Pretomanid, a new class of antimycobacterial medication, is used in conjunction with bedaquiline and linezolid to treat pulmonary tuberculosis that has developed a high level of drug resistance. Extensively drug-resistant tuberculosis formerly required treatment with 8 or more medications for a minimum of 18 months. In patients with severely drug-resistant pulmonary tuberculosis, the BPaL regimen can be administered for as little as 26 weeks (or 6 months). Patients who are unable to tolerate or are not responding to the MDR-TB regimen may also be given it. It is not indicated for:

• Use in combination with other antituberculous drugs
• Drug sensitive tuberculosis
• Latent tuberculosis
• Patients with multi-drug resistant tuberculosis who do not react negatively to the regimen and those who do.

Pretomanid dose in Adults

Pretomanid dose in the treatment of extensively drug-resistant Tuberculosis, or MDR pulmonary tuberculosis in patients who are treatment-intolerant or nonresponsive):

• For 26 weeks, 200 mg were given orally once a day along with bedaquiline and linezolid when receiving DOT (directly observed therapy).
• If more time is required, the treatment may last longer than 26 weeks.

• Missed doses:

  • The treatment may be continued than 26 weeks to make up for missed doses if the healthcare provider interrupts it due to safety concerns.

• Discontinuation of therapy:

  • During the first four weeks of treatment, if pretomanid, bedaquiline, or linezolid are permanently stopped, the entire regimen should also be stopped.
  • However, if linezolid is stopped after the first four weeks of treatment, pretomanid in conjunction with bedaquiline solely may be continued.

Pretomanid dose in Children

It has not been studied in children.

Pregnancy Risk Category: C

• Animal studies have shown adverse fetal events.
• It is often used with linezolid and bedaquiline, so safety should also be considered.

Pretomanid use during breastfeeding:

• It is unknown if the drug will be excreted into breastmilk.
• Manufacturers recommend that you weigh the risks to your infant and the benefits for the mother.
• It is administered in combination with linezolid or bedaquiline. Before initiating treatment, it is important to verify the safety of each drug.

Pretomanid dose in Kidney Disease:

The drug has not been studied in patients with kidney disease. The manufacturer has not recommended any adjustment in the dose.

Pretomanid dose in Liver Disease:

The drug has not been studied in patients with liver disease. The manufacturer has not recommended any adjustment in the dose.

Pretomanid side effects (common):

• Central Nervous System:

  • Peripheral Neuropathy
  • Headache
  • Severe Peripheral Neuropathy

• Dermatologic:

  • Acne Vulgaris
  • Skin Rash
  • Pruritus

• Endocrine & Metabolic:

  • Increased Gamma-Glutamyl Transferase
  • Hypoglycemia

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Dyspepsia
  • Decreased Appetite
  • Abdominal Pain
  • Increased Serum Amylase

• Hematologic & Oncologic:

  • Anemia

• Hepatic:

  • Increased Serum Transaminases
  • Increased Serum Alanine Aminotransferase

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain

• Ophthalmic:

  • Visual Impairment

• Respiratory:

  • Pleuritic Chest Pain
  • Lower Respiratory Tract Infection
  • Hemoptysis
  • Cough

Pretomanid side effects (less common):

• Cardiovascular:

  • Hypertension
  • Prolonged QT Interval On ECG

• Central Nervous System:

  • Insomnia
  • Dizziness
  • Seizure

• Dermatologic:

  • Xeroderma

• Endocrine & Metabolic:

  • Weight Loss
  • Hyperglycemia
  • Hyperkalemia
  • Hypokalemia
  • Hypomagnesemia
  • Hyponatremia

• Gastrointestinal:

  • Diarrhea
  • Constipation
  • Gastritis
  • Increased Serum Lipase
  • Dysgeusia
  • Pancreatitis

• Hematologic & Oncologic:

  • Neutropenia
  • Thrombocytopenia
  • Leukopenia

• Hepatic:

  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Bilirubin
  • Increased Serum Alkaline Phosphatase

• Neuromuscular & Skeletal:

  • Increased Creatine Phosphokinase In Blood Specimen

• Ophthalmic:

  • Optic Neuropathy

• Renal:

  • Increased Serum Creatinine

Pretomanid side effects (rare)

• Endocrine & metabolic:

  • Lactic acidosis

• Hematologic & oncologic:

  • Pancytopenia

• Hepatic:

  • Hepatotoxicity

Contraindication to Pretomanid Include:

Contraindications to linezolid or bedaquiline (or any other drug in the BPaL regime)

Warnings and precautions

• Hepatic effects
  • Patients who were treated with the combination regimen (in conjunction with linezolid and bedaquiline) have been diagnosed as having liver toxicities.
  • Patients with impaired liver function should avoid alcohol and other hepatotoxic substances.
  • It is important to monitor patients for any clinical or biochemical signs of hepatotoxicity, including anorexia and vomiting, dark urine and fatigue, jaundice and hepatomegaly as well as right hypochondrial pain, tenderness and hyperchondrial pain, and elevated liver enzymes.
  • If:
    • The patient has elevated liver enzymes and a higher total bilirubin than the normal upper limits.
    • Enhanced aminotransferases greater than 8x the normal upper limit
    • Having elevated levels of aminotransferases that exceed 5 times normal for more than two weeks.
• Lactic acidosis:
  • Patients who received the combination regimen (pretomanid combined with linezolid and bedaquiline) have been known to develop lactic acidosis.
  • Lactic acidosis, a side effect of linezolid, is well-known.
  • The patient should stop receiving treatment (the entire regimen or linezolid) immediately.
• Myelosuppression
  • Pretomanid, in combination with linezolid and bedaquiline, has been associated with myelosuppression.
  • Myelosuppression is an adverse reaction to linezolid.
  • The hematologic abnormalities could be reversed if linezolid dosage was decreased, stopped, or discontinued as part of the combination regimen.
  • Patients with myelosuppression should be monitored and treated accordingly.
• Neuropathy:
  • Patients who are prescribed a combination of pretomanid, bedaquline, and linezolid could develop optic and peripheral neuropathy.
  • Neuropathy is a side effect of linezolid. It can be reversed by treatment discontinuation, dose reduction and drug interruption.
  • It is important to monitor vision impairment and reduce the dose of linezolid. It is important to have an ophthalmologic evaluation done immediately.
• Extension of QT
  • Pretomanid can prolong QT when used in combination with linezolid and bedaquiline.
  • Patients with the following conditions may be at greater risk of QT prolongation:
    • Patients who have a history of torsades des pointes
    • Congenital long QT syndrome,
    • Hypothyroidism,
    • Bradyarrhythmia
    • Uncompensated Heart Failure, or
    • An electrolyte imbalance is a condition in which the levels of potassium, magnesium, and calcium are below their normal ranges. Low serum levels of potassium, magnesium, and calcium are indicative of electrolyte imbalance.
  • An ECG should always be taken at the beginning of the treatment, during it, and 2, 12, 24 and 48 weeks later. The ECG should also be taken if syncope develops.
  • At baseline, electrolytes (specifically serum calcium, magnesium and potassium) should be tested and corrected. If QT prolongation is suspected, repeat testing may be performed.
  • Patients with significant ventricular arrhythmias, or a QTcF interval greater than 500 msec, should stop taking the entire BPaL regimen.

Pretomanid: Drug Interaction

Monitor:

• Monitor blood CBC and LFTs (liver function tests) at baseline, after 2 weeks, and then every month.
• Patients with worsening liver dysfunction should be investigated for viral hepatitis.
• Monitor vision
• An ECG should be performed at the beginning of the treatment, then again at 2, 12, and 24 weeks.
• Before starting treatment, check the serum levels of calcium, magnesium, and potassium. If QT interval prolongation develops, repeat the test.

How to administer Pretomanid?

Administer the drug with food. Do not crush the tablet, swallow the tablet whole with water.

Pretomanid mechanism of action:

It is an antimycobacterial drug which blocks cell wall biosynthesis and kills active replicating mycobacterium tuberculosis. It also kills non-replicating bacteria by releasing Nitric Ox and acts as a respiratory poison in anaerobic environments. 86.4% of the drug is protein bound. It is metabolized via multiple reductive and oxidative pathways and CYP3A4 (about 20% of metabolism). The half-life elimination is 16 hours. The time to reach the peak serum concentration is 4.5 hours. Excretion is primarily in the urine: 53%  and Feces: 38%.

International Brands in Pretomanid:

Pretomanid 200 mg tablet

Pretomanid Brands in Pakistan:

Not available in Pakistan