Drug Interactions between Prevpac and Tri-Lo-Marzia

MONITOR CLOSELY: Coadministration of clarithromycin, telithromycin, or troleandomycin may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme, by reducing their clearance, as these antibiotics are potent 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 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 clarithromycin, telithromycin, or troleandomycin 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 CLOSELY: 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 CLOSELY: Coadministration of clarithromycin, telithromycin, or troleandomycin may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme, by reducing their clearance, as these antibiotics are potent 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 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 clarithromycin, telithromycin, or troleandomycin 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 CLOSELY: 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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MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

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Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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