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تعداد آیتم قابل مشاهده باقیمانده : 3 مورد

Pretomanid: Drug information

Pretomanid: Drug information
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For additional information see "Pretomanid: Patient drug information"

For abbreviations, symbols, and age group definitions show table
Pharmacologic Category
  • Antimycobacterial, Nitroimidazole;
  • Antitubercular Agent
Dosing: Adult
Tuberculosis, pulmonary

Tuberculosis, pulmonary (extensively drug-resistant or treatment-intolerant/nonresponsive multidrug-resistant):

Note: Expert consultation for optimal regimen and duration of treatment is advised.

Oral: 200 mg once daily in combination with bedaquiline and linezolid for 26 weeks, administered by directly observed therapy (Ref). Treatment may be extended beyond 26 weeks if necessary (Ref). Alternatively, 200 mg once daily for 24 weeks, in combination with bedaquiline, linezolid, and moxifloxacin, has also been studied (Ref).

Missed doses: If the combination regimen of pretomanid, bedaquiline, and linezolid is interrupted by a health care provider for safety reasons, missed doses may be made up at the end of the treatment.

Discontinuation of therapy: If pretomanid or bedaquiline is discontinued or if linezolid is permanently discontinued during the initial 4 consecutive weeks of treatment, the entire regimen should be discontinued. If linezolid is discontinued after the initial 4 weeks of consecutive treatment, pretomanid in combination with bedaquiline only may be continued.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Liver Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported in combination with bedaquiline and linezolid. Also see bedaquiline and linezolid monographs.

>10%:

Central nervous system: Peripheral neuropathy (81%), headache (28%), severe peripheral neuropathy (22%)

Dermatologic: Acne vulgaris (39%), skin rash (21%), pruritus (20%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (17%), hypoglycemia (11%)

Gastrointestinal: Nausea (37%), vomiting (34%), dyspepsia (24%), decreased appetite (22%), abdominal pain (19%), increased serum amylase (14%)

Hematologic & oncologic: Anemia (37%)

Hepatic: Increased serum transaminases (28%), increased serum alanine aminotransferase (11%)

Neuromuscular & skeletal: Musculoskeletal pain (29%)

Ophthalmic: Visual impairment (12%)

Respiratory: Pleuritic chest pain (19%), lower respiratory tract infection (15%), hemoptysis (13%), cough (12%)

1% to 10%:

Cardiovascular: Hypertension (7%), prolonged QT interval on ECG (6%)

Central nervous system: Insomnia (6%), dizziness (<5%), seizure (<5%)

Dermatologic: Xeroderma (7%)

Endocrine & metabolic: Weight loss (10%), hyperglycemia (<5%), hyperkalemia (<5%), hypokalemia (<5%), hypomagnesemia (<5%), hyponatremia (<5%)

Gastrointestinal: Diarrhea (10%), constipation (8%), gastritis (8%), increased serum lipase (5% to 6%), dysgeusia (<5%), pancreatitis (<5%)

Hematologic & oncologic: Neutropenia (8%), thrombocytopenia (6%), leukopenia (<5%)

Hepatic: Increased serum aspartate aminotransferase (8%), increased serum bilirubin (7%), increased serum alkaline phosphatase (<5%)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (<5%)

Ophthalmic: Optic neuropathy (2%)

Renal: Increased serum creatinine (<5%)

Frequency not defined:

Endocrine & metabolic: Lactic acidosis

Hematologic & oncologic: Pancytopenia

Hepatic: Hepatotoxicity

Contraindications

Use in patients for whom bedaquiline and/or linezolid are contraindicated.

Warnings/Precautions

Concerns related to adverse effects:

• Hepatic effects: Hepatic adverse reactions have been reported with pretomanid in combination with bedaquiline and linezolid. Avoid alcohol and hepatotoxic agents, especially in patients with impaired hepatic function. Monitor patients for signs and symptoms of hepatotoxicity (eg, anorexia, dark urine, elevations in liver function tests, fatigue, hepatomegaly, jaundice, liver tenderness, nausea); if new or worsening hepatic dysfunction occurs, test for viral hepatitides and discontinue other hepatotoxic medications. Interrupt treatment with the entire regimen if aminotransferase elevations are accompanied by total bilirubin elevation >2 times ULN, aminotransferase elevations are >8 times ULN, or aminotransferase elevations are >5 times ULN and persist >2 weeks.

• Lactic acidosis: Lactic acidosis has been reported with pretomanid in combination with bedaquiline and linezolid. Lactic acidosis is a known adverse reaction of linezolid. Immediately evaluate patients who develop recurrent nausea or vomiting, including assessment of bicarbonate and lactic acid levels, and consider interruption of treatment with linezolid or the entire regimen.

• Myelosuppression: Myelosuppression, including anemia, leukopenia, pancytopenia, and thrombocytopenia, has been reported with pretomanid in combination with bedaquiline and linezolid. Myelosuppression is a known adverse reaction of linezolid. When linezolid dosing, as part of this combination regimen, was reduced, interrupted, or discontinued, the hematologic abnormalities were reversible. Monitor CBC and consider decreasing or interrupting linezolid dosing in patients who develop or have worsening myelosuppression.

• Neuropathy: Peripheral and optic neuropathy have been reported with pretomanid in combination with bedaquiline and linezolid. Neuropathy is a known adverse reaction of long-term linezolid use that is generally reversible or improved with appropriate monitoring and interruption, dose reduction, or discontinuation of linezolid. Monitor visual function in all patients; if a patient experiences symptoms of visual impairment, interrupt linezolid dosing and promptly obtain an ophthalmologic evaluation.

• QT prolongation: QT prolongation was reported with pretomanid in combination with bedaquiline and linezolid. QT prolongation is a known adverse reaction of bedaquiline. Risk may be increased in patients with a history of torsades de pointes, congenital long QT syndrome, ongoing hypothyroidism, ongoing bradyarrhythmia, uncompensated heart failure, or serum calcium, magnesium, or potassium levels below the lower limits of normal; treatment could be considered in these patients after a favorable risk-benefit assessment and with frequent ECG monitoring. Obtain an ECG prior to initiation of treatment and ≥2, 12, and 24 weeks after starting treatment, or if syncope occurs. Obtain serum calcium, magnesium, and potassium at baseline; correct if abnormal and repeat testing if QT prolongation occurs. Discontinue treatment with the entire regimen if clinically significant ventricular arrhythmia or a QTcF interval >500 msec (confirmed by repeat ECG) occurs.

Product Availability

Pretomanid tablets: FDA approved August 2019; anticipated availability in 2019.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 200 mg

Generic Equivalent Available: US

Yes

Pricing: US

Tablets (Pretomanid Oral)

200 mg (per each): $29.37

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: Administer with food. Swallow tablet whole with water. In patients with swallowing difficulties, tablets may be either crushed and suspended in water or soaked in water and then crushed as follows:

Crush and suspend method: Crush tablets and suspend in ~5 mL of room temperature water in a drinking cup; vigorously stir to mix well. Administer immediately, then rinse cup with an additional ~5 mL of water and administer immediately to ensure all tablet residue is administered. Do not store mixture for later use.

Soak and crush method: Soak tablets in ~5 mL of room temperature water in a drinking cup for 4 to 5 minutes; crush any remaining solid tablet and vigorously stir. Administer immediately, then rinse cup with an additional ~5 mL of water and administer immediately to ensure all tablet residue is administered. Do not store mixture for later use.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2024) list; however, it may meet the criteria for a hazardous drug. Pretomanid may cause reproductive toxicity.

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/212862s008lbl.pdf#page=27, must be dispensed with this medication.

Use: Labeled Indications

Tuberculosis: Treatment, as part of an appropriate combination regimen, of adults with pulmonary tuberculosis (TB) resistant to isoniazid, rifamycins, a fluoroquinolone, and a second-line injectable antibacterial or pulmonary TB resistant to isoniazid and rifampin in patients who are treatment-intolerant or nonresponsive to standard therapy.

Limitations of use: Not indicated for patients with drug-sensitive TB, TB infection (latent TB) due to Mycobacterium tuberculosis, extra-pulmonary infection due to Mycobacterium tuberculosis, TB resistant to isoniazid and rifampin who are responsive to standard therapy and not treatment intolerant, or TB with known resistance to any component of the combination. Safety and efficacy have not been established for use in combination with drugs other than bedaquiline and linezolid.

Metabolism/Transport Effects

Substrate of CYP3A4 (Major with inducers), CYP3A4 (Minor with inhibitors); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Alcohol (Ethyl): May increase hepatotoxic effects of Pretomanid. Risk X: Avoid

BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Pretomanid may increase serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor

CYP3A4 Inducers (Moderate): May decrease serum concentration of Pretomanid. Risk X: Avoid

CYP3A4 Inducers (Strong): May decrease serum concentration of Pretomanid. Risk X: Avoid

OAT1/3 Substrates (Clinically Relevant): Pretomanid may increase serum concentration of OAT1/3 Substrates (Clinically Relevant). Risk C: Monitor

OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors): Pretomanid may increase serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor

P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Pretomanid may increase serum concentration of P-glycoprotein/ABCB1 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor

Food Interactions

Administration with a high-fat, high-calorie meal increased Cmax and AUC. Management: Administer with food.

Reproductive Considerations

Evaluate pregnancy status prior to treatment of multidrug-resistant tuberculosis (TB) in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment for multidrug resistant TB (Esmail 2018).

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Tuberculosis (TB) disease (active TB) is associated with adverse fetal outcomes, including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020), as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020).

Data are limited for use of second line drugs during pregnancy (ie, pretomanid). The treatment of multidrug-resistant TB in pregnant patients should be individualized; evidence to support a specific regimen is not available (ATS/CDC/ERS/IDSA [Nahid 2019]; WHO 2020). However, pretomanid is used in combination with bedaquiline and linezolid. Pregnant women were excluded from the initial studies using this 3-drug combination; therefore, use during pregnancy is not currently recommended (WHO 2020).

Breastfeeding Considerations

It is not known if pretomanid is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Pretomanid is used in combination with bedaquiline and linezolid; refer to the bedaquiline and linezolid monographs for additional information.

Monitoring Parameters

Monitor CBC and liver function tests (ALT, AST, alkaline phosphatase, bilirubin) at a minimum at baseline, at 2 weeks, and then monthly while on treatment. If evidence of new or worsening hepatic dysfunction occurs, test for viral hepatitides. Monitor visual function. Obtain an ECG prior to initiation of treatment and ≥2, 12, and 24 weeks after starting treatment. Obtain serum calcium, magnesium, and potassium at baseline; repeat testing if QT prolongation occurs.

Mechanism of Action

Pretomanid is an antimycobacterial drug that kills actively replicating Mycobacterium tuberculosis by inhibiting mycolic acid biosynthesis, blocking cell wall production. Against nonreplicating bacteria, under anaerobic conditions, pretomanid acts as a respiratory poison following nitric oxide release.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: Vd/F: 97 to 180 L.

Protein binding: ~86.4%.

Metabolism: Multiple reductive and oxidative pathways; CYP3A4 accounts for up to ~20% of metabolism.

Half-life elimination: 16 hours.

Time to peak: 4.5 hours (median).

Excretion: Urine: 53% (primarily metabolites [~1% as unchanged drug]); Feces: 38%.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (DE) Germany: Pretomanid FGK;
  • (IE) Ireland: Dovprela;
  • (IT) Italy: Dovprela;
  • (NO) Norway: Dovprela;
  • (PL) Poland: Dovprela;
  • (ZA) South Africa: Mypreto | Pretamyl | Pretomanid mylan
  1. Conradie F, Bagdasaryan TR, Borisov S, et al; ZeNix Trial Team. Bedaquiline-pretomanid-linezolid regimens for drug-resistant tuberculosis. N Engl J Med. 2022;387(9):810-823. doi:10.1056/NEJMoa2119430 [PubMed 36053506]
  2. Conradie F, Diacon AH, Ngubane N, et al; Nix-TB Trial Team. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):893-902. doi:10.1056/NEJMoa1901814 [PubMed 32130813]
  3. Esmail A, Sabur NF, Okpechi I, Dheda K. Management of drug-resistant tuberculosis in special sub-populations including those with HIV co-infection, pregnancy, diabetes, organ-specific dysfunction, and in the critically ill. J Thorac Dis. 2018;10(5):3102-3118. doi:10.21037/jtd.2018.05.11 [PubMed 29997980]
  4. Hodson L, Ovesen J, Couch J, et al; US Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. Managing hazardous drug exposures: information for healthcare settings, 2023. https://doi.org/10.26616/NIOSHPUB2023130. Updated April 2023. Accessed December 27, 2024.
  5. Miele K, Bamrah Morris S, Tepper NK. Tuberculosis in pregnancy. Obstet Gynecol. 2020;135(6):1444-1453. doi:10.1097/AOG.0000000000003890 [PubMed 32459437]
  6. Nahid P, Mase SR, Migliori GB, Sotgiu G, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med. 2019;200(10):e93-e142. doi:10.1164/rccm.201909-1874ST [PubMed 31729908]
  7. Nyang'wa BT, Berry C, Kazounis E, et al; TB-PRACTECAL Study Collaborators. A 24-week, all-oral regimen for rifampin-resistant tuberculosis. N Engl J Med. 2022;387(25):2331-2343. doi:10.1056/NEJMoa2117166 [PubMed 36546625]
  8. Ovesen JL, Sam­mons D, Connor TH, et al; US Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. NIOSH list of hazardous drugs in healthcare settings, 2024. https://doi.org/10.26616/NIOSHPUB2025103. Updated December 18, 2024. Accessed December 20, 2024.
  9. Pretomanid [prescribing information]. Morgantown, WV: Mylan Specialty LP; November 2024.
  10. Refer to manufacturer’s labeling.
  11. United States Pharmacopeia. <800> Hazardous Drugs—Handling in Healthcare Settings. In: USP-NF. United States Pharmacopeia; July 1, 2020. Accessed January 16, 2025. doi:10.31003/USPNF_M7808_07_01
  12. World Health Organization (WHO). WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. https://www.who.int/publications/i/item/9789240007048. Published 2020.
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