Rifampin isoniazid pyrazinamide overdosage

# Overdosage
There is no human experience with RIFATER overdosage.

## Acute Toxicity

### Rifampin
The minimum acute lethal or toxic dose is not well established. However, nonfatal acute overdoses in adults have been reported with doses ranging from 9 to 12 gm rifampin. Fatal acute overdoses in adults have been reported with doses ranging from 14 to 60 gm. Alcohol or a history of alcohol abuse was involved in some of the fatal and nonfatal reports. Nonfatal overdoses in pediatric patients ages 1 to 4 years old of 100 mg/kg for one to two doses has been reported.

### Isoniazid
Untreated or inadequately treated cases of gross isoniazid overdosage can be fatal, but good response has been reported in most patients treated within the first few hours after drug ingestion.
Ingested acutely, as little as 1.5 g isoniazid may cause toxicity in adults. Doses of 35 to 40 mg/kg have resulted in seizures. Ingestion of 80 to 150 mg/kg isoniazid has been associated with severe toxicity and, if untreated, significant mortality.

### Pyrazinamide
Overdosage experience with pyrazinamide is limited.
The following signs and symptoms have been seen with each individual component in an overdosage situation.

### Rifampin
Nausea, vomiting, abdominal pain, pruritus, headache, and increasing lethargy will probably occur within a short time after rifampin overdosage; unconsciousness may occur when there is severe hepatic disease. Transient increases in liver enzymes and/or bilirubin may occur. Brownish red or orange discoloration of the skin, urine, sweat, saliva, tears, and feces will occur, and its intensity is proportional to the amount ingested.
Liver enlargement, possibly with tenderness, can develop within a few hours after severe overdosage; bilirubin levels may increase and jaundice may develop rapidly. Hepatic involvement may be more marked in patients with prior impairment of hepatic function. Other physical findings remain essentially normal. A direct effect upon the hematopoietic system, electrolyte levels, or acid-base balance is unlikely.
Facial or periorbital edema has also been reported in pediatric patients. Hypotension, sinus tachycardia, ventricular arrhythmias, seizures and cardiac arrest were reported in some fatal cases.

### Isoniazid
Isoniazid overdosage produces signs and symptoms within 30 minutes to 3 hours. Nausea, vomiting, dizziness, slurring of speech, blurring of vision, and visual hallucinations (including bright colors and strange designs) are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected along with severe, intractable seizures. Severe metabolic acidosis, acetonuria, and hyperglycemia are typical laboratory findings.

### Pyrazinamide
In one case of pyrazinamide overdosage, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped.

## Treatment
The airway should be secured and adequate respiratory exchange should be established in cases of overdosage with RIFATER. Only then should gastric emptying (lavage-aspiration) be attempted; this may be difficult because of seizures.
Obtain blood samples for immediate determination of gases, electrolytes, BUN, glucose, etc; type and cross-match blood in preparation for possible hemodialysis.
Gastric lavage within the first 2 to 3 hours after ingestion is advised, but it should not be attempted until convulsions are under control. To treat convulsions, administer IV diazepam or short-acting barbiturates, and IV pyridoxine (usually 1 mg/1 mg isoniazid ingested). Following evacuation of gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting.
Rapid control of metabolic acidosis is fundamental to management.
Give IV sodium bicarbonate at once and repeat as needed, adjusting subsequent dosage on the basis of laboratory findings (e.g., serum sodium, pH, etc).
Forced osmotic diuresis must be started early and should be continued for some hours after clinical improvement to hasten renal clearance of drug and help prevent relapse; monitor fluid intake and output.
Bile drainage may be indicated in presence of serious impairment of hepatic function lasting more than 2448 hours. Under these circumstances and for severe cases, extracorporeal hemodialysis may be required; if this is not available, peritoneal dialysis can be used along with forced diuresis.
Along with measures based on initial and repeated determination of blood gases and other laboratory tests as needed, utilize meticulous respiratory and other intensive care to protect against hypoxia, hypotension, aspiration pneumonitis, etc.
Untreated or inadequately treated cases of gross isoniazid overdosage can terminate fatally, but good response has been reported in most patients brought under adequate treatment within the first few hours after drug ingestion.