Drug Interaction Report

MONITOR: Coadministration of chloramphenicol, dalfopristin, erythromycin, or fusidic acid may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme, by reducing their clearance, as these antibiotics are moderate inhibitors of this isoenzyme. Many estrogen and progestin type medications are CYP450 3A4 substrates. These medications are used for a variety of purposes including, but not limited to, contraception, acne treatment, hormone replacement therapy, and appetite stimulation. When telithromycin, a potent CYP450 3A4 inhibitor, was co-administered with oral contraceptives containing ethinyl estradiol and levonorgestrel, studies showed that the systemic concentration (AUC) of ethinyl estradiol did not change and the AUC of levonorgestrel increased by 50%. The study showed that telithromycin did not interfere with the anti-ovulatory effect of oral contraceptives containing ethinyl estradiol and levonorgestrel.

MANAGEMENT: Caution is advised if chloramphenicol, dalfopristin, erythromycin, or fusidic acid must be used concurrently with medications that undergo metabolism by CYP450 3A4. Patients should be monitored for increased adverse effects from the hormonal treatment if it must be co-administered with one of these antibiotics. Some serious side effects associated with hormonal treatment include, but are not limited to, cardiovascular disease (e.g., venous thromboembolism, myocardial infarction, and stroke); breast cancer; loss of bone mineral density; changes in mood; cholestatic jaundice; and dementia. Some of these side effects are affected by other factors such as medication dosage, concurrent medications, age, smoking status, and other disease states. If concurrent therapy with any of these antibiotics is necessary, please refer to the product labeling for more specific adverse effects to monitor for and counsel the patient and/or the patient's caregiver on the risks and benefits of concurrent therapy.

MONITOR: Estrogenic steroids, but not progestins, undergo enterohepatic cycling. It is possible that antimicrobials may interfere with the enterohepatic recirculation of estrogens by decreasing bacteria in the gastrointestinal tract that are responsible for regenerating parent estrogen molecules following first-pass metabolism. Most of the research regarding this possible interaction has been done with oral contraceptives; however, all estrogens appear to undergo enterohepatic recirculation so theoretically this interaction is a possibility with estrogen containing medications that are being used for alternative purposes. The risk appears to be small, and supportive data are primarily limited to anecdotal evidence from case reports and findings from uncontrolled or poorly controlled studies. Most antimicrobials, except for enzyme inducing medications like the rifamycins and possibly griseofulvin, have not been shown to significantly increase the clearance of estrogens present in combined hormonal contraceptives. It is possible that a small number of women may be more sensitive to the effects of antimicrobials on estrogen disposition in vivo, but risk factors or genetic predispositions have yet to be identified.

MANAGEMENT: If a person is using estrogen for a purpose other than contraception, it is important to note that there is a theoretical possibility of lower levels of systemic estrogen available during treatment with an antibiotic due to interference with enterohepatic cycling. These patients should be counseled to report any changes in efficacy of the hormonal product to their healthcare provider. In the case of contraception specifically, the Centers for Disease Control and Prevention do not consider most broad-spectrum antibiotics to significantly interfere with the effectiveness of combined hormonal contraception. However, the manufacturers of certain combined hormonal contraceptives and/or certain antibiotics do recommend using a back-up method of birth control for varying amounts of time; therefore, consulting the product labeling of each medication involved is advised. Some illnesses, as well as some antibiotics, may cause nausea, vomiting, and/or diarrhea. If the patient vomits within a few hours of taking an oral contraceptive pill, consult the product labeling for instructions on what to do in the event of a missed pill. Some authorities recommend a back-up method of birth control if an individual has persistent vomiting or diarrhea.

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MONITOR: Coadministration of chloramphenicol, dalfopristin, erythromycin, or fusidic acid may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme, by reducing their clearance, as these antibiotics are moderate inhibitors of this isoenzyme. Many estrogen and progestin type medications are CYP450 3A4 substrates. These medications are used for a variety of purposes including, but not limited to, contraception, acne treatment, hormone replacement therapy, and appetite stimulation. When telithromycin, a potent CYP450 3A4 inhibitor, was co-administered with oral contraceptives containing ethinyl estradiol and levonorgestrel, studies showed that the systemic concentration (AUC) of ethinyl estradiol did not change and the AUC of levonorgestrel increased by 50%. The study showed that telithromycin did not interfere with the anti-ovulatory effect of oral contraceptives containing ethinyl estradiol and levonorgestrel.

MANAGEMENT: Caution is advised if chloramphenicol, dalfopristin, erythromycin, or fusidic acid must be used concurrently with medications that undergo metabolism by CYP450 3A4. Patients should be monitored for increased adverse effects from the hormonal treatment if it must be co-administered with one of these antibiotics. Some serious side effects associated with hormonal treatment include, but are not limited to, cardiovascular disease (e.g., venous thromboembolism, myocardial infarction, and stroke); breast cancer; loss of bone mineral density; changes in mood; cholestatic jaundice; and dementia. Some of these side effects are affected by other factors such as medication dosage, concurrent medications, age, smoking status, and other disease states. If concurrent therapy with any of these antibiotics is necessary, please refer to the product labeling for more specific adverse effects to monitor for and counsel the patient and/or the patient's caregiver on the risks and benefits of concurrent therapy.

MONITOR: Estrogenic steroids, but not progestins, undergo enterohepatic cycling. It is possible that antimicrobials may interfere with the enterohepatic recirculation of estrogens by decreasing bacteria in the gastrointestinal tract that are responsible for regenerating parent estrogen molecules following first-pass metabolism. Most of the research regarding this possible interaction has been done with oral contraceptives; however, all estrogens appear to undergo enterohepatic recirculation so theoretically this interaction is a possibility with estrogen containing medications that are being used for alternative purposes. The risk appears to be small, and supportive data are primarily limited to anecdotal evidence from case reports and findings from uncontrolled or poorly controlled studies. Most antimicrobials, except for enzyme inducing medications like the rifamycins and possibly griseofulvin, have not been shown to significantly increase the clearance of estrogens present in combined hormonal contraceptives. It is possible that a small number of women may be more sensitive to the effects of antimicrobials on estrogen disposition in vivo, but risk factors or genetic predispositions have yet to be identified.

MANAGEMENT: If a person is using estrogen for a purpose other than contraception, it is important to note that there is a theoretical possibility of lower levels of systemic estrogen available during treatment with an antibiotic due to interference with enterohepatic cycling. These patients should be counseled to report any changes in efficacy of the hormonal product to their healthcare provider. In the case of contraception specifically, the Centers for Disease Control and Prevention do not consider most broad-spectrum antibiotics to significantly interfere with the effectiveness of combined hormonal contraception. However, the manufacturers of certain combined hormonal contraceptives and/or certain antibiotics do recommend using a back-up method of birth control for varying amounts of time; therefore, consulting the product labeling of each medication involved is advised. Some illnesses, as well as some antibiotics, may cause nausea, vomiting, and/or diarrhea. If the patient vomits within a few hours of taking an oral contraceptive pill, consult the product labeling for instructions on what to do in the event of a missed pill. Some authorities recommend a back-up method of birth control if an individual has persistent vomiting or diarrhea.

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MONITOR: The effectiveness of estrogen-containing medications may be impaired by concomitant treatment with antimicrobial agents. During metabolism, the estrogen component is conjugated, resulting in sulfation or glucuronidation of the original estrogenic steroid. The conjugates reach the intestine by way of the bile duct where hydrolytic enzymes of intestinal bacteria break down the conjugates into free, active estrogenic hormone. The active hormone is then available for enterohepatic cycling, which helps to maintain estrogen levels. It is important to note that the progestin component of a combined hormonal product does not undergo this process. It has been suggested that broad-spectrum antibiotics may reduce the effectiveness of estrogen-containing contraceptives because of their potential to reduce the number of intestinal bacteria and thus interfere with enterohepatic cycling of estrogen. Most of the research regarding this possible interaction has been done with oral contraceptives, but all estrogens appear to undergo enterohepatic recirculation so theoretically this interaction is a possibility with estrogen containing medications that are being used for alternative purposes. However, the risk appears to be small, and supportive data are primarily limited to anecdotal evidence from case reports and findings from uncontrolled or poorly controlled studies. Most antimicrobials, with the exception of enzyme inducing medications like the rifamycins and possibly griseofulvin, have not been shown to significantly increase the clearance of oral contraceptive estrogens. It is possible that a small number of women may be more sensitive to the effects of antimicrobials on estrogen disposition in vivo, but risk factors or genetic predispositions have yet to be identified.

MANAGEMENT: If a person is using estrogen for a purpose other than contraception, it is important to note that there is a theoretical possibility of lower levels of systemic estrogen available during treatment with an antibiotic due to interference with enterohepatic cycling. These patients should be counseled to report any changes in efficacy of the hormonal product to their healthcare provider. In the case of contraception specifically, the Centers for Disease Control and Prevention do not consider most broad-spectrum antibiotics to significantly interfere with the effectiveness of combined hormonal contraception. However, the manufacturers of certain combined hormonal contraceptives and/or certain antibiotics do recommend using a back-up method of birth control for varying amounts of time; therefore, consulting the product labeling of each medication involved is advised. Some illnesses, as well as some antibiotics, may cause nausea, vomiting, and/or diarrhea. If the patient vomits within a few hours of taking an oral contraceptive pill, consult the product labeling for instructions on what to do in the event of a missed pill. Some authorities recommend a back-up method of birth control if an individual has persistent vomiting or diarrhea.

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ADJUST DOSING INTERVAL: Food may variably affect the bioavailability of different oral formulations and salt forms of erythromycin. The individual product package labeling should be consulted regarding the appropriate time of administration in relation to food ingestion. Grapefruit juice may increase the plasma concentrations of orally administered erythromycin. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In an open-label, crossover study consisting of six healthy subjects, the coadministration with double-strength grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single dose of erythromycin (400 mg) by 52% and 49%, respectively, compared to water. The half-life was not affected. The clinical significance of this potential interaction is unknown.

MANAGEMENT: In general, optimal serum levels are achieved when erythromycin is taken in the fasting state, one-half to two hours before meals. However, some erythromycin products may be taken without regard to meals.

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MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of drugs that undergo significant presystemic metabolism by CYP450 3A4. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.

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Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

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Ethanol, when combined with erythromycin, may delay absorption and therefore the clinical effects of the antibiotic. The mechanism appears to be due to slowed gastric emptying by ethanol. Data is available only for erythromycin ethylsuccinate. Patients should be advised to avoid ethanol while taking erythromycin salts.

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The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction which is unpredictable.

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The central nervous system effects and blood levels of ethanol may be increased in patients taking oral contraceptives, although data are lacking and reports are contradictory. The mechanism may be due to enzyme inhibition. Consider counseling women about this interaction which is unpredictable.

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