Drug Interaction Report

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 It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement.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: A two-month regimen consisting of rifampin (RIF) and pyrazinamide (PZA) for the treatment of latent tuberculosis infection (LTBI) has been associated with liver injury resulting in high rates of hospitalization and death. The exact mechanism of interaction is unknown, although both agents are individually hepatotoxic and may have additive effects on the liver during coadministration. In one prospective cohort study of 224 patients in a community setting between 1999 and 2001, investigators found that the risk of hepatotoxicity in patients receiving the RIF-PZA regimen was increased threefold compared to patients receiving six months of isoniazid (INH). When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance.

MANAGEMENT: The American Thoracic Society and the Centers for Disease Control and Prevention recommend that the two-month RIF-PZA regimen generally not be offered to patients with LTBI (Note: This recommendation does not apply to the appropriate use of RIF and PZA in multidrug regimens for the treatment of persons with active TB disease). A nine-month course of daily INH remains the preferred treatment for LTBI in both HIV-negative and HIV-positive patients. Other acceptable options include nine months of twice-weekly INH, or six months of either daily or twice-weekly INH. Twice-weekly therapy must be administered under direct observed therapy (DOT), and the six-month regimens should generally not be used in HIV-infected individuals, those with fibrotic lesions on chest radiographs, and children. Four months of daily RIF may be considered for persons who are contacts of patients with INH-resistant, RIF-susceptible TB. The RIF-PZA regimen should never be offered to patients who are taking concomitant medications associated with liver injury; patients who drink alcohol excessively (even if alcohol use is discontinued during treatment); patients with underlying liver disease; and patients with a history of INH-associated liver injury. RIF-PZA may be considered in carefully selected patients if there is reason to believe they are not likely to complete the preferred six- or nine-month regimens. If RIF-PZA is prescribed, the PZA dosage should be no more than 20 mg/kg/day (up to a maximum of 2 g/day) or 50 mg/kg twice weekly (up to a maximum of 4 g twice weekly), and no more than a two-week supply of the medications should be dispensed at any given time. Patients should be evaluated in person by a healthcare provider at 2, 4, and 6 weeks of treatment for adherence, tolerance and adverse effects, and at 8 weeks to document treatment completion. Patients should also be instructed to discontinue the drugs promptly and seek medical attention if signs and symptoms of hepatic injury develop, including fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. Serum transaminases and bilirubin should be measured at baseline and at 2, 4, 6, and 8 weeks of treatment in patients taking RIF-PZA. Therapy should be withdrawn and not resumed if transaminase levels exceed five times the upper limit of normal or are anywhere above the normal range when accompanied by symptoms of hepatitis, or if serum bilirubin is greater than the normal range. U.S. healthcare providers should report possible cases of RIF-PZA hepatotoxicity to CDC's Division of Tuberculosis Elimination, telephone 404-639-8442.

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MONITOR: Coadministration of rifampin with agents known to induce hepatotoxicity may potentiate the risk of liver injury. There are various possible mechanisms related to rifampin-associated hepatotoxicity described in product labeling and medical literature, however no consensus has been made. These include increased mitochondrial oxidative stress, apoptotic liver cell injury (in rodent studies), the development of cholestasis, hepatic lipid accumulation, and elevated toxic metabolites caused by rifampin-mediated induction of cytochrome P450 enzymes. Cases of drug-induced liver injury (including fatal cases) have been reported within the first few days to months following rifampin treatment initiation. Additional data suggests that 1-2% of patients receiving rifampin monotherapy for tuberculosis prophylaxis experience hepatotoxicity. The severity of hepatotoxicity from rifampin ranges from asymptomatic elevations in liver enzymes, jaundice and/or hyperbilirubinemia, and symptomatic self-limiting hepatitis to fulminant liver failure and death. In most cases, liver function recovers upon on discontinuation of rifampin treatment, however, progression to acute liver failure requiring liver transplantation is possible. Known risk factors that may predispose the patient to rifampin related hepatotoxicity include: coadministration with other hepatotoxic agents, alcoholism, existing liver disease, malnutrition, extensive liver tuberculosis, liver adenocarcinoma and biliary tract neoplasm. Clinical data have been reported with concurrent use of rifampin with other antituberculosis agents (e.g. isoniazid, pyrazinamide), acetaminophen, antiretroviral agents (e.g., saquinavir/ritonavir) and halothane. Data with other hepatotoxic agents are limited.

MANAGEMENT: Caution and close clinical monitoring should be considered if rifampin is coadministered with other hepatotoxic medications. In addition, the manufacturer recommends patients with impaired liver function only be given rifampin in cases of necessity and then under strict medical supervision. Some authorities consider rifampin treatment in patients with existing liver injury contraindicated (Canada). In cases where coadministration of rifampin with hepatotoxic agents is required, careful monitoring of liver function, especially ALT and AST, should be done prior to therapy and then every 2 to 4 weeks during therapy. If hepatic damage is suspected, rifampin should be immediately discontinued. Furthermore, if hepatitis is attributed to rifampin in patients with tuberculosis, alternative agents should be considered. Patients should be instructed to contact their physician immediately if they experience symptoms such as itching, weakness, loss of appetite, nausea, vomiting, abdominal pain, yellowing of the eyes or skin or dark urine.

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MONITOR: The risk of peripheral neuropathy may be increased during concurrent use of two or more agents that are associated with this adverse effect. Patient risk factors include diabetes and age older than 60 years. In some cases, the neuropathy may progress or become irreversible despite discontinuation of the medications.

MANAGEMENT: Caution is advised during concomitant use of agents with neurotoxic effects. Patients should be monitored closely for symptoms of neuropathy such as burning, tingling, pain, or numbness in the hands and feet. Since the development of peripheral neuropathy may be dose-related for many drugs, the recommended dosages should generally not be exceeded. Consideration should be given to dosage reduction or immediate discontinuation of these medications in patients who develop peripheral neuropathy to limit further damage. If feasible, therapy should generally be reinstituted only after resolution of neuropathy symptoms or return of symptoms to baseline status. In some cases, permanent dosage reductions may be required.

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MONITOR: Coadministration of isoniazid (INH) with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of INH's acetylation is genetically determined and generally classified as slow or rapid, with slow acetylators characterized by a relative lack of N-acetyltransferase. While the rate of acetylation does not significantly alter INH's effectiveness, it can lead to higher blood levels of INH and an increase of adverse reactions. In addition, INH is an in vitro inhibitor of several CYP450 isoenzymes (2C9, 2C19, 2E1, and 3A4). Coadministration of hepatotoxic drugs eliminated by one or more of these pathways may lead to elevated concentrations of the concomitant drug and increase the risk of hepatotoxicity. Most of the INH-associated hepatitis cases occur during the first 3 months of treatment, but may occur at any time and have been reported to be severe or even fatal. INH is reported in medical literature to cause clinically apparent acute liver injury with jaundice in 0.5% to 1% and fatality in 0.05% to 0.1% of recipients. A United States Public Health Service Surveillance Study of 13,838 people taking INH reported 8 deaths among 174 cases of hepatitis. Risk factors for INH related liver injury may include: age > 35 years, female gender, postpartum period, daily consumption of alcohol, injection drug user, slow acetylator phenotype, malnutrition, HIV infection, pre-existing liver disease, extra-pulmonary tuberculosis, and concomitant use of hepatotoxic medications. Clinical data have been reported with concurrent use of acetaminophen, alcohol, carbamazepine, phenobarbital, phenytoin, and rifampin.

MANAGEMENT: Coadministration of isoniazid (INH) with other hepatotoxic medications should be done with caution and close clinical monitoring. Some authorities recommend avoiding concurrent use when possible. If coadministration is needed, baseline and monthly liver function testing as well as monthly interviewing of the patient to check for signs and symptoms of adverse effects is recommended. More frequent testing may be advisable in patients at increased risk of INH-associated liver injury. 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. 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. If hepatic damage is suspected, INH should be immediately discontinued as continuation may lead to more severe damage. If hepatitis is attributed to INH in patients with tuberculosis, alternative drugs should be used. 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. Consultation with product labeling and relevant guidelines is advisable.

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MONITOR: Coadministration with potent inducers of CYP450 2C19 and/or 3A4, such as rifampin and St. John's wort, may significantly decrease the plasma concentrations of drugs which are primarily metabolized by these isoenzymes.

MANAGEMENT: Caution is advised when potent inducers of CYP450 2C19 and/or 3A4 are used concomitantly with medications that are substrates of these CYP450 isoenzymes. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever St. John's wort or rifampin is added to or withdrawn from therapy.

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MONITOR: Coadministration with inhibitors of CYP450 2C19 may increase the plasma concentrations of escitalopram, which is primarily metabolized by the isoenzyme. The interaction has been studied with omeprazole, a potent CYP450 2C19 inhibitor. In study subjects, administration of a single 20 mg dose of escitalopram on day 5 of treatment with omeprazole 30 mg once daily for 6 days resulted in increases of escitalopram peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 10% and 50%, respectively. High plasma levels of escitalopram may increase the risk of serious side effects such as QT prolongation, which may lead to arrhythmias including torsade de pointes and sudden death, as well as serotonin syndrome, which is a rare but potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: Caution is advised when escitalopram is used concomitantly with CYP450 2C19 inhibitors. Pharmacologic response to escitalopram should be monitored more closely whenever a CYP450 2C19 inhibitor is added to or withdrawn from therapy, and the escitalopram dosage adjusted as necessary. This may be particularly important in patients receiving escitalopram at the upper end of the dosage range. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heartbeat, shortness of breath, or syncope. Patients should also be closely monitored for symptoms of the serotonin syndrome during treatment.

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GENERALLY AVOID: Concurrent use of rifampin in patients who ingest alcohol daily may result in an increased incidence of hepatotoxicity. The increase in hepatotoxicity may be due to an additive risk as both alcohol and rifampin are individually associated with this adverse reaction. However, the exact mechanism has not been established.

ADJUST DOSING INTERVAL: Administration with food may reduce oral rifampin absorption, increasing the risk of therapeutic failure or resistance. In a randomized, four-period crossover phase I study of 14 healthy male and female volunteers, the pharmacokinetics of single dose rifampin 600 mg were evaluated under fasting conditions and with a high-fat meal. Researchers observed that administration of rifampin with a high-fat meal reduced rifampin peak plasma concentration (Cmax) by 36%, nearly doubled the time to reach peak plasma concentration (Tmax) but reduced overall exposure (AUC) by only 6%.

MANAGEMENT: The manufacturer of oral forms of rifampin recommends administration on an empty stomach, 30 minutes before or 2 hours after meals. Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and rifampin concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with rifampin.

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GENERALLY AVOID: Concurrent use of isoniazid (INH) in patients who ingest alcohol daily may result in an increased incidence of both hepatotoxicity and peripheral neuropathy. The increase in hepatotoxicity may be due to an additive risk as both alcohol and INH are individually associated with this adverse reaction. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of acetylation is genetically determined and generally classified as slow or rapid. Slow acetylators have been identified by some studies as having a higher risk of hepatotoxicity; therefore, this interaction may be more significant for patients who fall into this category. Other studies have postulated that alcohol-mediated CYP450 2E1 induction may play a role, as this isoenzyme is involved in INH metabolism and may be responsible for producing hepatotoxic metabolites. However, available literature is conflicting. The labeling for some INH products lists daily alcohol use or chronic alcoholism as a risk factor for hepatitis, but not all studies have found a significant association between alcohol use and INH-induced hepatotoxicity. Additionally, INH and alcohol are both associated with pyridoxine (B6) deficiency, which may increase the risk of peripheral neuropathy.

GENERALLY AVOID: Concomitant administration of isoniazid (INH) with foods containing tyramine and/or histamine may increase the risk of symptoms relating to tyramine- and/or histamine toxicity (e.g., headache, diaphoresis, flushing, palpitations, and hypotension). The proposed mechanism is INH-mediated inhibition of monoamine oxidase (MAO) and diamine oxidase (DAO), enzymes responsible for the metabolism of tyramine and histamine, respectively. Some authors have suggested that the reactions observed are mainly due to INH's effects on DAO instead of MAO or the amounts of histamine instead of tyramine present in the food. A Japanese case report recorded an example in 8 out of 25 patients on the tuberculosis ward who developed an accidental histamine poisoning after ingesting a fish paste (saury). Patients developed allergy-like symptoms, which started between 20 minutes and 2 hours after ingesting the food. A high-level of histamine (32 mg/100 g of fish) was confirmed in the saury paste and all 8 patients were both on INH and had reduced MAO concentrations. The 17 remaining patients were not on INH (n=5) or reported not eating the saury paste (n=12).

ADJUST DOSING INTERVAL: Administration with food significantly reduces oral isoniazid (INH) absorption, increasing the risk of therapeutic failure or resistance. The mechanism is unknown. Pharmacokinetic studies completed in both healthy volunteers (n=14) and tuberculosis patients (n=20 treatment-naive patients during days 1 to 3 of treatment) have resulted in almost doubling the time to reach INH's maximum concentration (tmax) and a reduction in isoniazid's maximum concentration (Cmax) of 42%-51% in patients who consumed high-fat or high-carbohydrate meals prior to INH treatment.

MANAGEMENT: The manufacturer of oral forms of isoniazid (INH) recommends administration on an empty stomach (i.e., 30 minutes before or 2 hours after meals). Patients should be encouraged to avoid alcohol or strictly limit their intake. Patients who use alcohol and INH concurrently or have a history of alcohol use disorder may require additional monitoring of their liver function during treatment with INH. Concomitant pyridoxine (B6) administration is also recommended to reduce the risk of peripheral neuropathy, with some authorities suggesting a dose of at least 10 mg/day. Patients should be advised to avoid foods containing tyramine (e.g., aged cheese, cured meats such as sausages and salami, fava beans, sauerkraut, soy sauce, beer, or red wine) or histamine (e.g., skipjack, tuna, mackerel, salmon) during treatment with isoniazid. Consultation of product labeling for combination products containing isoniazid and/or relevant guidelines may be helpful for more specific recommendations.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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The recommended maximum number of medicines in the 'anti-infectives' category to be taken concurrently is usually three. Your list includes four medicines belonging to the 'anti-infectives' category:

• ethambutol
• isoniazid
• pyrazinamide
• rifampin

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'antituberculosis agents' category to be taken concurrently is usually three. Your list includes four medicines belonging to the 'antituberculosis agents' category:

• ethambutol
• isoniazid
• pyrazinamide
• rifampin

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'miscellaneous antituberculosis agents' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'miscellaneous antituberculosis agents' category:

• ethambutol
• pyrazinamide

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.