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Pretomanid

Last reviewed on RxList: 8/21/2019
Pretomanid Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

Last reviewed on RxList 8/21/2019

Pretomanid is an antimycobacterial indicated, as part of a combination regimen with bedaquiline and linezolid, for the treatment of adults with pulmonary extensively drug resistant (XDR) treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). Pretomanid is indicated for use in a limited and specific population of patients. Common side effects of Pretomanid include:

Pretomanid Tablets must be administered only as part of a regimen in combination with bedaquiline and linezolid. The dose of Pretomanid Tablets is 200 mg orally once daily for 26 weeks; along with bedaquiline 400 mg orally once daily for 2 weeks followed by 200 mg 3 times per week, with at least 48 hours between doses, for 24 weeks for a total of 26 weeks; and 1,200 mg linezolid daily orally for up to 26 weeks. Pretomanid may interact with strong or moderate CYP3A4 inducers (such as rifampin or efavirenz) and organic anion transporter-3 (OAT3) substrates. Tell your doctor all medications and supplements you use. Tell your doctor if you are pregnant or plan to become pregnant before using Pretomanid; it is unknown how it would affect a fetus. There are risks associated with active tuberculosis during pregnancy. It is unknown if Pretomanid passes into breast milk. Because of the potential for adverse reactions in nursing infants, breastfeeding is not recommended while using Pretomanid.

Our Pretomanid Tablets, for Oral Use Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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Pretomanid Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness (like you might pass out);
  • tremors, weakness, problems with balance;
  • vision changes;
  • severe ongoing nausea and vomiting;
  • cough with mucus or blood;
  • shortness of breath, chest pain that gets worse when you breathe or cough;
  • nerve problems--numbness, tingling, burning, or prickly feeling in your arms, hands, legs, or feet;
  • liver problems--nausea, loss of appetite, stomach pain (upper right side), tiredness, itching, dark urine, jaundice (yellowing of the skin or eyes); or
  • low blood cell counts--fever, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed.

Common side effects may include:

  • nerve problems;
  • heartburn, stomach pain, loss of appetite, nausea, vomiting, diarrhea;
  • cough, chest pain;
  • headache, muscle and bone pain;
  • acne, rash, itching;
  • abnormal blood tests that check the function of your liver or pancreas;
  • unusual weight loss; or
  • low blood sugar--headache, hunger, sweating, irritability, dizziness, fast heart rate, and feeling anxious or shaky.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Pretomanid (Pretomanid Tablets)

QUESTION

COPD (chronic obstructive pulmonary disease) is the same as adult-onset asthma. See Answer
Pretomanid Professional Information

SIDE EFFECTS

The following serious adverse reactions are discussed here and elsewhere in the labeling:

Clinical 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.

A total of 1168 subjects, 879 patients with tuberculosis and 289 healthy volunteers, have been exposed to Pretomanid Tablets, either alone or as part of a combination therapy in 19 trials.

Study 1 (NCT02333799) was a single-arm, open-label study conducted in three sites in South Africa in which patients with XDR, treatment-intolerant MDR, or non-responsive MDR pulmonary TB 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 subjects 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.

Common Adverse Reactions Reported In Study 1

Table 1 summarizes the incidence of select adverse reactions occurring in ≥5% of patients in Study 1.

Table 1: Select Adverse Reactions (All Grades) Reported in ≥5% of Subjects Receiving the Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid in Study 1

Adverse Reactions Pretomanid Tablets, Bedaquiline and Linezolid Combination Regimen
(N = 109)
All Grades
n (%)
  Peripheral neuropathy* 88 (81)
  Acne* 42 (39)
  Anemia* 40 (37)
  Nausea 40 (37)
  Vomiting 37 (34)
  Musculoskeletal Pain* 32 (29)
  Headache 30 (28)
  Transaminases increased* 30 (28)
  Dyspepsia 26 (24)
  Decreased appetite 24 (22)
  Rash* 23 (21)
  Pruritus* 22 (20)
  Abdominal pain* 21 (19)
  Pleuritic pain 21 (19)
  Gamma-glutamyltransferase increased 19 (17)
  Lower respiratory tract infection* 16 (15)
  Hyperamylasemia* 15 (14)
  Hemoptysis 14 (13)
  Cough* 13 (12)
  Visual impairment* 13 (12)
  Hypoglycemia 12 (11)
  Abnormal loss of weight 11 (10)
  Diarrhea 11 (10)
  Constipation 9 (8)
  Gastritis 9 (8)
  Neutropenia* 9 (8)
  Dry skin 8 (7)
  Hypertension* 8 (7)
  Electrocardiogram QT prolonged 6 (6)
  Hyperlipasemia* 6 (6)
  Insomnia 6 (6)
  Thrombocytopenia* 6 (6)
*Select terms are collapsed, as follows: peripheral neuropathy (burning sensation, hypoesthesia, hyporeflexia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy); acne (acne, dermatitis acneiform); anemia (anemia); musculoskeletal pain (arthralgia, back pain, costochondritis, myalgia, pain in extremity); transaminases increased (alanine aminotransferase [ALT]) increased, aspartate aminotransferase [AST] increased, drug-induced liver injury, hepatic enzyme increased, hepatic function abnormal, liver function test increased, transaminases increased); rash (rash, rash erythematous, rash maculo-papular, rash papular, rash vesicular); pruritus (pruritus, pruritus generalized, rash pruritic); abdominal pain (abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness); lower respiratory tract infection (bronchitis, influenza, lower respiratory tract infection, pneumonia); hyperamylasemia (amylase increased, hyperamylasemia);cough (cough, productive cough); visual impairment (vision blurred, visual acuity reduced, visual impairment); neutropenia (neutropenia); hypertension (blood pressure increased, hypertension); hyperlipasemia (hyperlipasemia, lipase increased); thrombocytopenia (thrombocytopenia).

The following select adverse reactions were reported in patients receiving the combination regimen of Pretomanid Tablets, bedaquiline and linezolid at a rate of less than 5% in Study 1:

Gastrointestinal Disorders: pancreatitis, dysgeusia

Laboratory Investigations: blood creatine phosphokinase increase, blood creatinine increase, blood alkaline phosphatase increase

Blood and Lymphatic System Disorders: leukopenia

Metabolism and Nutrition Disorders: hypomagnesemia, hyperglycemia, hypokalemia, hyperkalemia, hyponatremia

Nervous System Disorders: dizziness, seizure

Laboratory Abnormalities Reported In Study 1

Table 2 summarizes select laboratory abnormalities.

Table 2: Select Laboratory Abnormalities in Study 1

Parameter Multiples of Upper Limit of Normal (x ULN) Combination Regimen of Pretomanid Tablets, Bedaquiline, and Linezolid
(N = 109)
n (%)
Transaminases and Bilirubin
Alanine Aminotransferase (ALT)
  >3 and ≤ 5 X ULN 6 (6)
  >5 and ≤ 8 X ULN 5 (5)
  >8 X ULN 1 (1)
Aspartate Aminotransferase (AST)
  >3 and ≤ 5 X ULN 7 (6)
  >5 and ≤ 8 X ULN 2 (2)
  >8 X ULN 1 (1)
Total Bilirubin
  >1 X ULN and ≤ 2 X ULN 6 (6)
  >2 X ULN 2 (2)
Hematology
Hemoglobin
  ≤7.9 mg/dL 6 (6)
Neutrophils Absolute Count
  ≤749/mm3 5 (5)
Platelets
  ≤49,999/mm3 2 (2)
Serum Chemistry
Lipase
  > 2 X ULN 5 (5)
ULN = upper limit of normal

In Study 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.

Myelosuppression is a known adverse reaction of linezolid. 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.

Peripheral And Optic Neuropathy

Peripheral neuropathy is a known adverse reaction of linezolid. In Study 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.

Optic neuropathy is a known adverse reaction of linezolid. Two patients (2%) in Study 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.

Read the entire FDA prescribing information for Pretomanid (Pretomanid Tablets)

Related Resources for Pretomanid

© Pretomanid Patient Information is supplied by Cerner Multum, Inc. and Pretomanid Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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