DRUG INTERACTIONS

1. Effect of Other Drugs on Pretomanid

CYP3A4 Inducers Co-administration of pretomanid with rifampin and efavirenz resulted in a decrease in pretomanid plasma concentrations 

Avoid co-administration of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid with rifampin, efavirenz, or other strong or moderate CYP3A4 inducers. Refer to the prescribing information for bedaquiline for additional information about drug interactions with CYP3A4.

Lopinavir/ritonavir Co-administration of pretomanid with lopinavir/ritonavir did not affect the plasma concentrations of pretomanid 

Lopinavir/ritonavir can be co-administered with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid

2. Effect of Pretomanid on Other Drugs

Midazolam- Co-administration of pretomanid with the CYP3A4 substrate, midazolam, resulted in no clinically significant effect on the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy-midazolam 

The combination regimen of Pretomanid Tablets, bedaquiline, and linezolid can be administered with CYP3A4 substrate drugs.

Organic Anion Transporter-3 (OAT3) Substrates 

The effect of co-administration of pretomanid on the pharmacokinetics of OAT3 substrates in humans is unknown. However, in vitro studies indicate that pretomanid significantly inhibits the OAT3 drug transporter , which could result in increased concentrations of OAT3 substrate drugs clinically and may increase the risk of adverse reactions with these drugs. 

If pretomanid is co-administered with OAT3 substrate drugs (e.g., methotrexate), monitor for OAT3 substrate drug-related adverse reactions and consider dosage reduction for OAT3 substrate drugs, if needed. Refer to the prescribing information of the co-administered drug for dosage reduction information.

WARNINGS -                                                                                                         • Hepatic adverse reactions were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

Monitor symptoms and signs and liver-related laboratory tests. Interrupt treatment with the entire regimen if evidence of liver injury occurs.

ADVERSE REACTIONS

 Most common adverse reactions (=10%) are peripheral neuropathy, acne, anemia, nausea, vomiting, headache, increased transaminases, dyspepsia, decreased appetite, rash, pruritus, abdominal pain, pleuritic pain, increased gamma-glutamyltransferase, lower respiratory tract infection, hyperamylasemia, hemoptysis, back pain, cough, visual impairment, hypoglycemia, abnormal loss of weight, and diarrhea.

WARNINGS AND PRECAUTIONS

• Hepatic adverse reactions were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

Monitor symptoms and signs and liver-related laboratory tests. Interrupt treatment with the entire regimen if evidence of liver injury occurs. 

• Myelosuppression was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

Monitor complete blood counts. Decrease or interrupt linezolid dosing if significant myelosuppression develops or worsens. 

• Peripheral and optic neuropathy were reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

Monitor visual function. Obtain an ophthalmologic evaluation if there are symptoms of visual impairment. Decrease or interrupt linezolid dosing if neuropathy develops or worsens. 

• QT prolongation was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid. Use with drugs that prolong the QT interval may cause additive QT prolongation.

Monitor ECGs. Discontinue the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid if significant ventricular arrhythmia or if QTcF interval prolongation of greater than 500 ms develops. (

• Reproductive effects: Pretomanid caused testicular atrophy and impaired fertility in male rats. Advise patients of reproductive toxicities seen in animal studies and that the potential effects on human male fertility have not been adequately evaluated.

• Lactic acidosis was reported with the use of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid.

Consider interrupting linezolid or the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid dosing if significant lactic acidosis develops. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Important Information on Co-administration of Pretomanid Tablets in Combination with Bedaquiline and Linezolid

• Advise patients or their caregiver that the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid is for patients with XDR-TB or treatment-intolerant or nonresponsive MDR-TB.

• Instruct the patient or caregiver that the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid must be administered by directly observed therapy (DOT).

• Inform patients of safety concerns associated with linezolid and bedaquiline and advise the patient or their caregiver to read the Medication Guide for bedaquiline.

• Inform the patient or caregiver that Pretomanid Tablets administered as a combination regimen with bedaquiline and linezolid would be useful only in adult patients with XDR-TB or treatment-intolerant or nonresponsive MDR-TB.

This regimen is not indicated for treatment of latent infection or extra  pulmonary infection due to M. tuberculosis, drug-sensitive tuberculosis, or MDR-TB that is not treatment-intolerant or nonresponsive to standard therapy.

Adverse Reactions

Advise patients that the following serious adverse reactions can occur with the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid: liver enzyme abnormalities, myelosuppression including anemia, peripheral and optic neuropathy, and cardiac rhythm abnormalities.

Peripheral and Optic Neuropathy

Advise patients to promptly inform their physician if they experience changes in vision during linezolid therapy.

Monitor visual function in all patients receiving linezolid. Counsel patients to obtain prompt ophthalmological evaluation if the patient experiences symptoms of visual impairment.

Additional serious adverse reactions can occur with the use of linezolid, including serotonin syndrome, lactic acidosis, and convulsions.

Refer to the prescribing information for linezolid for additional counseling information for these serious adverse reactions.

Interruption of Linezolid Dosing to Manage Linezolid Adverse Reactions

Counsel patients that linezolid dosing may be modified or interrupted during the therapy to manage the known linezolid adverse reactions of myelosuppression, peripheral neuropathy, and optic neuropathy.

Compliance with Treatment:

Inform patients that Pretomanid Tablets must be taken as part of a combination regimen with bedaquiline and linezolid. Compliance with the full course of therapy must be emphasized.

Advise patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed for the full prescribed duration of dosing.

Skipping doses other than as directed by a physician or not completing the full course of therapy may

(1) decrease the effectiveness of the immediate treatment and

(2) increase the likelihood that their Mycobacterium may develop resistance and the disease will not be treatable by the regimen or other antibacterial drugs in the future.

Administration Instructions

Inform patients to take the regimen with food.

Doses of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid missed for safety reasons can be made up at the end of treatment; doses of linezolid alone missed due to linezolid adverse reactions should not be made up.

If bedaquiline and/or Pretomanid Tablets are permanently discontinued, the entire combination regimen of Pretomanid Tablets, bedaquiline, and linezolid should be discontinued.

Use in Patients with Hepatic or Renal Impairment

Advise patients to inform their physician if they have a history of liver or kidney problems. The safety and effectiveness of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid in populations with hepatic or renal impairment have not been established.

Use with Alcohol and Other Medications

Advise patients to discuss with their physician the other medications they are taking and other medical conditions before starting treatment with Pretomanid Tablets.

Advise patients to abstain from alcohol, hepatotoxic medications, and herbal products. Storage Instructions Advise patients to store Pretomanid Tablets, bedaquiline, and linezolid at room temperature below 86°F (30°C).

Manufactured for: The Global Alliance for TB Drug Development (TB Alliance) Reference ID: 4477119 18 Manufactured by: Mylan, Laboratories Limited, Hyderabad, 500 096, India

 CLINICAL PHARMACOLOGY

1.Mechanism of Action

Pretomanid is a nitroimidazooxazine antimycobacterial drug [see Microbiology

2. Pharmacodynamics

Cardiac Electrophysiology

A randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg), crossover, thorough QT study of pretomanid was performed in 74 healthy adult subjects. At 400 mg (2 times the approved recommended dosage) and 1,000 mg (5 times the approved recommended dosage) single doses of pretomanid, no significant QT prolongation effect was detected.

3. Pharmacokinetics

Pretomanid AUC and Cmax were approximately dose proportional over a range of single oral doses from 50 mg (0.25 times the approved recommended dosage) to 200 mg (approved recommended dosage); at single doses greater than 200 mg and up to 1,000 mg (5 times the approved recommended dosage), AUC and Cmax increased in a less than dose proportional manner.

Steady-state pretomanid plasma concentrations were achieved approximately 4 to 6 days following multiple dose administration of 200 mg, and the accumulation ratio was approximately

 Absorption

Effect of Food

Administration of an oral tablet dose of pretomanid with a high-fat, high-calorie meal (approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) increased mean Cmax by 76% and mean AUCinf by 88% as compared with the fasted state 

Distribution

The plasma protein binding of pretomanid is approximately 86.4%.

Metabolism

Pretomanid is 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 of pretomanid.

Excretion

In healthy adult males receiving 1,100 mg oral 14C-radiolabeled pretomanid, a mean (SD) of 53% (3.4%) of a radioactive dose was excreted in urine and 38% (2.7%) in feces, primarily as metabolites; approximately 1% of the radioactive dose was excreted in the urine as unchanged pretomanid.

Specific Populations

No clinically significant differences in the pharmacokinetics of pretomanid were observed based on sex, body weight, race (Black, White, or other), pulmonary TB status (XDR, treatment intolerant or non-responsive MDR), or HIV status.

The effect of renal or hepatic impairment on the pharmacokinetics of pretomanid is unknown.

Drug Interaction Studies

Clinical Studies Efavirenz: Co-administration of 200 mg QD of pretomanid with efavirenz 600 mg QD for 7 days resulted in a decrease of pretomanid mean AUC by 35% and Cmax by 28%.

Mean AUC and Cmax of efavirenz were not affected when given with pretomanid.

Lopinavir/ritonavir: Co-administration of 200 mg QD pretomanid with lopinavir/ritonavir 400/100 mg BID for 7 days resulted in a decrease of pretomanid mean AUC by 17% and Cmax by 13%.

Mean AUC and Cmax of lopinavir were decreased by 14% and 17%, respectively, when given with pretomanid.

Rifampin: Co-administration of 200 mg QD pretomanid with rifampin 600 mg QD for 7 days resulted in a decrease of pretomanid mean AUC by 66% and Cmax by 53%.

Midazolam: Co-administration of 400 mg (twice the approved recommended dosage) QD pretomanid for 14 days and a single 2 mg oral dose of midazolam on Day 14 resulted in a decrease in midazolam mean AUC by 15% and Cmax by 16%, and an increase in 1-hydroxy midazolam mean AUC by 14% and Cmax by 5%.

  USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

There are no studies or available data on pretomanid use in pregnant women to inform any drug-associated risks. There are risks associated with active tuberculosis during pregnancy (see Clinical Considerations).

When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, the pregnancy information for bedaquiline and linezolid also applies to this combination regimen. Refer to the bedaquiline and linezolid prescribing information for more information on bedaquiline and linezolid associated risks of use during pregnancy.

There were no adverse embryo fetal effects in rats or rabbits dosed with oral pretomanid during organogenesis at doses up to approximately 2 times the exposure in humans. 

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the United States general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. 

2 Lactation Risk Summary

There is no information regarding the presence of pretomanid in human milk, or its effects on milk production or the breastfed infant.

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 Pretomanid Tablets and any potential adverse effects on the breastfed infant from Pretomanid Tablets or from the underlying maternal condition.

3. Females and Males of Reproductive Potential Infertility

Males

Reduced fertility and/or testicular toxicity were observed in male rats and mice treated with oral pretomanid. These effects were associated with hormonal changes including decreased serum inhibin B and increased serum follicle stimulating hormone and luteinizing hormone in rodents 

Reduced fertility and testicular toxicity cannot be definitively ruled out in male human subjects at this time.

4. Pediatric Use

Safety and effectiveness of Pretomanid Tablets in pediatric patients have not been established.

5.Geriatric Use

Clinical studies of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

6. Hepatic Impairment

The effect of hepatic impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known.

7. Renal Impairment The effect of renal impairment on the safety, effectiveness, and pharmacokinetics of pretomanid is not known.

 OVERDOSAGE

There is no experience with the treatment of acute overdose with pretomanid. Take general measures to support basic vital functions including monitoring of vital signs and ECG (QT interval) in case of deliberate or accidental overdose.