Isoniazid (INH) is one of the first-line drugs in the treatment of patients with mycobacterium tuberculosis. It is used in combination with other first and second-line drugs (e.g. rifampicin, ethambutol, pyrazinamide, and streptomycin).

Isoniazid uses:

• Active tuberculosis infections:

  • It is used to treat infections caused by Mycobacterium tuberculosis.

• Latent tuberculosis infection:

  • Can treat latent tuberculosis or used as a preventive therapy against Mycobacterium tuberculosis.

• Off Label Use of Isoniazid in Adults:

  • Nontuberculous infection can be treated e.g Mycobacterium kansasii.

Isoniazid (INH) Dose in Adults:

Isoniazid (INH) Dose in the treatment of active drug-susceptible Tuberculosis: Oral, IM:

Note:

• Use along with other antitubercular agents.
• Use pyridoxin as a prophylactic drug against neuropathy.

• ATS/CDC/IDSA drug-susceptible tuberculosis guideline recommendations:

  • Dosing:

    • Once-daily therapy:
      • 5 mg per kg per dose one time per day.
      • Note:
        • During the intensive and continuation phases, a dose is administered once daily; however, directly observed therapy (DOT) administered five days a week is a viable alternative.
    • Three-times-weekly DOT:
      • 15 mg per kg per dose 3 times weekly (usual dose: 900 mg)
    • Twice-weekly DOT:
      • 15 mg per kg per dose two times a week (usual dose: 900 mg)
    • Once-weekly DOT:
      • 15 mg per kg per dose one time a week (usual dose: 900 mg)

  • Regimens:

    • The first phase of treatment for tuberculous meningitis and pulmonary tuberculosis lasts for two months and consists of a four-drug regimen. After that, there is a continuation phase that lasts for four to seven months for tuberculous meningitis and seven to ten months for pulmonary tuberculosis (optimal duration is not defined although continuation phase must continue for a minimum of 7 additional months).
    • For tuberculous meningitis, adjunctive corticosteroid therapy, tapered over 6 to 8 weeks, is also advised (examples: dexamethasone, prednisolone).
    • The frequency and dosage of isoniazid vary depending on the chosen treatment plan.

Isoniazid (INH) Dose in the treatment of Tuberculosis, latent infection: Oral, IM:

Note:

• In addition to this, pyridoxine is advised in cases of malnutrition, in cases of pregnancy or breastfeeding, and in cases of neuropathy-prone individuals (eg, patients with HIV-infection, diabetes, or chronic alcohol abusers).

• Isoniazid monotherapy:

  • Non-HIV infected:
    • 5 mg/kg (300 mg maximum per dosage) given once daily for six or nine months, or 15 mg/kg (900 mg maximum per dose) given twice weekly for six or nine months.
    • Note:
      • 9 months is the ideal time frame; 6 months may be taken into account to lower therapeutic expenses and boost adherence.
  • HIV-infected patients who are receiving antiretroviral therapy:
    • For 9 months, take 300 mg once daily or 900 mg twice a week; for HIV-positive patients in high-incidence areas, take it for longer.
    • Note:
      • HIV-infected patients who test positive for LTBI but have no symptoms of TB disease or a history of LTBI treatment are advised to do so, as are HIV-infected close contacts of anyone with infectious TB (regardless of screening tests for LTBI).

• Isoniazid and rifapentine combination regimen:

  • Once-weekly regimen:
    • Rifapentine in combination with 15 mg/kg/dose (maximum: 900 mg/dose) given once weekly for 12 weeks under directly observed therapy (DOT) or self-administered therapy.
    • Note:
      • If used in HIV-infected patients, it may only be used in those who are receiving antiretroviral therapy (ART) with acceptable drug-drug interactions with rifapentine. The once-weekly rifapentine-containing regimen is only to be used in patients who are not pregnant or who are not planning to become pregnant.
  • Once-daily regimen (HIV-infected patients):
    • For one month, use 300 mg once daily together with rifapentine.
    • Note:
      • Though not yet generally recommended, this regimen has been explored in HIV-infected individuals who reside in areas with high tuberculosis prevalence or who have indications of latent tuberculosis infection.

Dose for Nontuberculous mycobacterium (M. kansasii) (off-label):

• It is frequently used with ethambutol and rifampin. The recommended dosage is 5 mg/kg/day (maximum: 300 mg daily) for a period of time to include 12 months of culture-negative sputum.

Isoniazid (INH) Dose in Children:

Note:

• Due to epidemiology (resistance) and new research, recommendations frequently change. If necessary, check with the CDC and WHO for the most recent advice.
• Concomitant pyridoxine is advised for those at risk for isoniazid-induced neuropathy;
• Pregnancy, nursing, and having any of the following conditions are all risk factors for getting neuropathy.:
  • HIV,
  • diabetes,
  • malnutrition,
  • alcoholism,
  • chronic renal failure, or
  • advanced age.

Isoniazid (INH) Dose in the treatment of active drug-susceptible TB infection (excluding meningitis):

Note:

• Utilize at all times as part of a drug cocktail.
• Less frequent dose regimens should be administered as directly monitored therapy (DOT).
• The initial 2-month intense phase of a 4-drug regimen is followed by a continuation phase using isoniazid and rifampin that lasts an additional 4 to 7 months.
• Depending on the treatment regimen chosen, isoniazid frequency and dose varies; for further information, reference the most recent drug-sensitive TB guidelines.

• ATS/CDC/IDSA Recommendations:

  • Once-daily or 5 times weekly (DOT):

    • Infants, Children, and Adolescents <15 years, weighing ≤40 kg:
      • Oral, IM: 10 to 15 mg per kg per dose one time daily;
      • The maximum dose: 300 mg per dose
    • Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years:
      • Oral, IM: 5 mg per kg per dose one time daily (typical dose: 300 mg)

  • Three-times-weekly DOT:

Note:

• Though experts believe three-times-weekly regimens are more effective than twice-weekly DOT regimens, proposed dose is based on experience with a twice-weekly programme.
• A regimen of intensive phase and/or continuation phase doses may include three times per week of DOT.
  • • Infants, Children, and Adolescents <15 years, weighing ≤40 kg:
      • Oral, IM: 20 to 30 mg per kg per dose three times a week
      • The maximum dose: 900 mg per dose
      • In adolescents, some experts would use 15 mg per kg per dose three times a week
      • The maximum dose: 900 mg per dose
    • Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years:
      • Oral, IM: 15 mg per kg per dose three times a week

  • Twice-weekly DOT:

Note:

• Not generally advised; not to be used by anyone with cavitary disease, HIV, or smear positivity.
• Only after a once-daily (or five times weekly) intensive phase of two weeks may this therapy be administered.
• The equivalent of once-weekly dosage results from missed doses, which has been demonstrated to be inferior and is linked to treatment failure, relapse, and the emergence of drug resistance.
  • Infants, Children, and Adolescents <15 years, weighing ≤40 kg:
    • Oral, IM: 20 to 30 mg per kg per dose two times a week 
    • The maximum dose: 900 mg per dose
  • Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years:
    • Oral, IM: 15 mg per kg per dose two times a week (typical dose: 900 mg)

Isoniazid (INH) Dose in the treatment of Latent TB infection (LTBI):

• Isoniazid combination therapy:
• Note:
  • Should not be utilised in patients suspected of having isoniazid- or rifampin-resistant TB strains.
  • The CDC's recommended treatment plan for LTBI includes isoniazid and rifapentine in combination.
• Rifapentine combination (preferred): Regardless of HIV status:
• Note:
  • The clinician may choose to deliver it by DOT or self-administered therapy (SAT), depending on local custom, the characteristics and preferences of the patient, and other variables like the risk of TB disease progression.
  • When advised by knowledgeable clinicians, rifapentine combination is favoured in patients with HIV, including those with AIDS, who are receiving antiretroviral therapy (ART) and have tolerable drug-drug interactions.
  • Children 2 to 11 years, weighing at least 10 kg:
    • Oral: 25 mg per kg per dose one time a week of isoniazid for 12 weeks (12 doses);
    • 900 mg per dose is maximum dose
  • Children ≥12 years and Adolescents:
    • Oral: 15 mg per kg per dose one time a week of isoniazid for 12 weeks (12 doses), round dose up to nearest 50 or 100 mg;
    • 900 mg per dose is maximum dose

• Rifampin combination: HIV-exposed/-positive:

  • Children:
    • Oral: 10 to 15 mg/kg/dose once daily;
    • 300 mg/dose is maximum dose
    • 3 to 4 months duration of treatment

• Isoniazid monotherapy:

Note: The DOT should deliver intermittent regimens (once or twice weekly).

• Infants and Children:

  • Non-HIV-exposed/-positive:
    • Oral: One time a day 10 to 20 mg per kg per dose
    • 300 mg/dose OR 20 to 40 mg/kg/dose two times a week as DOT is maximum dose
    • 900 mg/dose is maximum dose
    • 9 months (270 daily doses or 76 twice-weekly doses) duration of treatment
  • HIV-exposed/-positive:
    • Oral: 10 to 15 mg/kg/dose one time a day 
    • 20 to 40 mg/kg/dose is maximum dose 
    • 9 months is duration of the treatment. 

• Adolescents:

  • Non-HIV-exposed/-positive:
    • Oral: 10 to 20 mg/kg/dose one time daily
    • 300 mg/dose or 20 to 40 mg/kg/dose two times a week as DOT is maximum dose
    • The maximum dose: 900 mg per dose
    • Treatment duration: 9 months (270 daily doses or 76 twice-weekly doses).
  • HIV-exposed/-positive:
    • Oral: 300 mg one time daily or 900 mg two times a week as DOT;
    • 9 months duration of treatment 

Isoniazid Pregnancy Risk Category: C

• Isoniazid can pass the placental barrier
• Treatment is advised when there is a high risk of developing tuberculosis in the fetus.
• It is advised to include it in the initial course of treatment.
• Because there is a higher risk of acquiring hepatitis during pregnancy and after birth, close monitoring is advised.
• This is advised for expecting mothers who also have HIV.
• It is advised to take pyridoxine to lower the risk of neuropathy.
• Pregnant women could be more susceptible to tuberculosis infection due to biological changes that occur during pregnancy or early postpartum.

Isoniazid use during breastfeeding:

• Breast milk contains the acetyl–isoniazid metabolite and isoniazid.
• The relative infant dose (RID) of isoniazid varies from 12% to 25% when using breast milk with the maximum content.
• This is in contrast to a therapeutic dose for infants of 10–20 mg/kg/day.
• If the RID of the medication is less than 10%, breastfeeding is acceptable. However, if it is greater than 25%, breastfeeding should be avoided.
• Based on a milk concentration of 16.6 mg/mL, the RID for isoniazid was computed. Accordingly, a daily newborn dose of 2.49 mg/kg/day via breastfeeding is estimated.
• The milk's concentration was assessed following a single 300mg oral dose of isoniazid for the mother.
• The peak concentrations of isoniazid in breast milk and the metabolite peaked 1 and 3 hours respectively after the dose.
• In another study, nine women were treated with chronic isoniazid 300 mg/day.
• Breast milk was tested for lower and more variable peak concentrations (1 hour after the dose).
• Breastfed infants can also detect isoniazid in their urine after high maternal doses (10 mg/kg).
• Based on the available data, these concentrations are nontoxic and not therapeutic to treat active tuberculosis or latent tuberculosis.
• Nursing mothers are not considered to be in any way contraindicated.
• The use of isoniazid in the treatment of drug-susceptible tuberculosis is not contraindicated.
• It is safe to breastfeed patients who have been treated with isoniazid.
• Breastfeeding infants should be checked for jaundice.
• If jaundice occurs, discontinue breastfeeding and/or switch to a different medication.
• For both mother and baby, pyridoxine supplementation should be considered.
• One review recommends that infants who have been given isoniazid should be administered the maternal dose within 30 minutes of the last feed.
• Patients with HIV or active infections should not breastfeed.
• Breastfeeding mothers who have tuberculosis may continue to breastfeed using the unaffected breast.

INH Dose in Kidney Disease:

No dosage adjustment is necessary.

• Hemodialysis:
  • No dosage adjustment needed if the patient is on dialysis, administer after hemodialysis on dialysis days.

Dose in Liver disease:

• No dosage adjustments are provided but use with caution as it may cause additional liver damage in patients with preexisting liver disease.
• In individuals with acute liver illness or prior isoniazid-associated hepatic damage, it is categorically contraindicated.
• For ALT or AST >3 times the ULN:
  • discontinue or temporarily withhold treatment.
  • Patients with acute hepatic disorders should postpone isoniazid treatment for latent tuberculosis infection.

Side Effects of Isoniazid (INH):

• Hepatic:

  • Increased serum transaminases
  • Hepatitis
  • Hyperbilirubinemia
  • Jaundice

• Cardiovascular:

  • Vasculitis

• Central Nervous System:

  • Brain Disease
  • Memory Impairment
  • Paresthesia
  • Peripheral Neuropathy
  • Psychosis
  • Seizure

• Dermatologic:

  • Skin Rash
    • Morbilliform
    • Maculopapular
    • Pruritic
    • Or Exfoliative
  • Toxic Epidermal Necrolysis

• Endocrine & Metabolic:

  • Gynecomastia
  • Hyperglycemia
  • Metabolic Acidosis
  • Pellagra
  • Pyridoxine Deficiency

• Gastrointestinal:

  • Epigastric Distress
  • Nausea
  • Pancreatitis
  • Vomiting

• Genitourinary:

  • Bilirubinuria

• Hematologic & Oncologic:

  • Agranulocytosis
  • Anemia
    • Sideroblastic
    • Hemolytic
    • Or Aplastic
  • Eosinophilia
  • Lymphadenopathy
  • Thrombocytopenia

• Immunologic:

  • DRESS Syndrome

• Neuromuscular & Skeletal:

  • Lupus-Like Syndrome
  • Rheumatic Disease

• Ophthalmic:

  • Optic Atrophy
  • Optic Neuritis

• Miscellaneous:

  • Fever

Contraindications to Isoniazid (INH):

• Hypersensitivity to any isoniazid component; history of hepatic injury while taking isoniazid therapy; drug-induced liver illness; acute liver disease.
  Isoniazid-related serious adverse events in the past (drug fevers, chills, arthritis)

Warnings and precautions

• Hepatitis: [US-Boxed Warning]

  • Hepatitis can become severe and even lethal. Within the first three months of treatment, it typically appears.
  • However, it could also appear after receiving treatment for a while.
  • Hepatitis risk may be increased by alcohol intake, chronic liver disease, and injection drug use.
  • Careful monitoring is required for patients who are given isoniazid.
  • Isoniazid-related fatal liver disease may affect more women than men, especially black and Hispanic women and women who gave birth within the previous six months.
  • These groups may allow for closer monitoring.
  • At baseline and every other month, patients over 35 should have their AST and ALT levels tested.
  • Any symptoms that may indicate hepatitis must be reported to the doctor.
  • If any of these symptoms are present, counsel the patient to immediately stop therapy and contact their doctor.
  • If liver dysfunction is greater than 3 to 5 times the upper limit for normal, you might want to stop taking isoniazid (ULN).
  • If you feel that isoniazid needs to be reinstituted for treatment, wait until symptoms and laboratory abnormalities are resolved.
  • Then, start slowly increasing the doses and withdrawing immediately if there is evidence of recurrent liver disease.

• Peripheral neuropathies:

  • Pyridoxine supplements should be taken by people who are at a high risk of developing peripheral neuropathies due to conditions including HIV infection, nutritional inadequacies, diabetes, obesity, chronic renal failure, and advanced age.

• Hepatic impairment

  • Patients with hepatic impairment should exercise caution; it is contraindicated in those with acute liver disease and those who have previously suffered an injury linked to isoniazid.
  • Patients with acute hepatic disease should delay treatment with isoniazid (LTBI) for latent tuberculosis.

• Renal impairment

  • Adjusting the dose is necessary for patients with severe renal impairment.

Isoniazid: Drug Interaction

Monitoring parameters:

Liver function tests (ALT and AST) at baseline and periodically (more frequently in patients at higher risk for hepatitis); sputum cultures monthly (until 2 consecutive negative cultures are reported)

Latent tuberculosis infection (LTBI) therapy:

American Thoracic Society/Centers for Disease Control (ATS/CDC) recommendations:

• A quick physical exam is part of the monthly clinical examination for negative occurrences.
• In the following groups, usage needs to be closely observed.:
  • daily users of alcohol,
  • active chronic liver disease,
  • severe renal dysfunction,
  • age >35 years,
  • concurrent use of any chronically administered drug,
  • history of previous isoniazid discontinuation,
  • existence of or conditions predisposing to peripheral neuropathy,
  • pregnancy,
  • injection drug use,
  • women in minority groups (particularly postpartum),
  • HIV seropositive patients.
• When using LTBI, AST and ALT should be measured at baseline and at least once per month.
• If liver function tests are >3 to 5 times ULN, stop treatment temporarily or permanently.
• Any patient with an aberrant baseline or who is more likely to experience hepatotoxicity should undergo routine, periodic monitoring.

How to administer Isoniazid?

• Oral:
  • Administer without food (bioavailability is decreased).
• Intramuscular:
  • Injection intramuscularly (IM) may be used for patients who are unable to swallow or absorb oral medication. IM a huge mass of muscles deeply.

Mechanism of action of Isoniazid (INH):

• Isoniazid blocks the production of mycolic acid, which is an essential component in the bacterial cell walls. 
• Isoniazid can be used to kill Mycobacterium tuberculosis organisms that are actively growing in intracellular and extracellular environments at therapeutic levels.

Notice:

• It is metabolized through acetylation or dehydrazination.
• Genetic factors determine the rate at which acetylation occurs. Blacks and whites make up approximately half of the "slow inactivators", while the rest are called "rapid activators".
• Most Eskimo and Asian patients can be described as "rapid activators". 
• Although acetylation rate doesn't affect effectiveness in any way, slow acetylation can lead to increased blood levels and possible adverse effects.

Absorption: Oral, IM:

• Rapid and complete;
• Its absorption rate is reduced if administer along with food

Distribution:

• It distributes in all over body fluids and tissues including CSF

Protein binding:

• 10% to 15%

Metabolism:

• The rate of genetic degradation of acetyl-isoniazid in the liver is determined by acetylation phenotype, and it is further hydrolyzed to form isonicotinic acid and acetyl-hydrazine.

Half-life:

• Patients who have impaired renal or hepatic function may have a longer recovery time.
  • Fast acetylators: 30 to 100 minutes
  • Slow acetylators: 2 to 5 hours

Time to peak, serum:

• 1 to 2 hours

Excretion:

• Approximately 75% to 95% of the medication and its metabolites are eliminated in urine; a minor quantity is also found in faeces and saliva.

International Brand Names of Isoniazid:

• DOM-Isoniazid
• Isotamine
• PDP-Isoniazid
• Antimic
• Bitub
• Cemidon
• Curazid Forte
• Dianicotyl
• Eutizon
• Fluodrazin
• Hidrazida
• Hydra
• Hydrazin
• N.H.
• INH Agepha
• INH Lannacher
• INH Waldheim
• Iscotin
• Iso
• Isocid
• Isokin
• Isonex
• Isoniac
• Isoniazid
• Isoniazid Atlantic
• Isoniazid ”Dak”
• Isoniazid ”Oba”
• Isoniazide Drank FNA
• Isoniazidum
• Isonicid
• Isonid
• Isozid
• Isozide
• Nicizina
• Nicotibine
• Nicozid
• Nidrazid
• Nisozid
• Nydrazide
• Pycazide
• Rimicid
• Rimifon
• Sheng Jun
• Solonex
• B.Zide
• Tebilon
• Tibinide
• Tubilysin
• Valifol
• Yuhan-Zid

Isoniazid Brand Names in Pakistan: