Drug Interactions between chloramphenicol and elagolix / estradiol / norethindrone

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.

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.

MONITOR: Coadministration with inhibitors of the OATP 1B1 hepatic uptake transporter, CYP450 3A4 metabolic isoenzyme, and/or P-glycoprotein (P-gp) efflux transporter may increase the plasma concentrations of elagolix. In 12 study subjects, coadministration of single doses of 150 mg elagolix and 600 mg rifampin, a known OATP 1B1 inhibitor, increased elagolix peak plasma concentration (Cmax) and systemic exposure (AUC) by 337% and 458%, respectively, compared to elagolix administered alone. When a single 150 mg dose of elagolix was administered to 11 study subjects during 400 mg once daily dosing of ketoconazole, a potent CYP450 3A4 inhibitor, elagolix Cmax and AUC increased by 77% and 120%, respectively. The effect of P-gp inhibitors on the pharmacokinetics of elagolix has not been studied, but some increases in elagolix exposure may occur, as it is a P-gp substrate. Increased exposure to elagolix may increase the risk of serious adverse effects such as bone loss, suicidal ideation and behavior, exacerbation of mood disorders, and hepatic transaminase elevations.

MANAGEMENT: Caution is advised when elagolix is used with OATP 1B1, CYP450 3A4, and/or P-gp inhibitors. Patients should be monitored for potentially altered effects of elagolix following the initiation or discontinuation of these inhibitors, and the elagolix dosage adjusted as necessary.

GENERALLY AVOID: Since endometriosis is fueled by estrogen, coadministration with estrogen-containing medications including combination oral contraceptive pills is expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives is unknown. Elagolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to decreased levels of the ovarian sex hormones, estradiol and progesterone.

MANAGEMENT: Women requiring contraception should be advised to use non-hormonal forms of contraception during treatment with elagolix and for one week after its discontinuation.

ADDITIONAL CONTRACEPTION RECOMMENDED: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of estrogens and progestins. Estrogens have been shown in in vitro and in vivo studies to be partially metabolized by CYP450 3A4, and other steroids including progestins are also believed to undergo metabolism by this isoenzyme. The interaction has been reported primarily with oral contraceptives. There have been case reports of menstrual breakthrough bleeding or unwanted pregnancy in women receiving low-dose oral contraceptives following the addition of known CYP450 3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort. Inadequate response to estrogen replacement therapy has also been reported in a patient treated with phenytoin. Aminoglutethimide, a CYP450 3A4 inducer, has been shown to decrease medroxyprogesterone and megestrol serum levels by 74% in six patients stabilized on their progestin regimen.

MANAGEMENT: Pharmacologic response to estrogens and progestins should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the hormone dosage adjusted as necessary. For patients receiving hormonal contraceptives, additional or alternative non-hormonal birth control may be advisable during concomitant therapy with CYP450 3A4 inducers. Additional or alternative non-hormonal birth control may be recommended beyond discontinuation of the CYP450 3A4 inducer(s). Individual product labeling should be consulted for specific time frames. Intrauterine systems are unlikely to be significantly affected because of their local action. Input from a gynecologist or similar expert on adequate contraception, including emergency contraception, should be sought as needed. Patients using replacement therapy should be advised to notify their physician if they experience inadequate control of symptoms associated with estrogen deficiency (e.g., nocturnal sweating, vasomotor disturbances, atrophic vaginitis) or changes in the uterine bleeding profile.