pre-TOE-ma-nid

Therapeutic Classification: antituberculars

Pharmacologic Classification:

• Pulmonary extensively drug resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis (in combination with bedaquiline and linezolid).

• Kills actively replicating Mycobacterium tuberculosisby inhibiting mycolic acid biosynthesis which subsequently blocks cell wall production. Acts as a respiratory poison following nitric oxide release against nonreplicating Mycobacterium tuberculosisunder anaerobic conditions.

• Bacteriostatic action against susceptible Mycobacterium tuberculosis.

Absorption: High-fat, high-calorie food ↑ drug exposure.

Distribution: Extensively distributed to extravascular tissues.

Metabolism/Excretion: Metabolized by several pathways with some metabolism via CYP3A4. Primarily excreted as metabolites in urine (53%) and feces (38%).

Half-life: 16–17 hr.

(plasma concentrations)

Contraindicated in:

• None.

Use Cautiously in:

• History of torsade de pointes, congenital long QT syndrome, hypothyroidism, bradycardia, decompensated HF, hypocalcemia, hypomagnesemia, or hypokalemia (↑ risk of QT interval prolongation)
• OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk
• Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant
• Rep: Men of reproductive potential
• Pedi: Safety and effectiveness not established in children.

Reflect side effects experienced with combination regimen of pretomanid, bedaquiline, and linezolid.

CV: hypertension, QT interval prolongation.

Derm: acne, pruritus, rash, dry skin.

EENT: optic neuropathy, visual impairment.

Endo: hypoglycemia, hyperglycemia.

F and E: LACTIC ACIDOSIS, hyperkalemia, hypokalemia, hypomagnesemia, hyponatremia.

GI: HEPATOTOXICITY, PANCREATITIS, abdominal pain, dyspepsia, ↑amylase, diarrhea, nausea, vomiting, constipation, gastritis, ↑ lipase.

GU: ↓fertility (males), ↑ serum creatinine, testicular abnormalities.

Hemat: anemia, NEUTROPENIA, leukopenia, thrombocytopenia.

Metab: ↓appetite, ↓weight.

MS: ↑creatine kinase, pain.

Neuro: peripheral neuropathy , SEIZURES, headache, dizziness, dysgeusia, insomnia.

Resp: cough, hemoptysis, lower respiratory tract infection, pleuritic pain.

Drug-Drug:

• Hepatotoxic drugs, including alcohol may ↑ risk of hepatotoxicity; avoid concurrent use.
• QT interval prolonging drugs may ↑ risk of QT interval prolongation or torsade de pointes; avoid concurrent use.
• Strong CYP3A4 inducers or moderate CYP3A4 inducers, including rifampin or efavirenz may ↓ levels and effectiveness; avoid concurrent use.
• May ↑ levels and toxicity of methotrexate.

Drug-Natural Products:

• St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

• PO (Adults): 200 mg once daily for 26 wk (in combination with bedaquiline and linezolid).

• Tablets: 200 mg;

• Assess lung sounds and character and amount of sputum periodically during therapy.
• Assess for symptoms and signs of liver disease (fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) periodically during therapy.
• Monitor visual function in patients receiving linezolid for 3 mo or who report visual symptoms (changes in acuity or color vision, blurred vision, visual field defect) regardless of length of therapy. Neuropathy associated with linezolid is generally reversible or improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid dosing. If optic neuropathy occurs therapy should be reconsidered.
• Assess ECG before starting and at least 2, 12, and 24 wk after starting therapy. If patient develops clinically significant ventricular arrhythmia or a QTc interval >500 msec, discontinue combination regimen of pretomanid, bedaquiline, and linezolid. If syncope occurs, obtain an ECG to detect QT prolongation.
• Monitor for signs and symptoms of lactic acidosis (recurrent nausea and vomiting, unexplained acidosis, low bicarbonate levels). May require interruption of linezolid or combination therapy.

• Perform mycobacterial studies and susceptibility tests prior to and periodically during therapy to detect possible resistance.
  • Monitor ALT, AST, alkaline phosphatase, and bilirubin at baseline, 2 wk, and monthly during therapy. If evidence of new or worsening liver dysfunction occurs, test for viral hepatitides and discontinue other hepatotoxic medications. If AST/ALT ↑ accompanied by total bilirubin ↑ >2 × ULN, or AST/ALT ↑ >8 × ULN, or AST/ALT ↑ >5 × ULN and persist >2 wk, interrupt therapy.
  • Monitor CBC at baseline, 2 wk, and monthly during therapy. Anemia can be fatal. Consider decreasing or interrupting linezolid therapy in patients with new or worsening myelosuppression.
  • Monitor serum potassium, calcium, and magnesium levels periodically during therapy. Correct if abnormal.

• Used only in combination with bedaquiline and linezolid. May be part of directly observed therapy (DOT).
• PO: Administer pretomanid, bedaquiline, and linezolid with food. Take pretomanid once daily for 26 wk. Swallow tablets whole with water; do not crush, break, or chew. Take bedaquiline 400 mg PO once daily for 2 wk followed by 200 mg 3 times per wk, with at least 48 hr between doses, for 24 wk for a total of 26 wk. Take linezolid starting at 1,200 mg PO per day for 26 wk, with dose adjustments to 600 mg daily and further reduction to 300 mg daily or interruption of dosing as necessary for adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy. If combination is interrupted by health care professional for safety, dose can be made up at end of therapy. Do not make up linezolid doses missed due to adverse reactions. Combination regimen can be extended beyond 26 wk.
  • If either bedaquiline or pretomanid are discontinued, discontinue entire combination. If linezolid is permanently discontinued during initial 4 consecutive wk of therapy, discontinue bedaquiline and pretomanid. If linezolid is discontinued after initial 4 wk of consecutive therapy, continue administering bedaquiline and pretomanid.

• Instruct patient to take pretomanid as directed for full course of therapy, even if feeling better. Missing doses may decrease effectiveness of therapy and increase chance that TB will not be treatable by the combination regimen of pretomanid, bedaquiline, and linezolid or other medicines. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
• Advise patient to notify health care professional promptly if signs and symptoms of hepatitis (yellow eyes and skin, nausea, vomiting, anorexia, unusual tiredness, weakness, dark urine, tenderness in right upper abdomen), thrombocytopenia (unusual bleeding or bruising), or prolonged QT interval (fast or irregular heartbeat, feeling dizzy or faint) occur.
• Caution patient to avoid the use of alcohol during this therapy, because this may increase the risk of hepatotoxicity.
• Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls.
• Advise patient to notify health care professional if signs and symptoms of peripheral neuropathy (numbness, burning, a feeling of “pins and needles”, tremors, problems with balance, weakness) or visual changes occur.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's Wort.
• Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding. May impair fertility in males.
• Emphasize the importance of regular follow-up exams to monitor progress and to check for side effects.

• Resolution of pulmonary extensively drug resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis.

NDC Code^*

• 49502- Mylan Specialty L.P.
  • 49502-476- Pretomanid
    • 49502-476-26- 26 TABLET in 1 BOTTLE (49502-476-26)