Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) INH
2) INAH
3) Isonicotinic acid hydrazide
4) Isonicotinylhydrazine
5) Isonicotinylhydrazide
6) Isoniazidum
7) Tubazid
8) Molecular Formula: C6-H7-N3-O
9) CAS 54-85-3
10) Hydrazide of isonicotinic acid
11) Hydrazide, isonicotinic acid

1.2.1) MOLECULAR FORMULA
1) C6-H7-N3-O

Available Forms Sources

A)

1) Isoniazid is available as 100 mg and 300 mg oral tablets, 50 mg/5 mL oral solution, and 100 mg/mL intramuscular solution (Prod Info isoniazid oral tablets, 2011; Prod Info RIFATER(R) oral tablets, 2013; Prod Info isoniazid oral tablets, 2004).

B)

1) Isoniazid is used to treat tuberculosis. It is usually used with other antituberculosis drugs such as rifampin and pyrazinamide (Prod Info isoniazid oral tablets, 2011; Prod Info RIFATER(R) oral tablets, 2013; Prod Info isoniazid oral tablets, 2004; Centers for Disease Control and Prevention et al, 2009).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Isoniazid is an agent used for the treatment of mycobacterium species infection including M. tuberculosis.
B) PHARMACOLOGY: Isoniazid interferes with enzymes that help produce mycobacterial cell walls.
C) TOXICOLOGY: Isoniazid causes a functional deficiency of pyridoxine by increasing its elimination and decreasing its conversion to the active form. The resulting deficiency of pyridoxine leads to decrease in GABA formation.
D) EPIDEMIOLOGY: Uncommon exposure which can result in significant morbidity and death.
E) WITH THERAPEUTIC USE

1) Peripheral neuropathy is the most common side effect of isoniazid and is often preceded by paresthesias of the hands and feet. The side effects appear to be dose-related and occur more in the malnourished, patients with risk factors for neuritis (eg, alcoholism, diabetes), and in patients who are slow-inactivators. Other neurotoxic effects (uncommon) include seizures, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis. Isoniazid can cause an idiosyncratic hepatitis with therapeutic use. Toxicity can range from mild asymptomatic elevation of transaminases to fulminant hepatic failure. The following adverse effects have also been reported following therapeutic use of isoniazid: Nausea, vomiting, epigastric distress, pancreatitis, agranulocytosis, hemolytic, sideroblastic, or aplastic anemia, thrombocytopenia, eosinophilia, hypersensitivity reactions, fever, rash, anaphylactic reactions, lymphadenopathy, vasculitis, pyridoxine deficiency, pellagra, hyperglycemia or hypoglycemia, metabolic acidosis, gynecomastia, rheumatic syndrome, and systemic lupus erythematosus-like syndrome.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Vomiting, slurred speech, dizziness, and tachycardia. These signs may represent early signs of toxicity which may then progress, rather than mild toxicity.
2) SEVERE TOXICITY: Seizures, which are classically intractable to traditional treatment, severe lactic acidosis, acidosis, coma, hyperthermia, rhabdomyolysis, renal failure, and hypotension may occur. Elevations in hepatic enzymes to fulminant hepatic failure (rare) have developed in overdose. Persisting dementia has also been reported following acute overdose.

0.2.3)

A) Fever has been reported with therapeutic use, and hyperthermia has developed following overdose.

0.2.20)

A) Isoniazid is classified as FDA pregnancy category C and is known to cross the placenta. Embryocidal effects have been seen in animals exposed to isoniazid during pregnancy. Isoniazid should be used for the treatment of active tuberculosis since the maternal benefit justifies the fetal risk. If a mother is treated with isoniazid during pregnancy, carefully observe the neonate for adverse effects. Isoniazid passes into breast milk at small concentrations that do not result in toxicity to the nursing newborn; women should not be discouraged from nursing during treatment with this drug.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Adult patients who present within 2 hours after a large ingestion should be given a prophylactic dose of pyridoxine. Intravenous access should be established and the patient should be placed in a resuscitation-ready room. Seizures may be the presenting sign of ingestion and represent a more severe poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) Intractable seizures are the hallmark of severe isoniazid ingestions. Following adequate airway, respiratory, and circulatory support, primary treatment is aimed at terminating seizure activity. The patient should receive intravenous pyridoxine on a gram for gram basis of isoniazid ingested or 5 grams empirically for unknown doses. Standard anticonvulsant therapy is likely to be of marginal benefit as sole treatment, but benzodiazepines or barbiturates may act synergistically with pyridoxine and should be administered as well. Sodium bicarbonate can be administered for severe metabolic acidosis. Coma should be treated with standard supportive care. Administration of pyridoxine may reverse isoniazid-induced coma. Initially treat hypotension with 0.9% NaCl at 10 to 20 mL/kg. If necessary, add dopamine or norepinephrine.

C) DECONTAMINATION

1) PREHOSPITAL: Because of the risk of seizures and aspiration, prehospital decontamination should generally be avoided.
2) HOSPITAL: Activated charcoal and orogastric lavage should be used with caution because of the risk of seizures and subsequent risk of pulmonary aspiration. They should only be used in patients who present soon after an ingestion and who have adequate airway protection.

D) AIRWAY MANAGEMENT

1) Patients who are comatose or with altered mental status generally need tracheal intubation and mechanical respiratory support.

E) ANTIDOTE

1) Pyridoxine can be used to reverse the isoniazid-induced pyridoxine deficiency, which can terminate seizures and may be helpful in reversing isoniazid-induced coma. Treatment is on a gram-for-gram basis for the amount of isoniazid ingested, up to a maximum of 5 grams, or an empiric dose of 5 grams for an unknown ingestion in an adult. The pediatric dose is 70 mg/kg. The exact dosing regimen has not been established. For patients actively seizing, pyridoxine can be given at a rate of 0.5 g/min until the seizures stop or 5 g has given. The remainder can then be given over 1 to 4 hours. If seizures persist after the first dose, a second dose should be given. Oral pyridoxine can be administered via nasogastric tube if intravenous supplies are exhausted, but there is no data demonstrating the utility of oral pyridoxine for severe isoniazid toxicity. Benzodiazepines and/or barbiturate should also be administered to patients with seizures secondary to isoniazid overdose.

F) ENHANCED ELIMINATION

1) Hemodialysis can eliminate isoniazid but is rarely indicated.

G) PATIENT DISPOSITION

1) HOME MANAGEMENT: Patients who intentionally ingest isoniazid should be referred to a health care facility. Asymptomatic unintentional ingestions of less than 20 mg/kg can be watched at home.
2) OBSERVATION CRITERIA: If patients are asymptomatic after 6 hours, they can be discharged after appropriate psychiatric clearance.
3) ADMISSION CRITERIA: Patients with persistently altered mental status, abnormal vital signs, or seizures should be admitted.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.

H) PITFALLS

1) Many hospitals may not stock sufficient quantities of pyridoxine. Phenytoin is likely to be of minimal effectiveness for seizure control. Patients with underlying seizure disorders may have seizures at lower doses.

I) PHARMACOKINETICS

1) Volume of distribution is approximately 0.6 L/kg and has negligible protein binding. Peak concentrations are achieved within 2 hours after a single ingestion. The plasma half-life is approximately 1 to 4 hours.

J) TOXICOKINETICS

1) Symptoms generally occur within 2 hours after an overdose but have been reported to occur up to 5 hours later.

K) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis includes conditions that present with seizures and hence, is quite broad. Seizures intractable to conventional therapy, however, are a hallmark of isoniazid poisoning.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) Peripheral neuropathy is the most common side effect of isoniazid and is often preceded by paresthesias of the hands and feet. The side effects appear to be dose-related and occur more in the malnourished, patients with risk factors for neuritis (eg, alcoholism, diabetes), and in patients who are slow-inactivators. Other neurotoxic effects (uncommon) include seizures, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis. Isoniazid can cause an idiosyncratic hepatitis with therapeutic use. Toxicity can range from mild asymptomatic elevation of transaminases to fulminant hepatic failure. The following adverse effects have also been reported following therapeutic use of isoniazid: Nausea, vomiting, epigastric distress, pancreatitis, agranulocytosis, hemolytic, sideroblastic, or aplastic anemia, thrombocytopenia, eosinophilia, hypersensitivity reactions, fever, rash, anaphylactic reactions, lymphadenopathy, vasculitis, pyridoxine deficiency, pellagra, hyperglycemia or hypoglycemia, metabolic acidosis, gynecomastia, rheumatic syndrome, and systemic lupus erythematosus-like syndrome.

F)

1) MILD TO MODERATE TOXICITY: Vomiting, slurred speech, dizziness, and tachycardia. These signs may represent early signs of toxicity which may then progress, rather than mild toxicity.
2) SEVERE TOXICITY: Seizures, which are classically intractable to traditional treatment, severe lactic acidosis, acidosis, coma, hyperthermia, rhabdomyolysis, renal failure, and hypotension may occur. Elevations in hepatic enzymes to fulminant hepatic failure (rare) have developed in overdose. Persisting dementia has also been reported following acute overdose.

Vital Signs

3.3.1)

A) Fever has been reported with therapeutic use, and hyperthermia has developed following overdose.

3.3.3)

A) WITH THERAPEUTIC USE

1) Fever has been reported in patients who received isoniazid (Prod Info isoniazid oral tablets, 2011).
2) Fever occurs in about 1.2% of patients following ingestion of therapeutic doses (Lopez-Contreras et al, 1991).

B) WITH POISONING/EXPOSURE

1) Hyperthermia develops in patients with protracted seizures after overdose (Shah et al, 1995).

Heent

3.4.3)

A) WITH THERAPEUTIC USE

1) OPTIC NEURITIS AND ATROPHY may be noted with chronic exposures (Prod Info isoniazid oral tablets, 2011; Gonzalez-Gay et al, 1993).
2) CASE REPORT: A 55-year-old male developed headache and decreased left visual acuity approximately 3 months after starting INH for treatment of latent TB infection. Other medications included etanercept, deflazacort, and piroxicam for treatment of rheumatoid arthritis. Examination noted optic disc edema bilaterally (left > right) with decreased bilateral visual acuity. Despite discontinuation of INH and etanercept, symptoms persisted for greater than 3 months (Noguera-Pons et al, 2005).

B) WITH POISONING/EXPOSURE

1) VISUAL DISTURBANCE: A 14-year-old ingesting isoniazid 3.6 grams complained of seeing spots minutes prior to developing a 10 minute generalized seizure (Black & Ros, 1989).
2) OPTIC NEURITIS: A 17-year-old Hispanic female developed headache and decreased visual acuity (light perception but difficulty identifying specific objects) after ingesting 9 grams (146 mg/kg) of isoniazid. Eight hours post-ingestion, a ophthalmoscopic examination revealed bilateral hyperemic fundi. She was treated with activated charcoal/sorbitol and intravenous pyridoxine (total dose of 10 grams). Funduscopic exam was normal 12 hours after ingestion, and vision returned to normal by 20 hours after ingestion (Lockman et al, 2001).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 73-year-old male presented with dyspnea and hypotension 8 months after starting INH and rifampicin for pulmonary TB. Echocardiography demonstrated a significant pericardial effusion with tamponade physiology. The patient was treated with surgical placement of a pericardial window and discontinuation of antituberculosis treatment. Pericardial biopsy and mycobacterial culture of pericardial fluid were both negative for tuberculosis. The patient had a positive ANA titer of greater than 1.320 and an elevated antihistone antibody levels. The patient remained symptom free following surgery (Siddiqui & Khan, 2002).

2) WITH POISONING/EXPOSURE

a) Hypotension may develop in patients with severe intoxication (Hankins et al, 1987; Brown, 1972).

B) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia is common in patients with seizures after INH overdose (Shah et al, 1995; Brown, 1972; Maw & Aitken, 2003).

C) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) A 15-year-old boy developed status epilepticus, mild hypotension (80 mmHg systolic) and tachycardia after ingesting up to 15 grams of INH (Hankins et al, 1987). On arrival to the Emergency Department he abruptly became bradycardic to 40 BPM which resolved with intubation and ventilation.

D) VASCULITIS

1) WITH THERAPEUTIC USE

a) Vasculitis has been reported in patients who received isoniazid (Prod Info isoniazid oral tablets, 2011).

Respiratory

3.6.2)

A) HYPOVENTILATION

1) WITH POISONING/EXPOSURE

a) Respiratory depression and resultant cyanosis frequently accompanies seizure activity.

B) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) Tachypnea and Kussmaul type respirations may be noted between periods of seizure activity (Gurnani et al, 1992; Miller et al, 1980; Terman & Teitelbaum, 1970).

C) HYPOREFLEXIA

1) WITH POISONING/EXPOSURE

a) AIRWAY PROTECTION: Patients with significant CNS toxicity generally have depressed airway protective reflexes and require intubation (Gurnani et al, 1992).

Neurologic

3.7.2)

A) SEIZURE

1) WITH THERAPEUTIC USE

a) Seizures have been reported in patients who received isoniazid; however, occurrence was uncommon with conventional isoniazid doses (Prod Info isoniazid oral tablets, 2011).
b) CASE REPORT: Generalized tonic-clonic seizures accompanied by coma developed in a 14-year-old female during preventive therapy with isoniazid 400 mg/day and pyridoxine 25 mg/day for 1 month. Seizures gradually disappeared following sedation, discontinuation of isoniazid, and treatment with pyridoxine (Martinjak-Dvorsek et al, 2000).
c) CHRONIC RENAL FAILURE: Seizures have been reported in dialysis patients without a history of seizure disorder taking therapeutic doses of INH (Siskind et al, 1993; Asnis et al, 1993).

1) Reduced metabolism of pyridoxine to its active form, pyridoxal phosphate, and increased dialysis clearance of pyridoxal phosphate are believed to be responsible for this phenomenon (Siskind et al, 1993).

d) RARE EFFECTS: Muscle twitching, hyperreflexia, dizziness, ataxia, paresthesia, stupor, and toxic encephalopathy have been noted but are rare.

2) WITH POISONING/EXPOSURE

a) Seizures are common after significant overdose (Gokhale et al, 2009; Panganiban et al, 2001; Temmerman et al, 1999; Shah et al, 1995; Olson et al, 1993; Gurnani et al, 1992; Cash & Zawada, 1991; Maw & Aitken, 2003; Tai et al, 2008).
b) ONSET: Seizures may develop abruptly within 30 minutes to 3 hours after overdose (Shah et al, 1995).
c) DURATION: Status epilepticus may ensue with seizures lasting for hours and requiring aggressive treatment (Shah et al, 1995; Blowey et al, 1995; Olson et al, 1993; Gurnani et al, 1992; Siefkin et al, 1987).
d) INCIDENCE: Seizures developed in all patients in a series of 8 Cambodian refugees with INH overdose (Blanchard et al, 1986). In another series of 6 patients with INH overdose all had seizures (Nolan et al, 1988). In the early 1980s, a "mini-epidemic" of INH-induced seizures occurred due to an influx of immigrants from Southeast Asia (Olson et al, 1993).
e) PEDIATRIC

1) CASE REPORT: An 11-year-old girl presented with tonic-clonic seizures after an accidental overdose of 4800 mg of Isoniazid. Her seizures started one hour after ingestion and continued for 30 minutes. The seizure episode lead to a fracture of the thoracic spine. The patient recovered with standard care with pyridoxine. (Kalaci et al, 2008).
2) CASE REPORT: A 14-year-old female experienced auditory hallucinations one day after initiating INH and pyridoxine therapy for latent TB infection. Her hallucinations prompted her to take an overdose of 20 INH tablets. Shortly after ingestion the patient described visual hallucination and paresthesia; she then developed generalized seizures which were treated with lorazepam, pyridoxine and phenytoin. The patient recovered over the next 3 days. (Iannaccone et al, 2002).
3) CASE REPORT: A 10-year-old girl developed prolonged generalized tonic-clonic seizures and encephalitis-like signs and symptoms after ingesting 5 grams of isoniazid in a suicide attempt. Although she was treated successfully with repeated doses of intravenous midazolam, she remained in a state of reduced consciousness. She was verbally unresponsive, agitated, and presented with uncoordinated athetotic limb movements. She recovered completely following pyridoxine therapy (Tibussek et al, 2006).

B) COMA

1) WITH POISONING/EXPOSURE

a) Coma commonly develops, particularly after or between seizure episodes (Topcu et al, 2005; Panganiban et al, 2001; Martinjak-Dvorsek et al, 2000; Gurnani et al, 1992; Brent et al, 1990; Hankins et al, 1987; Siefkin et al, 1987; Goldin et al, 1987).
b) DURATION: Coma may persist for hours after seizures have been controlled and may require additional doses of pyridoxine (Gurnani et al, 1992; Brent et al, 1990).
c) CASE REPORT: A 53-year-old man developed progressive lethargy, confusion, and finally coma after accidentally taking 1200 mg isoniazid per day for 6 weeks. The patient's clinical course may have been complicated by a history of neurosyphilis or phenytoin toxicity. However, the patient had a rapid reversal of his condition and regained full alertness within 30 minutes of a 1 gram pyridoxine infusion (Salkind & Hewitt, 1997).

C) NEUROPATHY

1) WITH THERAPEUTIC USE

a) Peripheral neuropathy is the most common side effect of isoniazid and is often preceded by paresthesias of the hands and feet. The side effects appear to be dose-related and occur more in the malnourished, patients with risk factors for neuritis (eg, alcoholism, diabetes), and in patients who are slow-inactivators (Prod Info isoniazid oral tablets, 2011). Although peripheral neuropathy is common in adults, it rarely occurs in children (AMA Department of Drugs, 1986).
b) INCIDENCE: Peripheral neuritis occurs in about 20% of patients receiving 6 mg/kg/day without supplemental pyridoxine (Figg, 1991).
c) Peripheral neuropathy occurred in 44% of patients receiving more than 16 mg/kg/day (Figg, 1991).
d) CASE REPORT: Isoniazid-induced peripheral neuropathy worsened following discontinuation of INH and initiation of pyridoxine therapy at a dose of 150 mg daily. Improvement of the neuropathy occurred following discontinuation of pyridoxine (Nisar et al, 1990).
e) CHRONIC RENAL FAILURE: Paresthesia, weakness, and ataxia have been reported in dialysis patients taking therapeutic doses of INH. Reduced metabolism of pyridoxine to its active form, pyridoxal phosphate, and increased dialysis clearance of pyridoxal phosphate are believed to be responsible for this phenomenon (Siskind et al, 1993).

2) WITH POISONING/EXPOSURE

a) ABNORMAL REFLEXES: Effects following acute overdose may include slurred speech and dizziness followed by stupor, hyperreflexia or areflexia, positive Babinski sign then seizures and coma (Orlowski et al, 1988; Siefkin et al, 1987; Wason et al, 1981a; Brown, 1972; Terman & Teitelbaum, 1970).

D) NEURITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT/OPTIC NEURITIS: A 17-year-old Hispanic female developed headache and decreased visual acuity (light perception but difficulty identifying specific objects) after ingesting 9 grams (146 mg/kg) of isoniazid. Eight hours post-ingestion, a ophthalmoscopic examination revealed bilateral hyperemic fundi. She was treated with activated charcoal/sorbitol and intravenous pyridoxine (total dose of 10 grams). Funduscopic exam was normal 12 hours after ingestion and vision returned to normal by 20 hours after ingestion (Lockman et al, 2001).
b) CASE REPORT: A 55-year-old male developed headache and decreased left visual acuity approximately 3 months after starting INH for treatment of latent TB infection. The patient was also taking etanercept, deflazacort, and piroxicam for treatment of rheumatoid arthritis. Examination noted optic disc edema bilaterally (left > right) with decreased bilateral visual acuity. Despite discontinuation of INH and etanercept, symptoms persisted for greater than 3 months (Noguera-Pons et al, 2005).

2) WITH POISONING/EXPOSURE

a) PERIPHERAL NEUROPATHY: Two adults developed sensory motor peripheral neuropathy after ingesting 7.5 and 5 grams of INH and receiving 7.5 and 5 grams of pyridoxine, respectively, as therapy. The neuropathy completely resolved by 14 days after ingestion (Gurnani et al, 1992).

E) HYPERACTIVE BEHAVIOR

1) WITH THERAPEUTIC USE

a) CASE REPORT: Hyperactivity, restlessness, insomnia, and character changes requiring psychiatric evaluation were reported in a 60-year-old female following the administration of isoniazid 300 mg/day for one month (Nelson et al, 1983).

F) NEUROTOXICITY

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 12-year-old developed CNS toxicity (ie, dizziness, tremor, ataxia, dysdiadochokinesia, dysmetria, and a positive Romberg test) 3 months after starting prophylactic isoniazid (10 mg/kg/day) with pyridoxine (25 mg/day). Cranial MRI revealed bilateral and symmetrical increased signal intensity at both cerebellar dentate nuclei and between the thalamus and mesencephalic areas on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging. Diffusion restriction in the thalami and posterior limb of internal capsula was observed on diffusion-weighted MRI images. All other laboratory results were within normal range. Blood isoniazid concentration was 16 mcg/mL (normal less than 3 mcg/mL). Isoniazid was discontinued and her condition gradually improved. All clinical and MRI findings were normal on 1-month followup (Hasiloglu et al, 2012).

G) ATAXIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Severe cerebellar ataxia possibly due to isoniazid toxicity developed in a 10-year-old child receiving isoniazid 300 mg daily for approximately 7 months without supplemental pyridoxine. Isoniazid therapy was discontinued and pyridoxine treatment initiated, with recovery occurring after 6 months (Lewin & McGreal, 1993).
b) CASE REPORT: A 12-year-old developed CNS toxicity (ie, dizziness, tremor, ataxia, dysdiadochokinesia, dysmetria, and a positive Romberg test) 3 months after starting prophylactic isoniazid (10 mg/kg/day) with pyridoxine (25 mg/day). Cranial MRI revealed bilateral and symmetrical increased signal intensity at both cerebellar dentate nuclei and between the thalamus and mesencephalic areas on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging. Diffusion restriction in the thalami and posterior limb of internal capsule was observed on diffusion-weighted MRI images. All other laboratory results were within normal range. Blood isoniazid concentration was 16 mcg/mL (normal less than 3 mcg/mL). Isoniazid was discontinued and her condition gradually improved. All clinical and MRI findings were normal on 1-month followup (Hasiloglu et al, 2012).

H) TOXIC ENCEPHALOPATHY

1) WITH THERAPEUTIC USE

a) Toxic encephalopathy has been reported in patients who received isoniazid; however, occurrence was uncommon with conventional isoniazid doses (Prod Info isoniazid oral tablets, 2011).
b) CHRONIC RENAL FAILURE: Dysarthria, euphoria, confusion, and lethargy have been reported in dialysis patients taking therapeutic doses of INH (Siskind et al, 1993; Asnis et al, 1993; Cheung et al, 1993).

1) Reduced metabolism of pyridoxine to its active form, pyridoxal phosphate, and increased dialysis clearance of pyridoxal phosphate are believed to be responsible for this phenomenon (Siskind et al, 1993).

c) CASE REPORTS

1) A 54-year-old male developed worsening confusion 2 weeks after initiation of INH therapy for latent TB infection. He demonstrated severe deficits of memory and concentration. Symptoms resolved rapidly with 100 mg of IV pyridoxine. The patient was able to continue INH therapy with pyridoxine supplementation and did not suffer any further symptoms (Reeves & Liberto, 2004).
2) A 64-year-old woman taking INH, ethambutol, pyrazinamide, and pyridoxine developed visual and tactile hallucinations (Gnam et al, 1993). These persisted after discontinuation of anti-tuberculosis medications and treatment with loxapine and perphenazine but resolved with reintroduction of pyridoxine.
3) Visual hallucinations and delusions developed in a 67-year-old man 7 days after beginning therapy with INH and rifampin. These effects resolved 2 days after INH and rifampin were discontinued and did not recur when rifampin and ethambutol were initiated (Pallone et al, 1993).
4) A 64-year-old man developed visual hallucinations, disorientation, and agitation 12 days after beginning therapy with INH and pyridoxine and returned to normal 48 hours after INH was discontinued (Ibrahim & Menke, 1994).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 10-year-old girl developed prolonged generalized tonic-clonic seizures and encephalitis-like signs and symptoms after ingesting 5 grams of isoniazid in a suicide attempt. Although she was treated successfully with repeated doses of intravenous midazolam, she remained in a state of reduced consciousness. She was verbally unresponsive, agitated, and presented with uncoordinated athetotic limb movements. She recovered fully with pyridoxine therapy (Tibussek et al, 2006).
b) CASE REPORT: After taking an estimated 9000 mg to 12,000 mg of isoniazid, a 20-year-old man presented to the hospital with fixed and dilated pupils and decerebrate posturing and persistent seizures. Following treatment in the ICU, he recovered medically, however, he experienced persisting deficits, specifically retrograde amnesia, anterograde learning difficulties, apraxia, and personality change in the form of a newly acquired passivity. A neurological examination revealed a basal ganglia injury. EEG revealed prominent slow delta and scattered theta activity, particularly in the temporal areas. Magnetic resonance imaging (MRI) revealed increased signal involving bilateral mesotemporal lobes, which could be consistent with the sort of learning difficulties exhibited. Although his condition improved following supportive therapy, he continued to have cognitive difficulties. However, the authors did not report the duration of the initial seizures; there is the possibility that the patient's persisting symptoms may have resulted from hypoxic injury sustained during prolonged seizures (Mclay et al, 2005).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) Nausea and vomiting have been reported in patients who received isoniazid (Prod Info isoniazid oral tablets, 2011).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting frequently develop prior to the onset of seizures (Tibussek et al, 2006; Panganiban et al, 2001; Shah et al, 1995; Brown, 1972).
b) CASE REPORT: A 21-year-old man who was taking isoniazid 300 mg and rifampicin 600 mg for tuberculosis, developed nausea and vomiting within an hour of ingesting 4 isoniazid tablets (300 mg each). He presented unconscious with generalized tonic-clonic seizures. Laboratory results revealed a high anion gap metabolic acidosis and elevated CPK and liver enzymes that peaked on days 4 and 5. Following supportive care, including 5 grams of pyridoxine therapy, he gradually recovered and was discharged on day 16 (Uzman et al, 2013).

B) ABDOMINAL PAIN

1) WITH THERAPEUTIC USE

a) Abdominal pain has been reported in patients who received isoniazid (Prod Info isoniazid oral tablets, 2011).

C) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea has also been reported after overdose (Shah et al, 1995).

D) PANCREATITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 31-year-old man developed pancreatitis 14 days after beginning INH, rifampin, and pyrazinamide. He improved when all medications were discontinued but pancreatitis recurred when INH was reintroduced. He ultimately tolerated treatment with rifampin, pyrazinamide, and ethambutol (Rabassa et al, 1994).

Hepatic

3.9.2)

A) ABNORMAL LIVER FUNCTION

1) WITH POISONING/EXPOSURE

a) Mild hepatic dysfunction has been reported following acute overdoses of isoniazid (Panganiban et al, 2001; Manchon et al, 1990; Orlowski et al, 1988a; Bear et al, 1976; Charpin et al, 1965; Lahori & Sharma, 1981; Tiszai et al, 1962). This is presumably due to production of acetylhydrazine, an active metabolite (Gurnani et al, 1992).
b) CASE REPORT (PEDIATRIC): A 7-year-old boy developed mild hepatic dysfunction after ingesting approximately 125 mg/kg isoniazid. The elevations in SGOT and SGPT resolved 7 days after exposure (Orlowski et al, 1988a).
c) CASE REPORT: Two adult patients became clinically jaundiced on the third and fourth days after acute isoniazid ingestions of 7.5 grams and 5 grams, respectively. Both had normal liver function tests by day 10 and 7 (Gurnani et al, 1992).

B) LIVER ENZYMES ABNORMAL

1) WITH THERAPEUTIC USE

a) Asymptomatic elevations in liver function tests develop in 10% to 20% of all patients taking INH (Meyers et al, 1994; Farrell et al, 1994) and 0% to 14% of children taking INH (Palusci et al, 1995).
b) Elevations of liver enzymes 2 to 3 times normal generally occur within the first 2 months of therapy and usually resolve even if therapy is continued (Meyers et al, 1994). When therapy is discontinued, liver enzyme levels typically improve within 4 weeks (Maddrey, 2005).
c) Risk factors for development of hepatotoxicity includes age over 50 years and baseline elevations of transaminase levels (Fountain et al, 2005; Cook et al, 2006). Patients who are slow acetylators of INH and have CYP2E1 cl/cl genotype may also be at increased risk (Maddrey, 2005). Patients with hepatitis C virus antibodies do not appear to have increased risk for toxicity (Fernandez-Villar et al, 2003). Chronic hepatitis B does not significantly increase risk of toxicity if only HBsAg is present. However, patients who are positive for both HBsAg and HBeAg (indicating active viral replication) are at much higher risk for hepatotoxicity (Patel & Voigt, 2002). Limited data suggests that patients taking INH simultaneously with anti-rheumatoid drug (methotrexate, infliximab, etanercept) are at much higher risk for hepatotoxicity (Vanhoof et al, 2003).
d) Jaundice may be noted and is thought to occur in about 0.6% of patients taking therapeutic doses. About 12% of adults taking INH prophylactically develop SGOT levels higher than 100 mU/mL (upper limits of normal, 40 mU/mL) which resolve when INH therapy is discontinued (Bailey et al, 1974).
e) CASE SERIES: In a study of 83 healthcare workers receiving isoniazid prophylaxis, 14 subjects (17%) had liver enzyme elevations greater than 2 times the upper limit of normal. Of these subjects, 5 patients had serum alanine aminotransferase levels more than 5 times the upper limit of normal and ceased isoniazid therapy (Stuart et al, 1999).
f) More recent studies have reported a lower incidence of toxicity. A 7 year study of public health clinic patients taking INH for latent TB infection noted AST greater than 5 times the upper limit of normal is 0.56% (19/3377) of subjects. Only one of these 19 patients was symptomatic (Fountain et al, 2005). In another study, an abnormal AST occurred in 11.4% of 149 patients treated for latent TB infection; only 2% had AST levels exceeding 5 times the upper limit of normal (Cook et al, 2006). A third study reported hepatotoxicity in 7.9% of 656 patients; 3.4% had severe hepatotoxicity using similar criteria as other studies (VanHest et al, 2004).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 21-year-old man who was taking isoniazid 300 mg and rifampicin 600 mg for tuberculosis, developed nausea and vomiting within an hour of ingesting 4 isoniazid tablets (300 mg each). He presented unconscious with generalized tonic-clonic seizures. Laboratory results revealed a high anion gap metabolic acidosis and elevated CPK and liver enzymes that peaked on days 4 and 5. Following supportive care, including 5 grams of pyridoxine therapy, he gradually recovered and was discharged on day 16 (Uzman et al, 2013).
b) CASE REPORT: An 18-year-old woman developed generalized tonic-clonic seizures, high anion gap metabolic acidosis (resistant to treatment with sodium bicarbonate), and coma after ingesting 2 grams of isoniazid. She also developed elevated liver enzymes on the fourth day, which resolved by day 15. She recovered and was discharged 7 days after admission (Topcu et al, 2005).

C) TOXIC HEPATITIS

1) WITH THERAPEUTIC USE

a) Clinical hepatitis with nausea, vomiting, fatigue, fever, abdominal pain, malaise, pruritus, and elevated liver function tests is less common, occurring in 0.3 to 1.3% of patients in most studies (Singh et al, 1995; Meyers et al, 1994; Veale et al, 1992).
b) It is more common in older patients, occurring in 2.3% of patients 50 to 64 years old (Meyers et al, 1994).
c) INCIDENCE: In a prospective cohort study of 11,141 patients receiving isoniazid preventive therapy, only 11 patients (0.1%) experienced hepatotoxic reactions compared to 0.5% to 2.0% reported in earlier studies (Nolan et al, 1999). The authors suggested that hepatotoxicity associated with isoniazid preventive therapy for latent tuberculosis may be lower than initially reported.

1) In another study, symptomatic hepatitis occurred in only 1 patient out 3377 studied over a 7 year period (Fountain et al, 2005).

d) In 430 patients treated for active TB over 10 years, there were 8 cases of hepatitis (2%) attributable to INH (transaminase level greater than 5 times the upper limit of normal). Incidence was estimated at 0.18 cases per person-months of exposure (Yee et al, 2003).
e) Hepatitis generally occurs within the first 2 months of therapy and resolves with discontinuation of INH (Meyers et al, 1994).
f) Patients with malnutrition and concomitant use of pyrazinamide or rifampin may be more likely to develop clinical hepatitis (Singh et al, 1995).

D) HEPATIC FAILURE

1) WITH THERAPEUTIC USE

a) Fulminant hepatic failure is a rare complication of INH use (Mitchell et al, 1995; Durand et al, 1995; Meyers et al, 1994; Farrell et al, 1994; Woo et al, 1992).
b) In one study of patients with fulminant hepatic failure taking INH and rifampin, those who were also taking pyrazinamide were more likely to have fatal hepatic failure. Other factors correlated with fatal liver failure were an interval of more than 15 days between the initiation of TB therapy and the onset of jaundice combined with grade III encephalopathy and factor V levels below 20% (Durand et al, 1995).
c) CASE REPORT: A 39-year-old male developed jaundice one month after initiation of INH, pyrazinamide, ethambutol and levofloxacin for vertebral TB. The patient had a bilirubin level of 12.2 mg/dL, AST 2062 Units/L, and ALT 1003 Units/L. Partial resolution was achieved following discontinuation of all medications. Treatment was changed to streptomycin, ciprofloxacin, and ethambutol, but the patient still progressed to fulminant hepatic failure over the next month with a maximum bilirubin level of 38 mg/dL and INR of 8. The patient underwent liver transplantation. Anti-TB treatment was continued along with immunosuppressant therapy (tacrolimus and mycophenolate); the patient had no symptomatic recurrence of hepatotoxicity 2 years following transplantation (Barcena et al, 2005).

2) WITH POISONING/EXPOSURE

a) Fulminant hepatic failure secondary to INH overdose has required liver transplantation (MMWR, 1993).

Genitourinary

3.10.2)

A) ANURIA

1) WITH POISONING/EXPOSURE

a) Albuminuria and oliguria progressing to anuria have been noted (Brown, 1972).

B) GLOMERULONEPHRITIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 13-year-old female developed anorexia, fever, weight loss, and abdominal pain 4 weeks after starting INH for latent TB infection. Urinalysis showed hematuria, proteinuria, and RBC casts. BUN was 42 mg/dL and creatinine was 1.8 mg/dL. Renal biopsy demonstrated crescentic glomerulonephritis involving 80% of glomeruli. Lab studies for drug induced lupus were negative. INH was discontinued, and the patient was treated with corticosteroids and cyclophosphamide. Renal function returned to normal after 6 months (Brik et al, 1998).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis has been reported in patients with seizures after INH overdose, and can be quite severe (pH less than 7.0) (Prod Info isoniazid oral tablets, 2011; Gokhale et al, 2009; Kalaci et al, 2008; Tibussek et al, 2006; Topcu et al, 2005; Panganiban et al, 2001; Blowey et al, 1995; Black & Ros, 1989). Severe anion gap metabolic acidosis (pH < 7.0) is common in patients who develop seizures after INH overdose (Topcu et al, 2005; Panganiban et al, 2001; Blowey et al, 1995; Black & Ros, 1989) Wason et al, 1982; (Brown, 1972; Maw & Aitken, 2003).

1) Metabolic acidosis is most likely due to the accumulation of lactate. Isoniazid blocks the conversion of lactate back to pyruvate by interfering with the cofactor in the reaction, nicotine adenine dinucleotide (NAD). INH also has an effect on the interconversion of beta hydroxybutyric acid and acetoacetic acid for similar reasons. A beta hydroxybutyric acidosis has been described in association with INH overdose (Pahl et al, 1984).

b) The acidosis is frequently refractory to IV sodium bicarbonate therapy alone (Topcu et al, 2005; Wason et al, 1981), but generally reverses after pyridoxine therapy (Blowey et al, 1995).
c) CASE REPORT: A 15-year-old male in status epilepticus after an INH overdose presented with an arterial pH of 6.49. He recovered fully with pyridoxine therapy (Hankins et al, 1987).
d) CASE REPORT: A 30-year-old woman developed severe metabolic acidosis (pH 6.92, HCO3 - 4.9; pO2 - 98; pCO2 - 20.6; anion gap, 14 mEq) and seizures after ingesting 15 isoniazid tablets. Following supportive care, including pyridoxine 5 g, she recovered and was discharged 5 days later. (Gokhale et al, 2009).

Hematologic

3.13.2)

A) ANEMIA

1) WITH THERAPEUTIC USE

a) The use of isoniazid has been associated with hemolytic anemia, sideroblastic anemia, and aplastic anemia (Prod Info isoniazid oral tablets, 2011).
b) CASE REPORT: Two siblings, a 6- and 7-year-old, both developed anemia due to pure red cell aplasia after 6 months of treatment with isoniazid for TB prophylaxis. Lab values were significant for decreased hemoglobin (6 grams/dL) in both patients with normal leukocyte and platelet counts. Recovery was complete following drug cessation (Marseglia & Locatelli, 1998).

B) AGRANULOCYTOSIS

1) WITH THERAPEUTIC USE

a) The use of isoniazid has been associated with agranulocytosis (Prod Info isoniazid oral tablets, 2011).

C) THROMBOCYTOPENIC DISORDER

1) WITH THERAPEUTIC USE

a) The use of isoniazid has been associated with thrombocytopenia (Prod Info isoniazid oral tablets, 2011).

D) EOSINOPHILIA

1) WITH THERAPEUTIC USE

a) The use of isoniazid has been associated with eosinophilia (Prod Info isoniazid oral tablets, 2011).

E) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) Leukocytosis is common after overdose (Topcu et al, 2005; Panganiban et al, 2001).

F) PANCYTOPENIA

1) WITH THERAPEUTIC USE

a) Pancytopenia attributed to hemophagocytosis within the bone marrow has been described during treatment with INH, rifampin, and pyrazinamide (Jain & Dash, 2004). It has also been reported in association with drug-induced lupus (Salazar-Paramo et al, 1992).

Dermatologic

3.14.2)

A) ERUPTION

1) WITH THERAPEUTIC USE

a) Skin eruptions (eg, morbilliform, maculopapular, purpuric, or exfoliative) have been reported with use of isoniazid (Prod Info isoniazid oral tablets, 2011).
b) Morbilliform, maculopapular, purpuric, and urticarial rashes are rare (about 2%) but have been noted. Delayed-type hypersensitivity reactions have been reported (Bakkum et al, 2002).

Musculoskeletal

3.15.2)

A) RHEUMATISM

1) WITH THERAPEUTIC USE

a) Rheumatic syndrome has been reported with isoniazid therapy (Prod Info isoniazid oral tablets, 2011).

B) RHABDOMYOLYSIS

1) WITH THERAPEUTIC USE

a) Rhabdomyolysis has been reported after therapeutic use (Cronkright & Szymaniak, 1989).

2) WITH POISONING/EXPOSURE

a) Rhabdomyolysis may develop in patients with protracted seizures after overdose (Shah et al, 1995).
b) CASE REPORT: A 21-year-old man who was taking isoniazid 300 mg and rifampicin 600 mg for tuberculosis, developed nausea and vomiting within an hour of ingesting 4 isoniazid tablets (300 mg each). He presented unconscious with generalized tonic-clonic seizures. Laboratory results revealed a high anion gap metabolic acidosis and elevated CPK (peak value: 56418 Units/L) and liver enzymes that peaked on days 4 and 5. Following supportive care, including 5 grams of pyridoxine therapy, he gradually recovered and was discharged on day 16 (Uzman et al, 2013).
c) CASE SERIES: In a retrospective study of 52 patients with INH overdose in whom creatine phosphokinase muscle fraction levels were available, 41% of patients had elevated CPK-MM levels (>485 Units/L). CPK-MM elevation did not correlate with the number of seizures, although there was some correlation between CPK-MM levels and both the duration of seizures and the amount of INH ingested (Panganiban et al, 2001).
d) CASE REPORT: A 17-year-old girl developed rhabdomyolysis (peak CPK 88,000 International Units/L) after INH overdose complicated by status epilepticus (Blowey et al, 1995).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Hyperglycemia has been reported (Uzman et al, 2013; Topcu et al, 2005; Miller et al, 1980; Brown, 1972).

B) HYPOGLYCEMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT (PEDIATRIC): A premature infant delivered at 29 weeks was started on INH (10 mg/kg daily) hours after birth due to active maternal pulmonary TB. Five days later the patient developed severe hypoglycemia requiring high dose IV dextrose (up to 18 mg/kg/min), hydrocortisone, and glucagon. Glucose level improved after INH was discontinued. Hypoglycemia recurred 6 days later when INH was reintroduced; improvement followed discontinuation. No other etiology for hypoglycemia was found (Ovali et al, 2004).

C) KETOSIS

1) WITH POISONING/EXPOSURE

a) KETONURIA has been reported (Miller et al, 1980; Brown, 1972).

D) GYNECOMASTIA

1) WITH THERAPEUTIC USE

a) Gynecomastia has been reported in patients who received isoniazid (Prod Info isoniazid oral tablets, 2011).

Immunologic

3.19.2)

A) LUPUS ERYTHEMATOSUS

1) WITH THERAPEUTIC USE

a) DRUG-INDUCED LUPUS

1) Systemic lupus erythematosus-like syndrome has been reported with isoniazid therapy (Prod Info isoniazid oral tablets, 2011).
2) Positive ANA titers are found in up to 25% of patients on INH therapy; however, less than 1% of patients develop a clinical lupus syndrome. Symptoms and findings are varied and can include arthritis, myalgia, rash, fever, weight loss, anemia, pleural effusions, pericarditis, renal impairment, and behavioral changes. Even after discontinuation of INH, symptoms may take up to 1 year to resolve (Yung & Richardson, 1994).
3) CASE REPORT: A 73-year-old male presented with fever, dyspnea, and malaise 1 year after initiation of INH, streptomycin, and pyrazinamide for pulmonary TB. Clinical effects included jaundice, malar rash, lymphadenopathy, and bilateral pleural effusion. Lab values were notable for pancytopenia, ESR of 125 mm/hr, AST of 144 Units/L, and ALT of 168 Units/L, and a positive ANA titer of 1:256. Anti-tuberculosis drugs were discontinued, and the patient was given prednisone of a total of 4 months. Symptoms resolved with treatment, and the ANA titer decreased to 1:16 (Salazar-Paramo et al, 1992).
4) CASE REPORT: A 73-year-old male presented with dyspnea and hypotension 8 months after starting INH and rifampicin for pulmonary TB. Echocardiography demonstrated a significant pericardial effusion with tamponade physiology. The patient was treated with surgical placement of a pericardial window and discontinuation of antituberculosis treatment. Pericardial biopsy and mycobacterial culture of pericardial fluid were both negative for tuberculosis. He had a positive ANA titer of greater than 1:320 and elevated antihistone antibody levels. The patient remained symptom free following surgery (Siddiqui & Khan, 2002).

B) ANAPHYLAXIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 40-year-old male developed dizziness, hypotension, tachypnea, and hypoxia 1 hour after taking 900 mg of INH. The patient was started on treatment 1 month prior for latent TB infection. He remained hypotensive despite treatment with epinephrine, methylprednisolone, and diphenhydramine. Dopamine infusion was required for 24 hours until the patient became hemodynamically stable. Rash, upper airway edema, or bronchospasm did not develop. No further reaction was reported after therapy was changed to rifampin and pyrazinamide (Crook, 2003).

C) LYMPHADENOPATHY

1) WITH THERAPEUTIC USE

a) Lymphadenopathy has been reported in patients who received isoniazid (Prod Info isoniazid oral tablets, 2011).

Reproductive

3.20.1)

A) Isoniazid is classified as FDA pregnancy category C and is known to cross the placenta. Embryocidal effects have been seen in animals exposed to isoniazid during pregnancy. Isoniazid should be used for the treatment of active tuberculosis since the maternal benefit justifies the fetal risk. If a mother is treated with isoniazid during pregnancy, carefully observe the neonate for adverse effects. Isoniazid passes into breast milk at small concentrations that do not result in toxicity to the nursing newborn; women should not be discouraged from nursing during treatment with this drug.

3.20.2)

A) ANIMAL STUDIES

1) MICE, RABBITS, RATS: No teratogenic effects were observed in reproduction studies with mice, rats, and rabbits (Prod Info isoniazid oral tablets, 2014; Prod Info RIFATER(R) oral tablets, 2008).

3.20.3)

A) PREGNANCY CATEGORY

1) The manufacturer has classified isoniazid as FDA pregnancy category C (Prod Info isoniazid oral tablets, 2014).
2) Isoniazid should be used for the treatment of active tuberculosis since the maternal benefit justifies the fetal risk. If a mother is treated with isoniazid during pregnancy, carefully observe the neonate for adverse effects (Prod Info isoniazid oral tablets, 2014).

B) PLACENTAL BARRIER

1) Isoniazid is known to cross the placenta (Prod Info isoniazid oral tablets, 2014).

C) ANIMAL STUDIES

1) RABBITS, RATS: Embryocidal effects have been observed rabbits and rats administered isoniazid during pregnancy (Prod Info isoniazid oral tablets, 2014; Prod Info RIFATER(R) oral tablets, 2008).

3.20.4)

A) BREAST MILK

1) Isoniazid passes into breast milk at small concentrations that do not result in toxicity to the nursing newborn; women should not be discouraged from nursing during treatment with this drug (Prod Info isoniazid oral tablets, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Isoniazid blood concentrations may be measured but are not clinically helpful in an acute setting.
B) Monitor serum electrolytes, serum lactate, and venous or arterial blood gases.
C) In patients with seizure, monitor renal function.
D) Monitor CBC and liver enzymes in symptomatic patients.
E) Monitor creatinine kinase if seizures are prolonged.
F) An EEG may be necessary to rule out status epilepticus.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Isoniazid blood concentrations may be measured but are not clinically helpful in an acute setting.
2) Monitor serum electrolytes and serum lactate.
3) In patients with seizure, monitor renal function.
4) Monitor CBC and liver enzymes in symptomatic patients.
5) Monitor creatinine kinase if seizures are prolonged.

B) ACID/BASE

1) Monitor venous or arterial blood gases.

C) HEMATOLOGIC

1) Obtain baseline CBC in symptomatic patients.

D) COAGULATION STUDIES

1) Monitor INR or PT and PTT in patients with evidence of hepatic injury.

E) LABORATORY INTERFERENCE BLOOD LACTATE

1) Toxic levels of isoniazid can interfere with blood lactate measurements performed by certain blood gas analyzers. Compared to controls, a blood isoniazid concentration of 16 mcg/mL increased lactate levels by 9% using the Ciba Corning Diagnostic 860 analyzer (CCD 860), but had no significant effects on the Nova Stat Profile 9 analyzer (Nova 9). In addition, isoniazid produced drift errors and lactate sensor instability in the Nova 9 analyzer (Lacoma et al, 1997).

4.1.3)

A) URINALYSIS

1) Monitor urinalysis and urine output in symptomatic patients.

4.1.4)

A) OTHER

1) ELECTROENCEPHALOGRAM

a) An EEG may be necessary to rule out status epilepticus.

2) MRI

a) CASE REPORT: A 12-year-old developed CNS toxicity (ie, dizziness, tremor, ataxia, dysdiadochokinesia, dysmetria, and a positive Romberg test) 3 months after starting prophylactic isoniazid (10 mg/kg/day) with pyridoxine (25 mg/day). Cranial MRI revealed bilateral and symmetrical increased signal intensity at both cerebellar dentate nuclei and between the thalamus and mesencephalic areas on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging. Diffusion restriction in the thalami and posterior limb of internal capsule was observed on diffusion-weighted MRI images. All other laboratory results were within normal range. Blood isoniazid concentration was 16 mcg/mL (normal less than 3 mcg/mL). Isoniazid was discontinued and her condition gradually improved. All clinical and MRI findings were normal on 1-month followup (Hasiloglu et al, 2012).

Methods

A)

1) The Scott and Wright method of determining serum INH levels does not detect the acetylated form but will measure as little as 0.01 mcg per ml of INH in serum (Scott & Wright, 1967).
2) Low serum INH concentration will result if protein is not removed from the blood collected within 1 to 2 hours (Scott & Wright, 1967). It has been reported that 45% of North Americans of European descent are rapid acetylators of INH (Harris et al, 1958).

B)

1) Official guidelines from the American Thoracic Society recommend liver function monitoring during TB therapy under certain scenarios:

a) LATENT: For treatment of latent TB, baseline and follow-up ALT and bilirubin levels should be checked in patients with chronic liver disease, chronic alcoholism, HIV requiring HAART or pregnancy (including women up to 3 months postpartum). Healthy patients over the age of 35 may also be considered for testing. Patients with baseline ALT elevations should have an etiology sought. INH should be held if ALT is greater than 5 times the upper limit of normal, or if the ALT is greater than 3 times the upper limit of normal with jaundice or symptomatic hepatitis.
b) ACTIVE: For treatment of active TB, baseline AST, ALT, bilirubin, alkaline phosphatase, creatinine and platelet count should be checked in all adult patients. Routine follow-up testing should be performed during therapy. INH should be held if ALT is greater than 5 times the upper limit of normal, or if the ALT is greater than 3 times the upper limit of normal with jaundice of symptomatic hepatitis (Saukkonen et al, 2006).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with persistently altered mental status, abnormal vital signs, or seizures should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients who intentionally ingest isoniazid should be referred to a health care facility. Asymptomatic unintentional ingestions of less than 20 mg/kg can be watched at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) If patients are asymptomatic after 6 hours, they can be discharged after appropriate psychiatric clearance.

Monitoring

A)

B)

C)

D)

E)

F)

Oral Exposure

6.5.1)

A) Because of the risk of seizures and aspiration, prehospital decontamination should generally be avoided.

6.5.2)

A) SUMMARY: Activated charcoal and orogastric lavage should be used with caution because of the risk of seizures and subsequent risk of pulmonary aspiration. They should only be used in patients who present soon after an ingestion and who have adequate airway protection.
B) ACTIVATED CHARCOAL

1) EFFICACY

a) Oral activated charcoal taken immediately after therapeutic isoniazid ingestion totally prevented the absorption of isoniazid in 3 volunteers (Siefkin et al, 1987).
b) Activated charcoal given 1 hour after therapeutic isoniazid ingestion in 6 volunteers failed to significantly reduce the area under the concentration-time curve. Likewise, the half-life was not changed significantly (Scolding et al, 1986).
c) CHARCOAL ADMINISTRATION

1) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

d) CHARCOAL DOSE

1) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

a) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

2) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

C) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) MONITORING OF PATIENT

1) Isoniazid blood concentrations may be measured but are not clinically helpful in an acute setting.
2) Monitor serum electrolytes, serum lactate, and venous or arterial blood gases.
3) In patients with seizure, monitor renal function.
4) Monitor CBC and liver enzymes in symptomatic patients.
5) Monitor creatinine kinase if seizures are prolonged.
6) An EEG may be necessary to rule out status epilepticus.

B) PYRIDOXINE

1) SUMMARY

a) If acute isoniazid overdose (acute ingestion of greater than 80 mg/kg) is suspected, even in an asymptomatic patient, the administration of intravenous pyridoxine should be strongly considered.
b) The earlier pyridoxine is administered in an isoniazid overdose the fewer the complications (Cash & Zawada, 1991).
c) It is recommended that all emergency departments have adequate stocks of pyridoxine (5 to 10 grams) on hand at all times.

2) DOSE

a) IV pyridoxine is the preferred formulation. In severely symptomatic patients with seizures, acidosis, and coma, pyridoxine should be given intravenous push until seizures are controlled and coma resolves (Brent et al, 1990).
b) DOSE: Administer an amount of pyridoxine equivalent to the estimated amount of isoniazid ingested (gram for gram basis). Initially administer up to 5 grams over 30 to 60 minutes. If necessary, the remainder may be given by intravenous drip in 500 to 1000 mL D5W over the next one to two hours (Wason et al, 1981a).
c) If the amount of isoniazid ingested is unknown, administer 5 grams of intravenous pyridoxine and repeat as needed until seizures are controlled (Sievers et al, 1982; Coyer & Nicholson, 1976; Wason et al, 1981a; Yarbrough & Wood, 1983).
d) CHILDREN: The pediatric dose is 70 mg/kg (not to exceed 5 g) (Christina et al, 2011; Erdman, 2004). However, the exact dosing regimen has not been established and some sources have found such doses to be insufficient (Minns et al, 2010).

1) CASE REPORT: A 10-month-old infant (weight, 9.3 kg) presented with generalized seizures after ingesting 4 to 5 isoniazid 300 mg tablets (about 2.7 g; 290 mg/kg total dose). Despite treatment with 650 mg of pyridoxine (based on a 70 mg/kg recommendation) and 1 mg diazepam IV, he experienced recurrent generalized seizures with brief periods of hypoxia. Following treatment with additional 2 g of pyridoxine (rate of 0.5 g/min), diazepam, and phenobarbital 20 mg/kg, his seizures resolved. He later developed respiratory depression and was intubated, however, after further supportive care, he recovered completely (Minns et al, 2010).

e) The maximum nontoxic pyridoxine dose is unknown. See Precautions.

3) HOSPITAL STOCKING POLICY

a) Published consensus guidelines for stocking emergency antidotes recommend that hospitals should maintain a minimum of 10 grams of intravenous pyridoxine HCL available. In one retrospective study, it was found that 85% of patients with isoniazid overdose did not receive an appropriate initial intravenous pyridoxine dose because of inadequate hospital stocking that did not meet published consensus guidelines (Burda et al, 2007). In some of these cases, crushed pyridoxine tablets were administered by nasogastric tube; however, this is not likely to be as effective as intravenous pyridoxine (Zell-Kanter, 2010; Burda et al, 2007).

4) ADVERSE EFFECTS

a) Pyridoxine can be neurotoxic in large doses. Administration of 0.2 to 5 grams for 2 to 40 months has produced neuropathy (Parry & Bredesen, 1985; Dalton, 1985; Berger & Schaumberg, 1984; Schaumberg et al, 1983). In isoniazid overdose, single intravenous doses of 70 to 357 mg/kg given over 1 hour (Wason et al, 1981a) and up to 52 grams have been administered without development of toxicity (Sievers & Herrier, 1975).
b) Current references only recommend administration of the amount of pyridoxine equivalent to the amount of isoniazid ingested, with no maximum dose stated (Prod Info, 1996).
c) In a randomized, controlled crossover trial with 5 healthy volunteers, the effects of intravenous pyridoxine (5 g) on acid-base status were assessed (LoVecchio et al, 1998). A statistically significant increase in base deficit compared to placebo was noted at 3, 10, and 20 minutes, with mean maximal increase in base deficit observed at 3 minutes (2.74 mEq/L). It is suggested that larger pyridoxine infusions, such as those given in overdose, may have the potential to cause some degree of metabolic acidosis.
d) One study reports the use of 10 grams of pyridoxine in a 24-year-old who ingested a "mouthful" of hydrazine. One week later the patient developed paresthesias of his hands and feet and mild distal limb weakness. Three weeks post injection he had diminished pinprick, vibration, touch and position senses in his distal arms to the wrists and distal legs to the ankles. The neuropathy spontaneously cleared over the next 6 months. Although the neuropathy may have been due to the hydrazine, the symptoms are similar to those of pyridoxine toxicity (Harati & NiaKan, 1986).
e) PRESERVATIVES : Excipient toxicity and adverse effects from intravenous pyridoxine hydrochloride products (standard dose of 5 to 10 grams) are expected to be minimal (Burda et al, 2002).
f) A 5 to 10 gram dose of pyridoxine hydrochloride (American Pharmaceutical Partners or APP) contains 250-500 mg of chlorobutanol (therapeutic dose 300-1200 mg/day). Chlorobutanol may cause mild CNS depression (Burda et al, 2002).
g) A 5 to 10 gram dose of pyridoxine hydrochloride (Legere Pharmaceuticals) contains 1 to 2 mg of parabens per kilogram. Since this amount is well below the World Health Organization's estimated total acceptable daily intake of 10 mg/kg for methylparaben, ethylparaben, and propylparaben, no acute toxicity is expected. Paraben-induced hypersensitivity reactions have been reported (Burda et al, 2002).

5) EFFICACY

a) Five isoniazid overdose cases were successfully treated with IV pyridoxine. Patients ingested 4 g to 25 g of isoniazid and were treated with an equivalent dose of pyridoxine (gram for gram). Pyridoxine was given as a 5% or 10% infusion over 30 minutes to 60 minutes. None of the patients developed recurrent seizures, metabolic acidosis resolved, and the mean duration of coma was 7 hours. These patients did not develop adverse effects to the large doses of pyridoxine. This regimen appears to be appropriate for isoniazid overdose, however more studies are indicated (Wason et al, 1981a).
b) FAILURE OF STANDARD ORAL PYRIDOXINE: Standard oral pyridoxine did not prevent seizures in 2 isoniazid-poisoned patients with isoniazid poisoning (Lee et al, 2015).
c) Large IV doses of pyridoxine were successfully used in 3 cases of massive isoniazid overdose, producing acidosis and seizures. One gram of pyridoxine was administered IV for each gram of isoniazid ingested (Yarbrough & Wood, 1983).
d) Large doses of pyridoxine (1 g IV) were used in isoniazid intoxication in a 13-year-old boy presenting with coma and seizures unresponsive to conventional treatment. Initially, 100 mg pyridoxine was given IV, then every 6 hours for 48 hours, resulting in abatement of seizures and acidosis; however, level II coma remained. IV injection of 1 g pyridoxine resulted in arousal within 15 minutes and progressive alertness over one hour (Brown et al, 1984).
e) Obtundation secondary to isoniazid overdose was immediately reversed by intravenous pyridoxine in 3 cases (Brent et al, 1990).
f) A 10-year-old girl suffering from severe cerebellar ataxia due to isoniazid toxicity completely recovered after 6 months of pyridoxine therapy 50 mg QD. The patient had been taking isoniazid 300 mg for approximately 7 months when the ataxia occurred and therapy was discontinued (Lewin & McGreal, 1993).

C) SEIZURE

1) Initial treatment for seizures is pyridoxine as above. This may be supplemented by intravenous benzodiazepines and/or barbiturates. Anticonvulsants that act by enhancing GABA effects (benzodiazepines, barbiturates) are preferred.
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

8) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

D) ACIDOSIS

1) The acidosis associated with acute isoniazid intoxication may be severe and is due to the production of lactic acid secondary to isoniazid induced seizures and metabolite reactions in which isoniazid interferes with metabolism of pyridoxine and also the conversion of lactate to pyruvate.
2) Control of seizures with intravenous pyridoxine and diazepam often resolves the acidosis without the use of IV sodium bicarbonate, however, severe acidosis (pH < 7.0) should treated (Sievers et al, 1982; Chin et al, 1979).
3) A reasonable initial dose is about 1 to 3 milliequivalents/kilogram. Monitor arterial blood gases to guide bicarbonate therapy. Up to 100 to 200 mEq of bicarbonate in the first hour in an adult may be needed. Children have required up to 3 mEq/kg/hr during the first few hours. IF LARGER DOSES ARE NEEDED, monitor serum sodium carefully to avoid hypernatremia and fluid overload.

E) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

F) FLUMAZENIL

1) PRECAUTION: One animal study indicated flumazenil has a proconvulsant effect when used to treat experimentally-induced murine isoniazid overdose. Doses of flumazenil were 0.05 and 0.5 mg/kg (Weisman et al, 1992).

G) EXPERIMENTAL THERAPY

1) N-ACETYLCYSTEINE (ANIMAL STUDY): In one animal study, n-acetylcysteine (hepatoprotective dose 100 mg/kg/day) prevented the induction of oxidative hepatic injury in young Wistar rats treated with hepatotoxic doses of isoniazid and rifampicin (50 mg/kg/day each intraperitoneally in sterile water) over a 3-week period, except in one animal which showed a mild degree of portal triaditis. In contrast, treatment with isoniazid and rifampicin alone caused hepatic lesions in all treated animals, which varied from a mild to moderate degree of portal triaditis, lobular inflammation, and patchy necrosis (Attri et al, 2000).

Enhanced Elimination

A)

1) Both peritoneal and hemodialysis have been used in the management of isoniazid overdose (Orlowski et al, 1988; Brown, 1972) Maher & Schreiner, 1967; (Cocco & Pazourek, 1963); however, these procedures are probably not required if control of seizures and acidosis is achieved with adequate doses of bicarbonate, pyridoxine, and diazepam (Cameron, 1978). In addition, isoniazid is rapidly cleared even in slow acetylators (half life greater than 5 hours), decreasing the need for dialysis.

B)

1) Although several authors (Coyer & Nicholson, 1976; Sievers & Herrier, 1975; Brown, 1972; Terman & Teitelbaum, 1970) recommend and/or suggest that forced diuresis enhances renal elimination of isoniazid, conclusive evidence is lacking.
2) Forced diuresis is not indicated in the patient who responds to adequate doses of intravenous pyridoxine and diazepam. Only 4 to 27 percent of isoniazid is eliminated as free drug in the urine. Fluid deficits should be corrected, avoiding excessive fluid administration.

C)

1) An average of 73 percent of the total dose of isoniazid was removed by 5 hours of hemodialysis (Gold, 1976).
2) One report confirmed the effectiveness of hemodialysis in reversing symptomatology refractory to pyridoxine therapy (Orlowski et al, 1988).
3) CASE REPORT: Hemodialysis, along with pyridoxine therapy, was used in the treatment of a 32-year-old man with open tuberculosis who intentionally ingested 12 grams of isoniazid (196 mg/kg). Upon presentation, the patient had been unconscious for two hours while having frequent seizures. An isoniazid level was measured at 28.9 mcg/mL. Hemodialysis was initiated after one round of treatment with pyridoxine 6 grams failed to awaken the patient. The patient was given 3 hours of hemodialysis, pyridoxine 6 grams and a diuretic for two days before regaining consciousness. Hemodialysis was discontinued after the patient regained consciousness, and after one week of therapy, the patient made a full recovery (Tai et al, 2008).
4) In general, good supportive care coupled with the administration of pyridoxine, GABA-enhancing anti-convulsants, and sodium bicarbonate (if necessary) should suffice. Extracorporeal elimination or hemoperfusion should be reserved for isoniazid overdose with persistent symptoms or for symptomatic patients with renal insufficiency.

D)

1) Peritoneal dialysis was employed in a severely intoxicated 3-year-old male who allegedly ingested isoniazid 5000 mg. The procedure employed 800 mL of standard peritoneal dialysate fluid instilled into the peritoneal cavity and allowed to equilibrate for 1 hour before removing. The procedure was continued for 72 hours. The authors estimate that 52.1 percent of the absorbed dose was recovered in the dialysate whereas 42.9 percent was recovered in the urine (Cocco & Pazourek, 1963).

E)

1) Exchange transfusion was performed in a 19-month-old, 11-kilogram child following ingestion of about 900 mg of isoniazid (Katz & Carver, 1956); however, this therapy is not recommended due to associated complications inherent in the procedure and the generally favorable outcome with the use of adequate doses of pyridoxine and diazepam.

Abstracts

Case Reports

A)

1) Large doses of pyridoxine (1 gram IV) were used in isoniazid intoxication in a 13-year-old male presenting with coma and seizures unresponsive to conventional treatment. Initially, 100 mg pyridoxine was given IV, then every 6 hours for 48 hours, resulting in abatement of seizures and acidosis; however, level II coma remained. IV injection of 1 gram pyridoxine resulted in arousal within 15 minutes and progressive alertness over one hour (Brown et al, 1984).
2) An intentional overdose occurred in a 40-year-old depressed man ingesting isoniazid 6 grams, ethambutol 20 grams, and rifampin 9 grams. He was admitted to the hospital 2 hours post-ingestion. The only complications included mild lactic acidosis and eosinophilia. Since overdose with single agents has been associated with a variety of symptoms, it is possible that complications did not develop due to prompt hemodialysis. Four hours post-ingestion, a 3 hour hemodialysis session was initiated, and the patient later received 10 grams of pyridoxine within a 12 hour period. Serum was not analyzed for drug concentrations before or after therapy. Confirmation of overdose was based on family history (Ducobu et al, 1982).
3) PEDIATRIC: A 7-year-old child ingesting isoniazid 125 mg/kg had a persistent metabolic acidosis and coma despite 6 grams of pyridoxine. Hemodialysis was initiated 11.5 hours after ingestion and continued for 5 hours, after which he was fully conscious and without seizure activity (Orlowski et al, 1988).
4) An 18-year-old female ingested isoniazid 100 mg/kg and developed seizures and coma refractory to both pyridoxine therapy and hemodialysis. Her mental status improved, and she was extubated 8 days after admission. EEG was normal by day 5 after exposure (Siefkin et al, 1987).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) 5 mg/kg (up to 300 mg/day) given as a single daily dose OR 15 mg/kg (up to 900 mg/day) 2 or 3 times per week (Prod Info isoniazid oral tablets, 2014).

7.2.2)

A) 10 to 15 mg/kg (up to 300 mg/day) given as a single daily dose OR 20 to 40 mg/kg (up to 900 mg/day) 2 or 3 times per week (Prod Info isoniazid oral tablets, 2014).

Minimum Lethal Exposure

A)

Maximum Tolerated Exposure

A)

1) CASE REPORT: A 21-year-old man who was taking isoniazid 300 mg and rifampicin 600 mg for tuberculosis, developed nausea and vomiting within an hour of ingesting 4 isoniazid tablets (300 mg each). He presented unconscious with generalized tonic-clonic seizures. Laboratory results revealed a high anion gap metabolic acidosis, elevated CPK and liver enzymes that peaked on days 4 and 5. Following supportive care, including 5 grams of pyridoxine therapy, he gradually recovered and was discharged on day 16 (Uzman et al, 2013).
2) CASE SERIES: Five cases of isoniazid (INH) overdose (amount ingested ranged from 100 to 417 mg/kg) resulted in serum INH concentrations ranging from 26 to 128 mcg/mL (189 to 933 mcmol/L). Therapeutic concentration is about 5 to 8 mcg/mL (36 to 58 mcmol/L) with a mean value of 78 mcg/mL (568 mcmol/L). All patients were symptomatic and 4 demonstrated seizures, coma, and acidosis. One patient was not comatose or acidotic but had seizures (Wason et al, 1982).
3) CASE REPORT: A 14-year-old male ingested 3.6 grams of isoniazid and developed generalized seizures and profound metabolic acidosis. He recovered fully following intensive supportive care and administration of 3.6 grams of intravenous pyridoxine (Black & Ros, 1989).
4) CASE REPORT: A 16-year-old male ingested between 7.5 and 13.5 grams of isoniazid which resulted in coma and seizures. Following treatment with 8.35 grams of pyridoxine, 8 mg of diazepam, and hemodialysis the patient recovered (Cash & Zawada, 1991).
5) CASE REPORT: A 17-year-old Hispanic female developed headache and decreased visual acuity after ingesting 9 grams (146 mg/kg) of isoniazid. Improvement of neuritis occurred after treatment with activated charcoal/sorbitol and intravenous pyridoxine (total dose of 10 grams) (Lockman et al, 2001).
6) CASE REPORT: Two patients (a 7-year-old girl and an 18-year-old woman) developed generalized tonic-clonic seizures, high anion gap metabolic acidosis (resistant to treatment with sodium bicarbonate), and coma after ingesting 1.5 grams and 2 grams of isoniazid, respectively. Following supportive therapy, both patients recovered and were discharged 7 days after admission (Topcu et al, 2005).
7) CASE REPORT: A 10-year-old girl developed prolonged generalized tonic-clonic seizures and encephalitis-like signs and symptoms after ingesting 5 grams of isoniazid in a suicide attempt. Although she was treated successfully with repeated doses of intravenous midazolam, she remained in a state of reduced consciousness. She was verbally unresponsive, agitated, and presented with uncoordinated athetotic limb movements. She recovered completely following pyridoxine therapy (Tibussek et al, 2006).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) Isoniazid blood levels higher than 10 mcg/mL (72.91 mcmol/L) have been associated with severe toxicity (Orlowski et al, 1988).
b) Isoniazid is detectable in urine and plasma with toxicity usually occurring at greater than 30 mcg/mL blood (218 mcmol/L).
c) There is overlap with therapeutic range. The range of normal levels should be requested from the lab completing the bio assay for accurate interpretation.

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Toxicologic Mechanism

A)

B)

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

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ISONIAZID

Classification | Detailed evidence-based information

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