Drug Interactions between Etrafon Forte and IsonaRif

MONITOR CLOSELY: The risk of hepatotoxicity is greater when rifampin and isoniazid (INH) are given concomitantly, than when either drug is given alone. The proposed mechanism is rifampin's induction of isoniazid hydrolase, an enzyme involved in the conversion of INH to isonicotinic acid and hydrazine. Hydrazine is the proposed toxic metabolite of INH, which has been shown in animal studies to cause steatosis, hepatocyte vacuolation and glutathione depletion. Some studies have also shown that slow acetylators have a two-fold increased risk of developing antituberculosis drug-induced hepatotoxicity (ATDH) as compared with fast acetylators due to more available INH for direct hydrolysis to hydrazine. Theoretically, a similar reaction may occur with rifabutin and isoniazid. Additional risk factors for developing hepatotoxicity include patients with advanced age, malnutrition, existing hepatic impairment, daily alcohol consumption, female gender, HIV infection, extra-pulmonary tuberculosis and/or patients who are taking other potent CYP450-inducing agents.

MANAGEMENT: Caution and close monitoring should be considered if isoniazid (INH) is coadministered with rifampin or rifabutin. In cases where coadministration is required, careful monitoring of liver function, especially ALT and AST, should be done at baseline and then every 2 to 4 weeks during therapy, or in accordance with individual product labeling. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Product labeling for rifampin also recommends the immediate discontinuation of therapy if hepatic damage is suspected. INH product labeling suggests alternate drugs be used if hepatitis is attributed to INH in patients with tuberculosis. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting.

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GENERALLY AVOID: Coadministration of isoniazid (INH), with drugs that possess serotonergic activity (e.g., serotonin reuptake inhibitors, 5-HT1 receptor agonists, ergot alkaloids, etc.) may increase the risk of serotonin syndrome, a rare but serious and potentially fatal condition. The proposed mechanism is an increase in serotonin resulting from INH's weak inhibition of monoamine oxidase (the enzyme primarily responsible for breaking down norepinephrine, serotonin, and dopamine) combined with the increase in serotonin from the serotonergic drug(s). In one case report, a patient taking mirtazapine (15 mg nightly) for depression was started on INH (300 mg daily) and pyridoxine (25 mg daily) for tuberculosis prophylaxis following a liver transplant from a donor with latent tuberculosis. Six days following the initiation of INH, the patient developed symptoms consistent with serotonin syndrome (e.g., diarrhea, nausea, tremors, hypertension, and altered mental status) which resolved upon the cessation of INH and mirtazapine. However, consensus on the safety of concomitant use of isoniazid with drugs possessing serotonergic activity is lacking and most of the existing data are limited to case reports.

MANAGEMENT: Until more information is available, coadministration of isoniazid with drugs that possess serotonergic activity (e.g., serotonin reuptake inhibitors, 5-HT1 receptor agonists, ergot alkaloids, etc.) should generally be avoided. If coadministration with a serotonergic drug is required, patients should be advised to promptly seek medical attention if they experience signs and symptoms of serotonin syndrome (including but not limited to confusion, hallucinations, tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, neuromuscular abnormalities and/or unexplained gastrointestinal symptoms).

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MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

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Rifampin may decrease the serum concentration of tricyclic antidepressants and their therapeutic effects. The proposed mechanism is metabolic induction. The clinical significance is unknown. Dosage adjustments may be required if an interaction is suspected.

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