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Brand Name
Pretomanid
View Brand InformationFDA approval date: November 07, 2019
Classification: Antimycobacterial
Form: Tablet
What is Pretomanid?
Limited Population: Pretomanid Tablet is indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary tuberculosis resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients. Limitations of Use: Pretomanid Tablets are not indicated in patients with: o Drug-sensitive TB o Latent infection due to Mycobacterium tuberculosis o Extra-pulmonary infection due to Mycobacterium tuberculosis o TB resistant to isoniazid and rifampin who are responsive to standard therapy and not treatment-intolerant o TB with known resistance to any component of the combination, Safety and effectiveness of Pretomanid Tablets have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen [see Dosage and Administration.
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Brand Information
Pretomanid (Pretomanid)
1INDICATIONS AND USAGE
Limited Population: Pretomanid Tablet is indicated, as part of a combination regimen with bedaquiline and linezolid for the treatment of adults with pulmonary tuberculosis (TB) resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug OR adults with pulmonary TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. Approval of this indication is based on limited clinical safety and efficacy data. This drug is indicated for use in a limited and specific population of patients.
Limitations of Use:
- Pretomanid Tablets are not indicated in patients with:
- Safety and effectiveness of Pretomanid Tablets have not been established for its use in combination with drugs other than bedaquiline and linezolid as part of the recommended dosing regimen
2DOSAGE FORMS AND STRENGTHS
Pretomanid Tablets, 200 mg, are white to off-white, oval tablets debossed with
3CONTRAINDICATIONS
Pretomanid Tablets used in the combination regimen with bedaquiline and linezolid are contraindicated in patients for whom bedaquiline and/or linezolid are contraindicated. Refer to the bedaquiline and linezolid prescribing information.
4ADVERSE REACTIONS
The following serious adverse reactions are discussed here and elsewhere in the labeling:
- Hepatotoxicity
- Myelosuppression
- Peripheral and Optic Neuropathy
- QT Prolongation
- Reproductive Effects
- Lactic Acidosis
4.1Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.
When Pretomanid Tablets are administered in combination with bedaquiline and linezolid, refer to the prescribing information for the respective drugs for a description of the adverse reactions associated with their use.
Approximately 3100 subjects have been exposed to Pretomanid Tablets, either alone or as part of a combination therapy in clinical trials.
The registrational trial, Trial 1 (NCT02333799), was a single-arm, open-label trial conducted in three sites in South Africa in which adult patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug or pulmonary TB resistant to isoniazid and rifampin, who were treatment-intolerant or non-responsive to standard therapy received the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 6 months (extendable to 9 months) with 24 months of follow-up. One hundred and nine patients were treated; 76% were black, and 23% were of mixed race. Their ages ranged from 17 years to 60 years (mean 36 years), and all patients were from South Africa. Fifty-six (51%) patients were HIV-positive. There were 8 deaths. Six patients died while receiving treatment; all surviving patients, excluding one patient who withdrew consent, completed treatment. Two patients died during follow-up at Day 369 and Day 486, respectively.
Trial 2 (NCT03086486) was a phase 3 partially-blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid in combination with Pretomanid Tablets plus bedaquiline in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug, or pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug, or pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy.
A total of 181 patients were randomized to one of the 4 treatment arms, Pretomanid Tablets plus bedaquiline plus either 1,200 mg or 600 mg of linezolid for 26 weeks or for 9 weeks (not an approved dosing regimen), followed by a linezolid placebo for 17 weeks. Males represented 67% of the patients in the trial and the median age of all patients was 36 years. 64% of patients were White and the remaining patients were Black (36%). The treatment groups were comparable with respect to demographic characteristics. Most patients (93%) completed treatment. One patient died in the linezolid 1,200 mg for 9 weeks (not an approved dosing regimen) arm.
4.1.1Common Adverse Reactions Reported in Trials 1 and 2
Table 1 summarizes the incidence of select adverse reactions occurring in ≥ 5% of patients treated for 26 weeks in Trials 1 and 2.
The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid (1,200 mg) at a rate of less than 5% in Trials 1 and 2:
Gastrointestinal Disorders: pancreatitis, dysgeusia
Investigations: blood creatine phosphokinase increase, blood creatinine increase, blood alkaline phosphatase increase
Blood and Lymphatic System Disorders: leukopenia, thrombocytopenia
Metabolism and Nutrition Disorders: hypomagnesemia, hyperglycemia, hypokalemia, hyperkalemia, hyponatremia
Nervous System Disorders: dizziness, seizure
The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid (600 mg) at a rate of less than 5% in Trial 2:
Blood and Lymphatic System Disorders: anemia, thrombocytopenia
Metabolism and Nutrition Disorders: decreased appetite, hyperlipasemia, hypoglycemia, hypophosphatemia, hypomagnesemia, hyperkalemia
Psychiatric Disorders: insomnia
Nervous System Disorders: headache
Vascular Disorders: hypertension
Respiratory, Thoracic and Mediastinal Disorders: cough, hemoptysis
Gastrointestinal Disorders: abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting
Skin and Subcutaneous Tissue Disorders: dry skin, rash
Musculoskeletal and Connective Tissue Disorders: musculoskeletal pain
4.1.2Laboratory Abnormalities Reported in Trials 1 and 2
Table 2 summarizes select laboratory abnormalities in patients treated for 26 weeks in Trials 1 and 2.
In Trial 1, 28% of patients experienced increased transaminases. Except for one patient who died due to pneumonia and sepsis, all patients who experienced increased transaminases were able to continue therapy and complete the full course of treatment. In Trial 2, 47 of 181 patients (26%) had one or more liver-related adverse reactions, with similar numbers in each group.
Myelosuppression is a known adverse reaction of linezolid. In Trial 1, the most common hematopoietic cytopenia was anemia (37%). The majority of cytopenias began after 2 weeks of treatment. Three patients experienced cytopenias that were considered serious: neutropenia in 1 patient and anemia in 2 patients. All 3 serious adverse reactions resulted in interruption of linezolid or all components of the combination regimen of Pretomanid Tablets, bedaquiline, and linezolid, and all resolved.
In Trial 2, there was a greater incidence of myelosuppression, 29% versus 13%, for the 1,200 mg compared to the 600 mg linezolid 26-week group. Most of the myelosuppression-related adverse reactions were either grade 1 or grade 2 in severity.
In the combined study data for Trial 1 and Trial 2, 2 patients reported serious adverse reactions of anemia with linezolid 1,200 mg, and none were reported in the 600 mg group.
4.1.3Peripheral and Optic Neuropathy
Peripheral neuropathy is a known adverse reaction of linezolid. In Trial 1, peripheral neuropathy was reported in 81% of patients. Most of these adverse reactions (64%) occurred after 8 weeks of treatment and resulted in dosing interruption, dose reduction, or discontinuation of linezolid. Severe, moderate, and mild peripheral neuropathy occurred in 22%, 32%, and 26% of patients, respectively. No adverse reaction related to peripheral neuropathy led to a discontinuation of the entire study regimen.
In Trial 2, 17 (38%) patients reported an adverse reaction of peripheral neuropathy in the 1,200 mg 26-week treatment group; one of these reactions led to treatment discontinuation. In the 600 mg 26-week treatment group, 10 (22%) patients reported peripheral neuropathy, and none required linezolid treatment interruption or treatment discontinuation.
Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%) in Trial 1 developed optic neuropathy after 16 weeks of treatment. Both were serious, confirmed on retinal examination as optic neuropathy/neuritis, and resulted in discontinuation of linezolid; both adverse reactions resolved.
Overall, patients administered a linezolid dose of 600 mg twice daily had a similar safety profile to those administered a dose of 1,200 mg once daily.
In Trial 2 overall, 4 (2%) patients reported an adverse reaction of optic neuropathy. All 4 patients were in the 1,200 mg linezolid 26-week treatment group (9%). The maximum severity was grade 1 (mild) for 1 patient, grade 2 (moderate) for 2 patients, and grade 3 (severe) for 1 patient. All patients had linezolid permanently discontinued except 1 patient who had already completed treatment when the adverse reaction occurred. Onset of optic neuropathy occurred after 3 months of treatment, and resolved.
5OVERDOSAGE
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.
6DESCRIPTION
Pretomanid is an oral nitroimidazooxazine antimycobacterial drug.
Pretomanid is a white to off-white to yellow-colored powder. The chemical name for pretomanid is (6
Each Pretomanid Tablet contains 200 mg of pretomanid. The inactive ingredients are colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and sodium starch glycolate.
7CLINICAL STUDIES
Trial 1
Trial 1 (NCT02333799) was an open-label trial conducted in three centers in South Africa in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug (Population 1), or pulmonary TB resistant to isoniazid and rifampin, who were treatment-intolerant or non-responsive to standard therapy (Population 2). Fifty-six (51%) patients were HIV-positive. The patients received a combination regimen of Pretomanid Tablets, bedaquiline, and linezolid for 26 weeks (extended to 9 months in 2 patients) with 24 months of follow-up. The dosage of Pretomanid Tablets was 200 mg orally once daily. The dosage of bedaquiline was 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week for 24 weeks. The starting dose of linezolid was either 600 mg orally twice daily or 1,200 mg orally once daily. One hundred seven of the 109 patients enrolled were assessable for the primary efficacy analyses with two patients remaining in follow-up for the primary outcome assessment.
Treatment failure was defined as the incidence of bacteriologic failure (reinfection – culture conversion to positive status with a different
Trial 2
Trial 2 (NCT03086486) was a phase 3 partially blinded, randomized trial assessing the safety and efficacy of various doses and treatment durations of linezolid plus Pretomanid Tablets and bedaquiline in patients with pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug, or pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug, or pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy.
A total of 181 patients were randomized to receive one of 4 treatment regimens, of which 45 each received 1,200 mg or 600 mg linezolid orally plus Pretomanid Tablets and bedaquiline for 26 weeks, and 46 and 45 patients received 1,200 mg or 600 mg linezolid orally for 9 weeks (not an approved dosing regimen), followed by linezolid placebo for 17 weeks, respectively, plus Pretomanid Tablets and bedaquiline for 26 weeks. The dosage of Pretomanid Tablets was 200 mg orally once daily for 26 weeks. The dosage of bedaquiline was 200 mg daily for 8 weeks, followed by 100 mg daily for 18 weeks.
Treatment failure was defined as the incidence of bacteriologic failure, bacteriologic relapse or clinical failure through follow-up until 6 months after the end of treatment, which was identical to the definition of treatment failure in Trial 1.
The success rate in each treatment arm significantly exceeded the historical success rates for TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug based on a literature review used in Trial 1. When used in combination with Pretomanid Tablets and bedaquiline, linezolid 600 mg once daily for 26 weeks is preferred over linezolid 1,200 mg once daily for 26 weeks [see Dosage and Administration (2.2)].
Among the 90 patients receiving linezolid for 26 weeks, the mean age of the patients was 38 years old with 68% being males. Most patients were White (64%), and the remaining patients were Black (36%). Most patients had a current diagnosis (a stratification factor) of pulmonary TB resistant to rifamycins and either a fluoroquinolone or a second line injectable antibacterial drug (46%) or pulmonary TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug (44%), and the remainder were patients having pulmonary TB resistant to isoniazid and rifampin who were treatment intolerant or non-responsive to standard therapy (6% and 4%, respectively). The results are presented in Table 5 below.
8HOW SUPPLIED/STORAGE AND HANDLING
Pretomanid Tablet 200 mg is packaged in either white, round, high-density polyethylene bottles with polypropylene child-resistant closure or child-resistant blister packages comprised of a polyvinylchloride film with foil and paper backing.
Pretomanid Tablet 200 mg is a white to off-white, oval tablet debossed with
Store below 30°C (86°F).
Dispense only in original container and keep container tightly closed.
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (
Important Information on Co-administration of Pretomanid Tablets in Combination with Bedaquiline and Linezolid Dosage and Administration (2.1)]
- 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 TB resistant to isoniazid, rifamycins, a fluoroquinolone and a second line injectable antibacterial drug or TB resistant to isoniazid and rifampin, who are treatment-intolerant or nonresponsive to standard therapy. This regimen is not indicated for treatment in patients with latent infection or extra-pulmonary infection due to
- 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.
Serious 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
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.
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
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.
Important 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.
- Advise patients who have difficulty swallowing tablets that Pretomanid Tablets can be crushed and suspended in water at room temperature. Alternately, the tablet can be soaked for 4 to 5 minutes in room temperature water and then the remaining solid crushed
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
Manufactured by:
Manufactured for:
MS:MXA:PRET:R4
10MEDICATION GUIDE
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: 11/2024
11PRINCIPAL DISPLAY PANEL – 200 mg
NDC 49502-476-26
Rx only
Pretomanid
200 mg
Limited
Dispense the enclosed
*See the full prescribing
26 tablets
Each tablet contains:
Recommended Dosage:
see Prescribing Information.
see Prescribing Information.
Keep this and all medication
Store below 30°C (86°F).
Dispense only in original container.
Keep container tightly closed.
Manufactured by:
Manufactured for:
Under license from TB Alliance.
Code No.: MH/DRUGS/AD/089
MS:MXA:47626:1C:R3
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