for 7 days resulted in decreased mean area-under-curve (AUC) by 35% and maximum concentration (Cmax) by 28%.(1) In a clinical study, concurrent use of pretomanid 200 mg with rifampin 600 mg for 7 days resulted in decreased mean AUC by 66% and Cmax by 53%.(1) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, belzutifan, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, etravirine, fexinidazole, fosphenytoin, ivosidenib, lesinurad, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, rifampin, rifapentine, St. John's wort, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

There are no moderate interactions for this drug.

The manufacturer does not state any specific contraindications for use of pretomanid.

Because pretomanid must be used in conjunction with bedaquiline and linezolid, the contraindications for these drugs must be considered. Prescribing information for bedaquiline and linezolid should be consulted for information on contraindications regarding use of these drugs.

There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• No disease contraindications

Adverse effects reported in 10% or more of patients receiving pretomanid in conjunction with bedaquiline and linezolid include peripheral neuropathy, acne, anemia, nausea, vomiting, headache, increased transaminase concentrations (ALT, AST), dyspepsia, decreased appetite, rash, pruritus, abdominal pain, pleuritic pain, increased concentrations of gamma-glutamyltransferase (GGT), lower respiratory tract infection, hyperamylasemia, hemoptysis, back pain, cough, visual impairment, hypoglycemia, abnormal loss of weight, and diarrhea.

More Frequent

• Anemia
• Elevated serum amylase
• Hypoglycemic disorder
• Increased alanine transaminase
• Increased aspartate transaminase
• Lower respiratory infection

Rare or Very Rare

• Leukopenia
• Optic neuropathy
• Pancytopenia
• Thrombocytopenic disorder

More Frequent

• Acne vulgaris
• Acute abdominal pain
• Anorexia
• Back pain
• Cough
• Diarrhea
• Dyspepsia
• Headache disorder
• Hemoptysis
• Nausea
• Peripheral neuropathy
• Pleuritic chest pain
• Pruritus of skin
• Skin rash
• Visual changes
• Vomiting
• Weight loss

Less Frequent

• Constipation
• Dry skin
• Elevated serum lipase
• Gastritis
• Insomnia
• Musculoskeletal pain
• Neutropenic disorder

No enhanced messaging available.

Safety and efficacy of pretomanid have not been established in pediatric patients.

Data are not available regarding use of pretomanid in pregnant women to inform a drug-associated risk of adverse developmental outcomes. In animal studies, no adverse embryofetal toxicities were observed in pregnant rats or rabbits receiving pretomanid at doses that resulted in exposures approximately 2 times higher than human exposures at the recommended dosage. In rabbits receiving doses resulting in exposures approximately 4 times higher than human exposure at the recommended dosage, increased postimplantation loss in the presence of maternal toxicity (including reduced body weight and feed consumption) was reported.

Pregnant women are at increased risk for complications from active tuberculosis, which may lead to adverse maternal and/or neonatal outcomes (e.g., maternal anemia, cesarean delivery, preterm delivery, low birthweight, birth asphyxia, perinatal infant death).

Because pretomanid must be used in conjunction with bedaquiline and linezolid, precautions related to use of these drugs in pregnant women also should be considered.

It is not known whether pretomanid is distributed into human milk, affects the breast-fed infant, or affects milk production. The drug is distributed into milk in rats.

The benefits of breast-feeding and the importance of pretomanid to the woman should be considered along with the potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

Because pretomanid must be used in conjunction with bedaquiline and linezolid, precautions related to use of these drugs in breast-feeding women also should be considered.

Clinical studies of pretomanid did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.