Dosing & Uses
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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (102)
- acetaminophen
acetaminophen, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- adefovir
pretomanid will increase the level or effect of adefovir by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- allopurinol
allopurinol, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- amiodarone
amiodarone, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- amobarbital
amobarbital will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- amoxicillin
amoxicillin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- apalutamide
apalutamide will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- armodafinil
armodafinil will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- atorvastatin
atorvastatin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- auranofin
auranofin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- azathioprine
azathioprine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- baricitinib
pretomanid will increase the level or effect of baricitinib by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- bexarotene
bexarotene will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- bosentan
bosentan will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- brigatinib
brigatinib will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- busulfan
busulfan, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- butabarbital
butabarbital will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- butalbital
butalbital will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- carbamazepine
carbamazepine will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
carbamazepine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid. - cefaclor
pretomanid will increase the level or effect of cefaclor by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- clavulanate
clavulanate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- clobazam
clobazam will increase the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- conjugated estrogens
pretomanid will increase the level or effect of conjugated estrogens by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- dabrafenib
dabrafenib will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- danazol
danazol, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- dienogest/estradiol valerate
dienogest/estradiol valerate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- efavirenz
efavirenz will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
efavirenz, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid. - encorafenib
encorafenib will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- enzalutamide
enzalutamide will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- erythromycin base
erythromycin base, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- erythromycin ethylsuccinate
erythromycin ethylsuccinate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- erythromycin lactobionate
erythromycin lactobionate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- erythromycin stearate
erythromycin stearate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- eslicarbazepine acetate
eslicarbazepine acetate will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of pretomanid with strong or moderate CYP3A4 inducers.
- etravirine
etravirine will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- famotidine
pretomanid will increase the level or effect of famotidine by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- floxuridine
floxuridine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- fluoxymesterone
fluoxymesterone, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- flutamide
flutamide, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- fosphenytoin
fosphenytoin will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- furosemide
pretomanid will increase the level or effect of furosemide by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- ganciclovir
pretomanid will increase the level or effect of ganciclovir by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- hydralazine
hydralazine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- ibuprofen
ibuprofen, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- imatinib
imatinib, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- infliximab
infliximab, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- interferon alfa 2b
interferon alfa 2b, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- interferon beta 1a
interferon beta 1a, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- interferon beta 1b
interferon beta 1b, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- isoniazid
isoniazid, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- ivosidenib
ivosidenib will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- ketoconazole
ketoconazole, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- levoketoconazole
levoketoconazole, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- levonorgestrel oral
levonorgestrel oral, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- levonorgestrel oral/ethinylestradiol/ferrous bisglycinate
levonorgestrel oral/ethinylestradiol/ferrous bisglycinate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- lorlatinib
lorlatinib will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- lumacaftor/ivacaftor
lumacaftor/ivacaftor will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- methotrexate
pretomanid will increase the level or effect of methotrexate by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
methotrexate, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid. - methyldopa
methyldopa, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- methyltestosterone
methyltestosterone, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- minocycline
minocycline, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- mitotane
mitotane will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- nafcillin
nafcillin will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- nevirapine
nevirapine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- nitrofurantoin
nitrofurantoin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- oseltamivir
pretomanid will increase the level or effect of oseltamivir by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- oxandrolone
oxandrolone, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- oxymetholone
oxymetholone, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- peginterferon alfa 2a
peginterferon alfa 2a, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- peginterferon alfa 2b
peginterferon alfa 2b, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- peginterferon beta-1a
peginterferon beta-1a, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- penicillin G aqueous
pretomanid will increase the level or effect of penicillin G aqueous by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
- pentobarbital
pentobarbital will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4. inducers
- phenobarbital
phenobarbital will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers
- phenytoin
phenytoin will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
phenytoin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid. - primidone
primidone will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- propylthiouracil
propylthiouracil, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- pyrazinamide
pyrazinamide, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- quinidine
quinidine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- rifabutin
rifabutin will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- rifampin
rifampin will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
rifampin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid. - rifapentine
rifapentine will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- secobarbital
secobarbital will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- simvastatin
simvastatin, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- St John's Wort
St John's Wort will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of strong or moderate CYP3A4 inducers.
- sulfadiazine
sulfadiazine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- sulfamethoxazole
sulfamethoxazole, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- sulfasalazine
sulfasalazine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- sulfisoxazole
sulfisoxazole, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- sulindac
sulindac, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- tegaserod
tegaserod, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- telotristat ethyl
telotristat ethyl will decrease the level or effect of pretomanid by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Pretomanid is a CYP3A4 substrate. Avoid coadministration of pretomanid with strong or moderate CYP3A4 inducers.
- testosterone
testosterone, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- testosterone buccal system
testosterone buccal system, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- testosterone intranasal
testosterone intranasal, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- testosterone topical
testosterone topical, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- thioguanine
thioguanine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- ticlopidine
ticlopidine, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- valproic acid
valproic acid, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- vitamin A
vitamin A, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- vitamin D
vitamin D, pretomanid. Either increases toxicity of the other by Other (see comment). Avoid or Use Alternate Drug. Comment: Pretomanid regimen associated with hepatotoxicity. Avoid alcohol and hepatotoxic agents, including herbal supplements and drugs other than bedaquiline and linezolid.
- zidovudine
pretomanid will increase the level or effect of zidovudine by Other (see comment). Avoid or Use Alternate Drug. In vitro studies demonstrated that pretomanid significantly inhibits OAT3; monitor for increased adverse effects and consider dosage reduction for OAT3 substrates.
Monitor Closely (0)
Minor (0)
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
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
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.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%
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
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