Pretomanid is a novel class of antimycobacterial drug that is used in combination with bedaquiline and linezolid for the treatment of extensively drug-resistant pulmonary tuberculosis. Previous regimens of extensively drug-resistant tuberculosis included 8 or more drugs for a minimum of 18 months. The BPaL regimen can be given for as short as 26 weeks (that is 6 months) in patients with extensively drug-resistant pulmonary tuberculosis. It may also be given to patients who are intolerant to the MDR-TB regimen or are not responding to the MDR-TB regimen. It is not indicated for:

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

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):

• 200 mg orally once a day in combination with bedaquiline and linezolid, administered by DOT (directly observed therapy) for 26 weeks.
• The treatment may be extended beyond 26 weeks if necessary.

• Missed doses:

  • If the treatment is interrupted by the healthcare provider because of safety concerns, the treatment may be extended beyond 26 weeks to cover the missed doses.

• Discontinuation of therapy:

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

Pretomanid dose in Childrens

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.
  • ECG should always be performed at baseline, during treatment, and 2, 12, 24 and 48 weeks after the treatment has begun. If syncope occurs, ECG should also be taken.
  • 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
• ECG should be done at baseline, then repeated at 2, 12, and 24 weeks of starting the treatment.
• Check serum calcium, magnesium, and potassium prior to initiating therapy and repeat if QT interval prolongation occurs.

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