Side Effects of Isoniazid (isoniazid)

Isoniazid is an anti-bacterial drug used to prevent active tuberculosis, an infectious disease caused by a bacterium, in persons who have an abnormal skin test for tuberculosis (latent tuberculosis) or in combination with other drugs for the treatment of active tuberculosis.

Once the infection is acquired, it usually remains dormant in the lungs for up to many years. Later, the infection may become active in the lungs and sometimes spreads throughout the body.

Patients with a tuberculosis skin test that has recently become abnormal (demonstrating recent infection with tuberculosis) but a normal chest X-ray (demonstrating inactive infection) are given isoniazid alone for 9 months. Patients with active infection on chest X-ray are given isoniazid combined with other antituberculosis drugs.

The mechanism of action of isoniazid is not known, but it is thought to work through its effects on lipids (fats) and DNA within the tuberculosis bacterium. It is very selective for the tuberculosis bacteria and it has few if any effects on other bacteria.

Common side effects of isoniazid include

• nausea,
• vomiting,
• abdominal pain,
• dry skin,
• fever,
• skin rashes and eruptions,
• swollen lymph nodes,
• reduced white blood cells (which increases the risk of infection),
• reduced platelets (which increases the risk of bleeding),
• high blood sugar levels,
• enlarged breasts in men (gynecomastia),
• ringing in the ears,
• urinary retention,
• blood disorders,
• hypersensitivity reactions, and
• painful joints.

Serious side effects of isoniazid include

• hepatitis. Symptoms include
  • unexplained loss of appetite,
  • nausea,
  • vomiting,
  • dark urine,
  • yellow skin or eyes,
  • persistent fatigue,
  • weakness,
  • fever lasting
  • longer than 3 days,
  • abdominal tenderness or discomfort, especially in the right upper part of the abdomen.

Rare side effects of isoniazid include

• encephalopathy (inflammation of the brain),
• optic neuritis (inflammation of the nerve coming from the eye),
• atrophy (degeneration) of the nerve coming from the eye,
• seizures,
• impaired memory,
• peripheral neuropathy, and
• psychosis.

Drug interactions of isoniazid include antacids containing aluminum, which reduce the amount of isoniazid absorbed from the intestine, which can result in reduced blood levels and effects of isoniazid.

• Isoniazid can increase the effectiveness of the blood thinner warfarin by interfering with the enzyme in the liver that eliminates warfarin. Isoniazid can increase the effect of certain benzodiazepines by interfering with the enzymes in the liver that eliminate benzodiazepines, resulting in excessive sedation.
• Carbamazepine taken at the same time as isoniazid can result in an increased risk of side effects from both drugs.
• Isoniazid can decrease the rate at which the liver eliminates phenytoin, which can raise the blood levels and result in side effects of phenytoin.
• Because rifampin can be toxic to the liver, the use of rifampin and isoniazid together increases the risk of liver toxicity to a level that is greater than with either drug alone.

Isoniazid may be used as a treatment for active tuberculosis during pregnancy because the benefit justifies the potential risk to the fetus.

Isoniazid passes into breast milk in small amounts but is not considered harmful to nursing infants. However, the amount that passes is so low it cannot be relied upon for prophylaxis or therapy of nursing infants. Consult your doctor before breastfeeding. 

Hepatitis

• When isoniazid is broken down by the liver, one of the products is acetylhydrazine, a potent toxin for the liver.
• When taken over a long period of time at standard doses, isoniazid can cause important and even fatal liver injury (hepatitis) in approximately 1 out of every 100 patients.
• Isoniazid-associated hepatitis usually occurs during the first three months of treatment but can occur at any time during therapy or even many months after starting treatment.
• Elevated blood liver tests occur in between 1 in 20 and 1 in 10 patients.
• Usually, enzyme levels return to normal despite continuation of the isoniazid, but in some cases progressive liver damage and even death occurs.
• The risk of developing hepatitis is age-related. It occurs in less than 1 per 1,000 patients under 20 years of age, 3 per 1,000 patients 20-34 years of age, 12 per 1,000 patients 35-49 years of age, 23 per 1,000 patients 50-64 years of age, and 8 per 1,000 patients over 65 years of age.
• The risk of hepatitis is increased by daily consumption of alcohol.
• Among individuals who complete a full course of prophylaxis (prevention of tuberculosis), the hepatitis-related death rate (mortality) is 23-58 patients per 100,000 patients, far lower than the frequency of hepatitis.
• The mortality rate among individuals who develop symptoms of isoniazid-induced hepatitis (not just minor abnormalities of liver tests) is approximately 10%. In one U. S. Public Health Service Surveillance Study involving 13,838 persons taking isoniazid, there were 8 deaths among 174 cases of hepatitis, a mortality rate of 5%.

There seems to be an increased risk of fatal hepatitis among women, particularly African-American and Hispanic women. The risk also may be increased during postpartum or immediately after pregnancy.

Because of the risk of hepatitis, patients taking isoniazid should have their blood liver tests monitored monthly and should notify their physicians immediately if symptoms or signs of hepatitis arise. These symptoms and signs include:

• Unexplained loss of appetite
• Nausea
• Vomiting
• Dark urine
• Yellow skin or a yellowish tinge to the whites of the eyes
• Persistent fatigue
• Weakness
• Fever of greater than 3 days duration
• Abdominal tenderness or discomfort, especially in the right upper part of the abdomen

Other rare side effects

Damage to nerves (peripheral neuropathy) may occur with isoniazid and cause numbness and tingling of the hands or feet (parethesia).

Other rare side effects related to the nervous system include:

• Encephalopathy (inflammation of the brain)
• Optic neuritis (inflammation of the nerve coming from the eye)
• Atrophy (degeneration) of the nerve coming from the eye
• Seizures
• Impaired memory
• Peripheral neuropathy
• Psychosis

Pyridoxine (vitamin B6), 10-50 mg/day, decreases the risk of neural side effects.

The rate at which isoniazid is eliminated by the liver is race-dependent. Thus, 60% of African Americans and whites eliminate isoniazid slowly compared with only 10%-20% of Asians. Individuals who eliminate isoniazid slowly are more prone to develop hepatitis and neural side effects with long-term use of isoniazid.

Other important side effects of isoniazid include:

• Nausea
• Vomiting
• Abdominal pain
• Dry skin
• Fever
• Skin rashes and eruptions
• Swollen lymph nodes
• Reductions in white blood cells (which increases the risk of infection)
• Reductions in platelets (which increases the risk of bleeding)
• Anemia
• High blood sugar levels in the blood
• Gynecomastia (enlargement of the breasts in men)
• Ringing in the ears
• Urinary retention (difficulty passing urine)
• Blood disorders
• Hypersensitivity reactions
• Painful joints

The most frequent reactions are those affecting the nervous system and the liver.

• Nervous system: Peripheral neuropathy is the most common toxic effect. It is dose related, occurs most often in the malnourished and in those predisposed to neuritis (e.g., alcoholics and diabetics), and is usually preceded by paresthesias of the feet and hands. The incidence is higher in slow acetylators.
• Other neurotoxic effects which are uncommon with conventional doses are
  • convulsions,
  • toxic encephalopathy,
  • optic neuritis and atrophy,
  • memory impairment, and
  • toxic psychosis.
• Gastrointestinal: Nausea, vomiting, and epigastric distress.
• Hepatic: See prescription labeling. Elevated serum transaminases (SGOT; SGPT), bilirubinemia, bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis.
• The common prodromal bilirubinuria, jaundice, and occasionally severe and sometimes fatal hepatitis. The common prodromal symptoms of hepatitis are
  • anorexia,
  • nausea,
  • vomiting,
  • fatigue,
  • malaise, and
  • weakness.
• Mild hepatic dysfunction, evidenced by mild and transient elevation of serum transaminase levels occurs in 10 to 20 percent of patients taking isoniazid. This abnormality usually appears in the first 1 to 3 months of treatment but can occur at any time during therapy.
• In most instances, enzyme levels return to normal, and generally, there is no necessity to discontinue medication during the period of mild serum transaminase elevation.
• In occasional instances, progressive liver damage occurs, with accompanying symptoms. If the SGOT value exceeds three to five times the upper limit of normal, discontinuation of the isoniazid should be strongly considered. The frequency of progressive liver damage increases with age. It is rare in persons under 20, but occurs in up to 2.3 percent of those over 50 years of age.
• Hematologic: Agranulocytosis; hemolytic, sideroblastic, or aplastic anemia; thrombocytopenia; and eosinophilia.
• Hypersensitivity: Fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, and vasculitis.
• Metabolic and endocrine: Pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia.
• Miscellaneous: Rheumatic syndrome and systemic lupus erythematosus-like syndrome. Local irritation has been observed at the site of intramuscular injection.

Food

• Isoniazid should not be administered with food. Studies have shown that the bioavailability of isoniazid is reduced significantly when administered with food.
• Tyramine- and histamine-containing foods should be avoided in patients receiving isoniazid.
• Because isoniazid has some monoamine oxidase inhibiting activity, an interaction with tyramine-containing foods (cheese, red wine) may occur.
• Diamine oxidase may also be inhibited, causing exaggerated response (e.g., headache, sweating, palpitations, flushing, hypotension) to foods containing histamine (e.g., skipjack, tuna, other tropical fish).

Acetaminophen

• A report of severe acetaminophen toxicity was reported in a patient receiving Isoniazid.
• It is believed that the toxicity may have resulted from a previously unrecognized interaction between isoniazid and acetaminophen and a molecular basis for this interaction has been proposed.
• However, current evidence suggests that isoniazid does induce P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites, in the liver.
• Furthermore it has been proposed that isoniazid resulted in induction of P-450IIE1 in the patients liver which, in turn, resulted in a greater proportion of the ingested acetaminophen being converted to the toxic metabolites.
• Studies have demonstrated that pretreatment with isoniazid potentiates acetaminophen hepatotoxicity in rats.

Carbamazepine

• Isoniazid is known to slow the metabolism of carbamazepine and increase its serum levels.
• Carbamazepine levels should be determined prior to concurrent administration with isoniazid, signs and symptoms of carbamazepine toxicity should be monitored closely, and appropriate dosage adjustment of the anticonvulsant should be made.

Ketoconazole

• Potential interaction of Ketoconazole and Isoniazid may exist.
• When Ketoconazole is given in combination with isoniazid and rifampin the AUC of Ketoconazole is decreased by as much as 88% after 5 months of concurrent Isoniazid and Rifampin therapy.

Phenytoin

• Isoniazid may increase serum levels of phenytoin. To avoid phenytoin intoxication, appropriate adjustment of the anticonvulsant should be made.

Theophylline

• A recent study has shown that concomitant administration of isoniazid and theophylline may cause elevated plasma levels of theophylline, and in some instances a slight decrease in the elimination of isoniazid.
• Since the therapeutic range of theophylline is narrow, theophylline serum levels should be monitored closely, and appropriate dosage adjustments of theophylline should be made.

Valproate

• A recent case study has shown a possible increase in the plasma level of valproate when coadministered with isoniazid.
• Plasma valproate concentration should be monitored when isoniazid and valproate are co-administered, and appropriate dosage adjustments of valproate should be made.