What are the complications following initiation of rifampicin (Rifampin) for latent tuberculosis (TB) within the first three weeks of treatment?

From the Guidelines

Rifampicin treatment for latent tuberculosis infection (LTBI) can lead to significant complications within the first three weeks, including hepatotoxicity, flu-like syndrome, cutaneous reactions, and gastrointestinal disturbances, necessitating close monitoring and prompt intervention if severe adverse effects occur. Complications within the first three weeks of rifampicin treatment for LTBI include:

• Hepatotoxicity, which is the most serious concern, manifesting as elevated liver enzymes, jaundice, nausea, or abdominal pain, and requires immediate medication discontinuation if significant 1
• Flu-like syndrome, which typically occurs with intermittent dosing and presents with fever, headache, and myalgia, usually resolving with continued treatment
• Skin reactions, ranging from mild rashes to severe reactions like Stevens-Johnson syndrome, necessitating prompt discontinuation if severe
• Gastrointestinal side effects, including nausea, vomiting, and diarrhea, which can often be managed by taking medication with food Patients should be monitored with baseline liver function tests and regular follow-up during the first month, with instructions to report symptoms like jaundice, persistent nausea, fever, or rash immediately 1. The potential disadvantages of rifamycin-based regimens, such as rifampicin, include many drug interactions, which can be a concern in patients taking other medications, such as warfarin, oral contraceptives, azole antifungals, and HIV antiretroviral therapy 1.

Key considerations for healthcare providers during treatment of LTBI with rifampicin include:

• Evaluating all patients for active tuberculosis disease both before and during treatment of LTBI
• Informing the patient or parents or legal guardians about possible adverse effects and instructing them to seek medical attention when symptoms of possible adverse reaction first appear
• Conducting monthly evaluations to assess treatment adherence and adverse effects, with repeated patient education regarding adverse effects at each visit 1
• Ordering baseline hepatic chemistry blood tests for patients with specific conditions, such as human immunodeficiency virus infection, liver disorders, or regular alcohol use, and conducting blood tests at subsequent clinical encounters for patients whose baseline testing is abnormal or for others at risk for liver disease.

From the FDA Drug Label

WARNINGS Hepatotoxicity of hepatocellular, cholestatic, and mixed patterns has been reported in patients treated with rifampin. Systemic hypersensitivity reactions were reported with Rifampin for Injection administration Signs and symptoms of hypersensitivity reactions may include fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, chills, aches, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations) Cases of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with rifampin Rifampin may cause vitamin K–dependent coagulation disorders and bleeding

The complications following initiation of rifampicin for latent tuberculosis within the first three weeks of treatment may include:

• Hepatotoxicity: hepatocellular, cholestatic, and mixed patterns
• Systemic hypersensitivity reactions: fever, rash, urticaria, angioedema, hypotension, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia, elevated liver transaminases or flu-like syndrome
• Severe cutaneous adverse reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms syndrome
• Vitamin K–dependent coagulation disorders and bleeding 2

From the Research

Complications of Rifampicin for Latent Tuberculosis

• Hepatotoxicity is a significant complication associated with rifampicin treatment for latent tuberculosis, with studies indicating a higher risk of hepatotoxicity compared to isoniazid treatment 3, 4, 5
• The risk of hepatotoxicity is increased in patients with baseline hepatic dysfunction, and close monitoring of transaminases is necessary in these patients 6
• Severe hepatotoxicity, defined as a significant increase in liver enzymes, has been reported in patients receiving rifampicin for latent tuberculosis, particularly in the first few months of treatment 3, 4, 6
• Other complications, such as asymptomatic reduction in platelet and leukocyte counts, have also been reported in patients receiving rifampicin for latent tuberculosis 4

Comparison of Rifampicin Regimens

• A 2-month course of pyrazinamide and rifampin has been associated with a higher risk of hepatotoxicity compared to a 6-month course of isoniazid 3, 5
• A 3-month course of isoniazid and rifampin has been shown to have better adherence and a lower percentage of discontinued treatments compared to a 6-month isoniazid course 7
• A 4-month course of rifampin has been associated with fewer serious adverse events and better adherence compared to a 9-month course of isoniazid 4

Monitoring and Management

• Close monitoring of liver enzymes is necessary in patients receiving rifampicin for latent tuberculosis, particularly in the first few months of treatment 3, 4, 6
• Patients with baseline hepatic dysfunction require increased vigilance in monitoring transaminases 6
• Treatment interruption or discontinuation may be necessary in patients who develop severe hepatotoxicity 3, 4, 6