pretomanid (Rx)

Brand and Other Names:
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 200mg

Tuberculosis

Indicated as part of a combination regimen with bedaquiline and linezolid for treatment of adults with pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB)

Dosage regimen

  • Pretomanid 200 mg PO qDay x 26 weeks
  • Bedaquiline 400 mg PO qDay x 2 weeks, THEN, 200 mg 3x/week with at least 48 hr between doses for x 24 weeks (total of 26 weeks)
  • Linezolid 1200 mg PO qDay for 26 weeks; adjust dose as necessary (600 mg/day, further reduction to 300 mg/day, or interrupt dosing) for myelosuppression, peripheral neuropathy, or optic neuropathy

Dosage Modifications

Renal or hepatic impairment: Effect on the safety, effectiveness, and pharmacokinetics unknown

Hepatotoxicity

  • Interrupt treatment of entire regimen
    • Aminotransferase elevations and total bilirubin elevations >2x ULN
    • Aminotransferase elevations >8 x ULN
    • Aminotransferase elevations >5x ULN and persist beyond 2 weeks

Dosing Considerations

Indicated for use in a limited and specific patient population

Safety and effectiveness not established for use in combination with drugs other than bedaquiline and linezolid

Assessments before initiating

  • Assess for symptoms and signs of liver disease (eg, fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly)
  • Obtain laboratory tests (ALT, AST, alkaline phosphatase, bilirubin)
  • Obtain complete blood cell count
  • Obtain serum potassium, calcium, and magnesium and correct if abnormal
  • Obtain ECG

Limitations of use

  • Not indicated for
    • Drug-sensitive TB
    • Latent infection due to Mycobacterium tuberculosis
    • Extrapulmonary infection due to M tuberculosis
    • MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy

Safety and efficacy not established

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Interactions

Interaction Checker

and pretomanid

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            Adverse Effects

            Incidence refers to use of pretomanid in combination with bedaquiline and linezolid

            >10%

            Peripheral neuropathy (81%)

            Acne (39%)

            Anemia (37%)

            Nausea (37%)

            Vomiting (34%)

            Musculoskeletal pain (29%)

            Headache (28%)

            Transaminases increased (28%)

            Dyspepsia (24%)

            Decreased appetite (22%)

            Rash (21%)

            Pruritus (20%)

            Abdominal pain (19%)

            Pleuritic pain (19%)

            GGT increased (17%)

            Lower respiratory tract infection (15%)

            Hyperamylasemia (14%)

            Hemoptysis (13%)

            Cough (12%)

            Visual impairment (12%)

            Hypoglycemia (11%)

            1-10%

            Abnormal weight loss (10%)

            Diarrhea (10%)

            Constipation (8%)

            Gastritis (8%)

            Neutropenia (8%)

            Dry skin (7%)

            Hypertension (7%)

            ECG QT prolonged (6%)

            Hyperlipasemia (6%)

            Insomnia (6%)

            Thrombocytopenia (6%)

            <5%

            • Gastrointestinal disorders: Pancreatitis, dysgeusia
            • Laboratory investigations: Blood creatine phosphokinase increase, blood creatinine increase, blood alkaline phosphatase increase
            • Blood and lymphatic system disorders: Leukopenia
            • Metabolism and nutrition disorders: Hypomagnesemia, hyperglycemia, hypokalemia, hyperkalemia, hyponatremia
            • Nervous system disorders: Dizziness, seizure
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            Warnings

            Contraindications

            Pretomanid is contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated

            Cautions

            Hepatic adverse reactions were reported with the combination; interruption of treatment may be necessary; obtain ALT, AST, alkaline phosphatase, and bilirubin at a minimum at baseline, at 2 weeks, and then monthly

            Myelosuppression reported with combination (known adverse effect of linezolid); consider decreasing or interrupting linezolid dosing if patient has worsening myelosuppression

            Peripheral and optic neuropathy reported (known adverse effect of linezolid); interrupt linezolid if necessary

            QT prolongation reported with combination, although cardiac electrophysiology testing of pretomanid did not demonstrate prolonged QTc; discontinue if clinically significant ventricular arrhythmia or a QTcF interval of greater than 500 ms develops; if syncope occurs, obtain an ECG to detect QT prolongation

            Pretomanid caused testicular atrophy and impaired fertility in male rats; effects on human male fertility have not been fully evaluated

            Lactic acidosis reported with combination (known adverse effect of linezolid); immediately evaluate patient (including bicarbonate and lactic acid levels) if recurrent nausea or vomiting occurs; consider interrupting linezolid dosing or entire combination

            Drug interaction overview

            • Regimen associated with hepatotoxicity; avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid
            • Pretomanid may be in part metabolized by CYP3A4; avoid coadministration of strong or moderate CYP3A4 inducers
            • In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates
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            Pregnancy & Lactation

            Pregnancy

            No data are available on use in pregnant women

            Animal studies

            • In animal reproduction studies, there was increased postimplantation loss in the presence of maternal toxicity (reduced bodyweight and feed consumption) with oral administration of pretomanid during organogenesis in rats at doses ~4 times the exposure at the recommended dose in humans
            • No adverse embryofetal effects observed in rats or rabbits dosed with oral pretomanid during organogenesis at doses up to ~2 times the exposure in humans

            Clinical considerations

            • Active TB in pregnancy associated with adverse maternal and neonatal outcomes, including maternal anemia, caesarean delivery, preterm birth, low birth weight, birth asphyxia, and perinatal infant death

            Infertility

            • Males: Reduced fertility and testicular toxicity cannot be definitively ruled out as of August 2019

            Lactation

            No data are available regarding the presence of pretomanid in human milk, or its effects on milk production or the breastfed infant

            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 the drug and any potential adverse effects on the breastfed infant

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Nitroimidazooxazine antimycobacterial drug; kills actively replicating M tuberculosis by inhibiting mycolic acid biosynthesis, thereby blocking cell wall production

            Under anaerobic conditions, against nonreplicating 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 deazaflavin-dependent nitroreductase (Ddn), which is dependent on the reduced form of cofactor F420

            Absorption

            Steady-state achieved: ~4-6 days

            Peak plasma time

            • Single-dose, fasting: 4 hr
            • Single-dose, fed: 5 hr
            • Steady-state: 4.5 hr

            Peak plasma concentration

            • Single-dose, fasting: 1.1 mcg/mL
            • Single-dose, fed: 2 mcg/mL
            • Steady-state: 1.7 mcg/mL

            AUC

            • Single-dose, fasting: 28.1-28.8 mcg⋅hr/mL
            • Single-dose, fed: 51.6-53 mcg⋅hr/mL
            • Steady-state: 30.2 mcg⋅hr/mL

            Distribution

            Protein bound: ~86.4%

            Vd

            • Single-dose, fasting: 180 L
            • Single-dose, fed: 97 L

            Metabolism

            Metabolized by multiple reductive and oxidative pathways, with no single pathway considered as major

            In vitro studies using recombinant CYP3A4 demonstrated that this enzyme is responsible for up to approximately 20% of the metabolism

            Elimination

            Half-life

            • Single-dose, fasting: 16.9 hr
            • Single-dose, fed: 17.4 hr
            • Steady-state: 16 hr

            Clearance

            • Single-dose, fasting: 7.6 L/hr
            • Single-dose, fed: 3.9 L/hr

            Excretion

            • Excreted primarily as metabolites
            • Urine: 53%
            • Feces: 38%
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            Administration

            Oral Administration

            Take with food

            Swallow tablet whole with water

            Must be used only in combination with bedaquiline and linezolid as part of the recommended dosing regimen

            Emphasize the need for compliance with the full course of therapy to patients

            Administer the combination regimen of pretomanid, bedaquiline, and linezolid by directly observed therapy

            Missed dose

            • Missed doses of the regimen for safety reasons: Can be made up at the end of treatment
            • Doses of linezolid alone missed owing to linezolid adverse reactions should not be made up

            Discontinuation

            If either bedaquiline or pretomanid are discontinued, the entire combination regimen should also be discontinued

            Linezolid permanently discontinued during initial 4 consecutive weeks: Bedaquiline and pretomanid should also be discontinued

            Linezolid discontinued after initial 4 consecutive weeks: Continue administering bedaquiline and pretomanid

            Storage

            Store at room temperature <86ºF (30ºC)

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.