Professional Drug Information > INAT

Isoniazid and Thiacetazone (Systemic)

INN:
Thiacetazone—Thioacetazone ^{30}
USAN: Thiacetazone—Amithiozone ^{30}
VA CLASSIFICATION
Primary: AM500

Commonly used brand name(s): INAT; Thiazina; Thisozide.

Another commonly used name for isoniazid is
INH . Other commonly used names for thiacetazone are amithiozone and thioacetazone . ^{{54} {55} {56} {57} {58} {59} {60} {61} {62} {63} {64} {65}}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:


Antibacterial (antimycobacterial)—

Indications

Note: Because isoniazid and thiacetazone combination is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication.


Accepted

[Tuberculosis (treatment)]¹—Isoniazid and thiacetazone combination is used in the treatment of tuberculosis. ^{{21} {50} {51} {64} {65} {66}} However, because of the high frequency of thiacetazone-induced side effects ^{{21} {50} {51} {64} {65} {66}}, especially in patients infected with human immunodeficiency virus (HIV) ^{{21} {50} {53} {57}}, this combination is used only in countries in which safer, more effective medications are less readily available and affordable. ^{{02} {50} {51}} The primary role of thiacetazone is to prevent the emergence of isoniazid-resistant strains of Mycobacterium tuberculosis . ^{70} The World Health Organization (WHO) has recommended that thiacetazone not be given to patients with HIV infection or at increased risk of HIV infection. ^{{21} {53}}

—Not all species or strains of a particular organism may be susceptible to isoniazid and thiacetazone combination.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
^{30}    Isoniazid: 137.14
    Thiacetazone: 236.30

Mechanism of action/Effect:

Isoniazid (INH) is a synthetic, bactericidal antitubercular agent that is active against many mycobacteria, primarily those that are actively dividing. ^{02} Its exact mechanism of action is not known, but it may relate to inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms. ^{{08} {15}}

Thiacetazone is bacteriostatic, even at very high concentrations. ^{{21} {55}}

Absorption:

Isoniazid is readily absorbed following oral administration; however, it may undergo significant first pass metabolism. ^{{15} {16}} Absorption and bioavailability are reduced when isoniazid is administered with food. ^{16}

Thiacetazone is well absorbed ^{{21} {46} {55}}, although its absolute bioavailability is unknown. ^{21}

Distribution:


Isoniazid:

Widely distributed to all fluids and tissues, including cerebrospinal fluid (CSF), pleural and ascitic fluids, skin, sputum, saliva, lungs, and muscle. Crosses the placenta and is distributed into breast milk. ^{{02} {08} {16}}

Vol _D=0.57 to 0.76 L per kg of body weight. ^{{17} {18}}


Protein binding:

Isoniazid—Very low (0–10%). ^{{15} {16} {19}}

Biotransformation:

Isoniazid—Hepatic; isoniazid is acetylated by N-acetyltransferase to N-acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine forms a hepatotoxic, reactive intermediate metabolite when N-hydroxylated by the cytochrome P-450 mixed oxidase system. ^{16} The rate of acetylation is genetically determined ^{02}; slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase. ^{15}

Thiacetazone—Unknown; primarily via hydroxylation and conjugation, possibly also by acetylation, hydrolysis, and glucuronidation. ^{21} Suspected or probable metabolites include para-acetylaminobenzaldehyde and para-aminobenzaldehyde. ^{48}

Half-life:


Isoniazid:


Adults (including elderly patients) ^{15}—

Fast acetylators—0.5 to 1.6 hours.

Slow acetylators—2 to 5 hours.

Acute or chronic liver disease—May be prolonged (6.7 hours vs 3.2 hours in controls).



Children (age 1.5 to 15 years)—

2.3 to 4.9 hours. ^{16}



Neonates—

7.8 and 19.8 hours in 2 newborns who received isoniazid transplacentally. The long half-life may be due to the limited acetylation capacity of neonates. ^{22}




Thiacetazone:

Approximately 12 to 14 hours. ^{{46} {48} {55}}


Time to peak serum concentration

Isoniazid—1 to 2 hours. ^{{02} {15} {30}}

Thiacetazone—4 to 6 hours. ^{{46} {48} {55}}

Peak serum concentration

Isoniazid—3 to 7 mcg per mL (21.9 to 51 micromoles per L) after a single 300-mg oral dose. ^{{16} {20}}

Thiacetazone—1.2 to 3.2 mcg per mL (5.1 to 13.5 micromoles per L) after 150 mg per day. ^{{21} {46} {48}}

Elimination:


Isoniazid—
        Renal; approximately 75 to 95% excreted by the kidneys within 24 hours, primarily as the inactive metabolites, N -acetylisoniazid and isonicotinic acid ^{15}; of this amount, 93% of the isoniazid excreted in the urine may occur as the acetylated form in fast acetylators and 63% in slow acetylators, with the remainder, in both cases, occurring as the free or conjugated form.
        Small amounts are excreted in feces. ^{02}


In dialysis—
         Significant amounts of isoniazid are removed from the blood by hemodialysis. A single 5-hour hemodialysis period has removed up to 73% of the isoniazid in the blood. ^{16}
        Peritoneal dialysis is of limited benefit. ^{02}




Thiacetazone—
        Renal; 15 to 36% of a dose is excreted unchanged in the urine ^{{21} {46} {48}}, with less than 6% as metabolites. ^{48}
        Small amounts (< 3%) are excreted in feces. ^{21}



Precautions to Consider

Carcinogenicity/Tumorigenicity

Isoniazid—Isoniazid has been shown to cause pulmonary tumors in a number of strains of mice. However, it has not been shown to be carcinogenic or tumorigenic in humans. ^{02}

Thiacetazone—No information could be found concerning the carcinogenicity or tumorigenicity of thiacetazone.

Pregnancy/Reproduction

Pregnancy—
For isoniazid: Isoniazid crosses the placenta, resulting in fetal serum concentrations that may exceed maternal serum concentrations. ^{02} Problems in humans have not been documented. It is recommended that pregnant women with tuberculosis be treated for a minimum of 9 months with multi-drug therapy, including isoniazid. ^{39}

Studies in rats and rabbits have shown that isoniazid may be embryocidal. However, isoniazid has not been shown to be teratogenic in mice, rats, or rabbits. ^{02}

FDA Pregnancy Category C. ^{02}

For thiacetazone: No information could be found concerning the effects of thiacetazone during pregnancy.


Breast-feeding

Isoniazid—Isoniazid is distributed into breast milk. ^{02} An estimated 0.75 to 2.3% of the daily adult dose could be ingested by the infant. ^{16} Problems in nursing newborns have not been documented and breast-feeding should not be discouraged. However, because isoniazid concentrations are so low in breast milk, breast-feeding cannot be relied upon for adequate tuberculosis prophylaxis or therapy for nursing infants. ^{39}

Thiacetazone—It is not known whether thiacetazone is distributed into breast milk.

Pediatrics

Studies performed in children have not demonstrated pediatrics-specific problems that would limit the usefulness of isoniazid and thiacetazone combination in children. ^{{42} {43} {44} {52} {53}} However, newborn infants, especially those of low birth weight, ^{69} may have a limited acetylation capacity, prolonging the elimination half-life of isoniazid. ^{43}

Peripheral neuritis secondary to pyridoxine deficiency is very rare in children; therefore, pyridoxine supplementation is not usually required in children if dietary intake is adequate. ^{42} Also, the risk of isoniazid–induced hepatotoxicity is most likely to occur in patients over 50 years of age; it is usually unnecessary to routinely check liver function in children, unless they have pre-existing hepatic disease. ^{43}


Geriatrics


Isoniazid—Patients over 50 years of age are more likely to develop hepatitis while receiving isoniazid than are patients in younger age groups. ^{{02} {43}}

Thiacetazone—No information is available on the relationship of age to the effects of thiacetazone in geriatric patients.


Pharmacogenetics:

Isoniazid—Patients can be divided into 2 groups: slow and fast acetylators of isoniazid. Patients who are slow acetylators may be more prone to develop adverse effects, especially peripheral neuritis, and may require lower-than-usual doses. ^{02} Fast acetylators do not generally require higher doses, nor is isoniazid less effective in these patients. Eskimo, Oriental, and American Indian populations have the lowest prevalence of slow acetylators, while Egyptian, Israeli, Scandinavian, other Caucasian, and Black populations have the highest prevalence of slow acetylators. ^{02}


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Acetaminophen (paracetamol)^{04}{31}{32}    (concurrent use of acetaminophen [paracetamol] with isoniazid and thiacetazone combination may increase the potential for hepatotoxicity and, possibly, nephrotoxicity; isoniazid is thought to induce ^{31} cytochrome P-450, resulting in a greater proportion of acetaminophen [paracetamol] being converted to a toxic metabolite)


» Alcohol^{02}    (concurrent daily use of alcohol may result in increased incidence of isoniazid and thiacetazone combination-induced hepatotoxicity and increased metabolism of isoniazid; patients consuming alcohol regularly should be monitored closely for signs of hepatotoxicity and all patients should be advised to restrict intake of alcoholic beverages)


» Alfentanil^{03}    (chronic preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil)


Antacids, especially aluminum-containing^{07}{09}    (antacids may delay and decrease absorption and serum concentrations of orally administered isoniazid; concurrent use should be avoided, or patients should be advised to take isoniazid and thiacetazone combination at least 1 hour before aluminum-containing antacids)


Anticoagulants, coumarin- or indandione-derivative^{07}{71}    (concurrent use with isoniazid and thiacetazone combination may result in increased anticoagulant effect because of the inhibition of enzymatic metabolism of anticoagulants by isoniazid)


Benzodiazepines^{09}{25}    (isoniazid may decrease the hepatic metabolism of benzodiazepines, such as diazepam, chlordiazepoxide, flurazepam, and prazepam, that are metabolized by phase I reactions [ N-demethylation and hydroxylation]; it may also impair the oxidation of triazolam, thereby increasing plasma benzodiazepine concentrations; isoniazid may decrease first-pass metabolism and elimination of midazolam in the liver, probably by competitive inhibition at the cytochrome P-450 binding sites, increasing steady-state plasma concentrations of midazolam)


» Carbamazepine^{25}    (concurrent use with isoniazid and thiacetazone combination increases serum carbamazepine concentrations and toxicity, probably through inhibition of carbamazepine metabolism by isoniazid; ^{{12} {13}} also, carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of an INH-reactive intermediate metabolite, which may lead to hepatotoxicity)


Cheese, such as Swiss or Cheshire or
Fish, such as tuna, skipjack, or Sardinella^{07}{23}{24}    (concurrent ingestion with isoniazid and thiacetazone combination may result in redness or itching of the skin, hot feeling, rapid or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness; this is thought to be due to the inhibition of plasma monoamine oxidase and diamine oxidase by isoniazid, interfering with the metabolism of tyramine and histamine found in fish and cheese)


Corticosteroids, glucocorticoid^{09}{40}{71}    (concurrent use of prednisolone, and probably other related corticosteroids, with isoniazid and thiacetazone combination may increase hepatic metabolism and/or excretion of isoniazid, leading to decreased plasma concentrations and effectiveness of isoniazid, especially in patients who are rapid acetylators; isoniazid dosage adjustments may be required)


Cycloserine^{09}    (concurrent use may result in increased incidence of central nervous system [CNS] effects such as dizziness or drowsiness; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity)


» Disulfiram^{09}    (concurrent use may result in increased incidence of CNS effects such as dizziness, incoordination, irritability, or insomnia; reduced dosage or discontinuation of disulfiram may be necessary)


Enflurane^{09}    (isoniazid may increase formation of the potentially nephrotoxic inorganic fluoride metabolite of enflurane)


» Hepatotoxic medications, other (See Appendix II )^{02}    (concurrent use of other hepatotoxic medications with isoniazid and thiacetazone combination may increase the potential for hepatotoxicity and should be avoided)


» Ketoconazole^{11}{72}    (concurrent use of ketoconazole with isoniazid and thiacetazone combination has been reported to decrease serum concentrations of ketoconazole; isoniazid and thiacetazone combination should be used with caution when given concurrently with ketoconazole)


Neurotoxic medications, other (See Appendix II )^{10}    (concurrent use of other neurotoxic medications with isoniazid and thiacetazone combination may produce additive neurotoxicity)


» Phenytoin^{02}{41}    (isoniazid inhibits the metabolism of phenytoin, resulting in increased phenytoin serum concentrations and toxicity; phenytoin dosage adjustments may be necessary during and after isoniazid and thiacetazone combination therapy, especially in slow acetylators of isoniazid)


Pyridoxine^{02}    (isoniazid may cause peripheral neuritis by acting as a pyridoxine antagonist or increasing renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving isoniazid and thiacetazone combination ^{02}, although, because peripheral neuritis rarely occurs in children, supplementation is usually not needed in children if dietary intake is adequate ^{42})


» Rifampin^{09}    (concurrent use of rifampin with isoniazid may increase the risk of hepatotoxicity, especially in patients with pre-existing hepatic impairment and/or in fast acetylators of isoniazid; patients receiving rifampin and isoniazid and thiacetazone combination concurrently should be monitored closely for signs of hepatotoxicity during the first 3 months of therapy)


Streptomycin^{47}{55}    (thiacetazone may potentiate the ototoxic effects of streptomycin, increasing the risk of vertigo, ataxia, tinnitus, or deafness)


Theophylline^{28}    (concurrent use may reduce the metabolism of theophylline, increasing theophylline plasma concentrations)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Glucose, urine^{01}    (isoniazid may cause hyperglycemia with secondary glycosuria, producing a positive response to copper sulfate tests; glucose enzymatic tests are not affected)

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin, serum^{{02}{14}{55}{60}}    (transient, asymptomatic increases in values may occur in approximately 10 to 20% of patients treated with isoniazid; also, isoniazid may cause hepatitis, and, rarely, thiacetazone has been reported to cause acute hepatic failure)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Human immunodeficiency virus (HIV) infection^{21}{51}    (patients with HIV infection are at increased risk of severe cutaneous hypersensitivity reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, from the thiacetazone component of this medication; because of this, isoniazid and thiacetazone combination is not recommended for the treatment of tuberculosis in HIV-infected patients, or patients at increased risk of HIV, if other antituberculous agents are available; if isoniazid-thiacetazone combination must be used in patients at risk of HIV infection, patients should be carefully educated about skin reactions and told to discontinue the medication promptly if any signs or symptoms of toxicity appear ^{70})


Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or in remission or^{02}
» Hepatic function impairment^{02}{55}{60}    (increased risk of isoniazid-induced hepatitis with daily consumption of alcohol or hepatic function impairment; in rare cases, acute hepatic failure has been reported with thiacetazone)


» Hypersensitivity to isoniazid or thiacetazone
Renal failure, severe^{02}{33}{68}    (there may be an increased risk of isoniazid toxicity in patients who have severe renal failure [creatinine clearance < 10 mL/min]; this is thought to be due to the reduced elimination of acetylated metabolites; dosage may need to be reduced by 50% in patients with renal failure who are known to be slow acetylators)


Seizure disorders^{02}{33}    (isoniazid may be neurotoxic and cause seizures)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hepatic function determinations^{{02}{15}{55}{60}}    (AST [SGOT], ALT [SGPT], and serum bilirubin determinations may be required prior to treatment and monthly or more frequently during treatment; however, elevated serum enzyme values may not be predictive of clinical hepatitis and values may return to normal despite continued treatment; therefore, routine measurement of hepatic function is generally not recommended unless there is pre-existing hepatic disease ^{{08} {45}}; patients should be instructed to report promptly any prodromal symptoms of hepatitis; if signs and symptoms of hepatotoxicity occur, isoniazid and thiacetazone combination should be discontinued promptly; if isoniazid and thiacetazone combination therapy must be reinstituted, very small and gradually increasing doses should be used, and then only after signs and symptoms of hepatotoxicity have cleared; isoniazid and thiacetazone combination should be withdrawn immediately if any further evidence of hepatotoxicity occurs)


» Ophthalmologic examinations^{02}    (if symptoms of optic neuritis occur during treatment, ophthalmologic examinations may be required immediately and periodically thereafter; ophthalmologic examinations are not recommended in asymptomatic patients)




Side/Adverse Effects

Note: Patients with advanced HIV disease have been reported to have an increased incidence of adverse reactions to antitubercular medications. ^{{25} {26}} In addition, the incidence of severe cutaneous reactions to isoniazid and thiacetazone combination (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) was found to be significantly higher in HIV-infected patients than in HIV-negative patients. ^{51} These effects have been primarily associated with the thiacetazone component of the medication ^{{21} {51}} and are thought to be due to thiacetazone itself or a reactive metabolite. ^{21} Thiacetazone causes a high rate of side effects, especially skin rash ^{{64} {66} {67}}, gastrointestinal disturbances ^{{64} {66} {67}}, blood dyscrasias ^{{47} {55} {64}}, and jaundice ^{{64} {67}}, even in non–HIV-infected patients. In one report, 14% of non–HIV-infected patients had side effects, 11% severe enough to require discontinuation of the medication. ^{62} As many as one-third of HIV-positive patients have developed severe skin reactions due to thiacetazone. ^{61} The risk of these reactions may increase with advancing immunosuppression. ^{21} Itching usually precedes the onset of the maculopapular rash, which typically occurs 2 to 4 weeks after the start of therapy. ^{{51} {53}} Isoniazid and thiacetazone combination should be discontinued at the first appearance of skin rash or any other serious adverse effect, and should be reported to the doctor or health care worker immediately. ^{53}
Isoniazid has been reported to cause severe, and sometimes fatal, hepatitis, which is more prevalent in patients over 50 years of age. Thiacetazone has been reported rarely to cause acute hepatic failure. ^{{55} {60}} If signs and symptoms of hepatotoxicity occur, isoniazid and thiacetazone combination should be discontinued promptly. ^{02} The incidence of clinical hepatitis in young, healthy adults is 0.3%, but can increase to 2.6% for patients who drink alcohol daily, have chronic liver disease, or are elderly. ^{14}
Peripheral neuritis due to isoniazid can usually be prevented by administration of pyridoxine (10 to 25 mg per day). Pyridoxine is recommended for patients at risk of neuritis, including patients over 65 years of age, pregnant women, patients with diabetes mellitus, chronic renal failure, alcoholism, malnutrition, and patients taking anticonvulsant medications. ^{{02} {14}}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hepatitis ^{{02}{55}{60}{64}}(dark urine, yellow eyes or skin)
    
hepatitis prodromal symptoms ^{02}(loss of appetite, nausea or vomiting, unusual tiredness or weakness)
    
peripheral neuritis ^{02}(clumsiness or unsteadiness; numbness, tingling, burning, or pain in hands and feet)
    
Stevens-Johnson syndrome ^{21}{58}(aching joints and muscles; redness, blistering, peeling, or loosening of skin; unusual tiredness or weakness)
    
toxic epidermal necrolysis ^{21}{58}(difficulty in swallowing; redness, blistering, peeling, or loosening of skin)

Incidence rare
    
Blood dyscrasias ^{{08}{15}{47}{55}{64}}(fever and sore throat, unusual bleeding and bruising, unusual tiredness or weakness)
    
conjunctivitis ^{21}(redness of eyes with oozing)
    
hypersensitivity ^{08}{15}{64}(fever, joint pain, skin rash)
    
neurotoxicity ^{02}(seizures, mental depression, mood or other mental changes)
    
optic neuritis ^{02}(blurred vision or loss of vision, with or without eye pain)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Dizziness^{47}{60}
    
gastrointestinal disturbances ^{{02}{08}{21}{47}{55}{60}{64}}(diarrhea; loss of appetite; nausea and vomiting; stomach pain)





Overdose
For specific information on the agents used in the management of isoniazid and thiacetazone overdose, see:

   • Pyridoxine (Systemic) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph; and/or
   • Thiopental in Barbiturates (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

The information below applies to the clinical effects and treatment of isoniazid overdose only. The effects of thiacetazone overdose are unknown.

Clinical effects of isoniazid overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)
—not necessarily inclusiveAcute and chronic effects
    
Gastrointestinal disturbances (severe nausea and vomiting)
    
neurotoxicity (dizziness; slurred speech; lethargy; disorientation; hyperreflexia; seizures; coma)

Note: Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to treatment with usual anticonvulsants. Lactic acid accumulation produces an anion-gap metabolic acidosis within a few hours, which is often severe and refractory to treatment with sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported.




Treatment of isoniazid overdose ^{{36} {37} {38}}


To decrease absorption:
Because seizures may occur soon after ingestion, induction of emesis with ipecac is not recommended. Gastric lavage may be performed within 2 to 3 hours of ingestion, and activated charcoal and a cathartic may be administered if the patient's seizures are controlled and the airway protected.



Specific treatment:
Administering intravenous pyridoxine in a gram-for-gram dose, equivalent to the amount of isoniazid ingested; dose should be administered as a 5 or 10% solution in water for injection over 30 to 60 minutes. If the amount of isoniazid ingested is unknown, administering 5-gram doses of pyridoxine every 5 to 30 minutes until seizures stop or consciousness is regained.

Controlling seizures with diazepam, which acts synergistically with pyridoxine. Phenytoin should be used with caution, if at all, since isoniazid inhibits phenytoin metabolism. Thiopental has been effective in treating refractory seizures.

Carefully administering sodium bicarbonate if pyridoxine and diazepam do not control seizure activity. Use caution against overcorrection and watch for hypokalemia or hyperkalemia.



Supportive care:
Supportive measures such as establishing intravenous lines, hydration, correction of electrolyte imbalance, oxygenation, and support of ventilatory function are essential for maintaining the vital functions of the patient. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Isoniazid and Thiacetazone (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to isoniazid or thiacetazone

Pregnancy—Isoniazid crosses the placenta; fetal serum concentrations may exceed maternal serum concentrations





Breast-feeding—Isoniazid is distributed into breast milk





Use in children—Children may be less susceptible to pyridoxine deficiency; children also may be less susceptible to hepatotoxicity than are adults, unless they have pre-existing hepatic disease; newborn infants may have prolonged isoniazid elimination






Use in the elderly—Patients over 50 years of age have the highest incidence of isoniazid-induced hepatitis
Other medicines, especially daily alcohol use, alfentanil, carbamazepine, disulfiram, other hepatotoxic medications, ketoconazole, phenytoin, or rifampin
Other medical problems, especially alcoholism, hepatic function impairment, or human immunodeficiency virus (HIV) infection

Proper use of this medication
Taking this medication with food or antacids, but not within 1 hour of aluminum-containing antacids, if gastrointestinal irritation occurs

» Compliance with full course of therapy, which may take 8 to 12 months ^{21}

» Taking pyridoxine concurrently to prevent or minimize symptoms of peripheral neuritis due to isoniazid; supplementation not usually required in children if dietary intake is adequate

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician or health care worker to check progress

» Receiving ophthalmologic examinations if signs of optic neuritis occur

» Checking with physician or health care worker if rash, even mild rash, occurs

Checking with physician or health care worker if vascular reactions occur following concurrent ingestion of cheese or fish

Checking with physician or health care worker if no improvement within 2 to 3 weeks

» Avoiding alcoholic beverages while taking this medication

» Promptly reporting to physician or health care worker prodromal signs of hepatitis or peripheral neuritis

» Diabetics: Possible false-positive reactions with copper sulfate urine glucose tests


Side/adverse effects
Stevens-Johnson syndrome and toxic epidermal necrolysis are more likely to occur in HIV-infected patients

Isoniazid-induced hepatitis may be more likely to occur in patients over 50 years of age

Signs of potential side effects, especially hepatitis, peripheral neuritis, Stevens-Johnson syndrome, toxic epidermal necrolysis, blood dyscrasias, conjunctivitis, hypersensitivity, neurotoxicity, and optic neuritis


General Dosing Information
The recommended regimens for treating tuberculosis with isoniazid and thiacetazone combination are either 8 or 12 months long. The 8-month regimen includes administration of isoniazid, rifampin, and pyrazinamide, together with streptomycin or ethambutol ^{55} for the first two months, after which isoniazid and thiacetazone combination is administered daily for the remaining 6 months. ^{{21} {55} {56}} The 12-month regimen includes isoniazid, thiacetazone, and streptomycin for the first 2 months, after which isoniazid and thiacetazone combination is continued daily for the remaining 10 months. ^{{21} {49} {55} {56}}

Because of the high incidence of cutaneous hypersensitivity reactions, isoniazid and thiacetazone combination is not recommended for the treatment of tuberculosis in HIV-infected patients, or patients at increased risk of HIV, if other antituberculous agents are available. If isoniazid and thiacetazone combination must be used, health care workers and patients should be educated to recognize side effects; patients should be told to stop the medication if a rash is noted and to report to the health care worker immediately. ^{{51} {53}} Desensitization should not be attempted. ^{53}

Isoniazid and thiacetazone combination may be taken with meals or antacids if gastrointestinal irritation occurs. However, administration with food and antacids, especially with aluminum-containing antacids, may decrease absorption of oral isoniazid and thiacetazone. This combination should be taken at least 1 hour before aluminum-containing antacids. ^{{07} {09}}


Oral Dosage Forms

ISONIAZID AND THIACETAZONE TABLETS

Usual adult and adolescent dose
Tuberculosis (treatment)
Oral, 300 mg of isoniazid and 150 mg of thiacetazone once a day. ^{{55} {56}}


Usual pediatric dose
Tuberculosis (treatment)—Dose is based on body weight ^{{62} {70}}.

Body Weight (kg)	Dose
	Number of Tablets *	Milligrams of Isoniazid/Thiacetazone
< 10	1/2	50/25
10–20	1	100/50
20–30	2	200/100
30–40	21/2	250/125
> 40	3	300/150

^* Refers to the 100 mg isoniazid and 50 mg thiacetazone strength tablets.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—
Not commercially available.

Others (Africa; Asia; Latin America^{70} )—


100 mg isoniazid and 50 mg thiacetazone (Rx) [Thiazina] [Thisozide^{{49}{54}{57}{63}}]


133 mg isoniazid and 50 mg thiacetazone (Rx) [INAT^{59}]


300 mg isoniazid and 150 mg thiacetazone (Rx) [Thiazina] [Thisozide^{49}{54}{63}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing.

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Avoid alcoholic beverages.

Developed: 06/22/1995

References

1. Wallach J, editor. Interpretation of diagnostic tests. 4th ed. Boston: Little, Brown and Company, 1986: 669.
   

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