Pretomanid

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 200 mg

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_d/F: 97 to 180 L.

Metabolism

Multiple reductive and oxidative pathways; CYP3A4 accounts for up to ~20% of metabolism.

Excretion

Urine: 53% (primarily metabolites [~1% as unchanged drug]); Feces: 38%.

Time to Peak

4.5 hours (median).

Half-Life Elimination

16 hours.

Protein Binding

~86.4%.

Use: Labeled Indications

Tuberculosis: Treatment of pulmonary extensively drug resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis (TB), as part of a combination regimen with bedaquiline and linezolid, in adult patients.

Limitations of use: Not indicated for drug-sensitive tuberculosis, latent infection due to Mycobacterium tuberculosis, or multidrug-resistant TB that is not treatment-intolerant or nonresponsive to standard therapy. Safety and efficacy have not been established for use in combination with drugs other than bedaquiline and linezolid.

Contraindications

Use in patients for whom bedaquiline and/or linezolid are contraindicated.

Dosage and Administration

Dosing: Adult

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.

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.

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer with food. Swallow tablet whole with water.

Storage

Store <30°C (86°F). Dispense only in original container.

Drug Interactions

Alcohol (Ethyl): May enhance the hepatotoxic effect of Pretomanid. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Pretomanid. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Pretomanid. Avoid combination

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

OAT1/3 Substrates: Pretomanid may increase the serum concentration of OAT1/3 Substrates. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

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

Warnings/Precautions

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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

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.

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Pretomanid is used in combination with bedaquiline and linezolid; refer to the bedaquiline and linezolid monographs for additional information.

Patient Education

What is this drug used for?

• It is used to treat TB (tuberculosis).

Frequently reported side effects of this drug

• Constipation
• Diarrhea
• Abdominal pain
• Nausea
• Vomiting
• Lack of appetite
• Heartburn
• Acne
• Cough
• Weight loss
• Dry skin
• Trouble sleeping
• Bone pain

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps
• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating
• Infection
• Severe headache
• Dizziness
• Passing out
• Vision changes
• Burning or numbness feeling
• Tremors
• Change in balance
• Weakness
• Coughing up blood
• Chest pain
• Fast heartbeat
• Abnormal heartbeat
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.