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Drug overview for NIKKI (28) (ethinyl estradiol/drospirenone):
Generic name: ethinyl estradiol/drospirenone (ETH-in-il ess-tra-DYE-ole/dro-SPY-re-nown)
Drug class: Contraceptives
Therapeutic class: Contraceptives
Estrogen-progestin combinations are contraceptive combinations containing estrogenic and progestinic steroids.
No enhanced Uses information available for this drug.
Generic name: ethinyl estradiol/drospirenone (ETH-in-il ess-tra-DYE-ole/dro-SPY-re-nown)
Drug class: Contraceptives
Therapeutic class: Contraceptives
Estrogen-progestin combinations are contraceptive combinations containing estrogenic and progestinic steroids.
No enhanced Uses information available for this drug.
DRUG IMAGES
NIKKI 3 MG-0.02 MG TABLET
The following indications for NIKKI (28) (ethinyl estradiol/drospirenone) have been approved by the FDA:
Indications:
Acne vulgaris
Pregnancy contraception
Premenstrual dysphoric disorder
Professional Synonyms:
Acne simplex
Common acne
Contraception
Simple acne
Indications:
Acne vulgaris
Pregnancy contraception
Premenstrual dysphoric disorder
Professional Synonyms:
Acne simplex
Common acne
Contraception
Simple acne
The following dosing information is available for NIKKI (28) (ethinyl estradiol/drospirenone):
Estrogen-progestin oral contraceptives are usually classified according to their formulation:
*those monophasic preparations containing 50 mcg of estrogen,
*those monophasic preparations containing less than 50 mcg of estrogen (usually 20-35 mcg),
*those containing less than 50 mcg of estrogen with 2 sequences of progestin doses (biphasic),
*those containing less than 50 mcg of estrogen with 3 sequences of progestin doses (triphasic), and
*those containing 3 sequences of estrogen (e.g., 20, 30, 35 mcg) with a fixed dose of progestin (estrophasic).
Although the progestin content of the formulations also varies, oral contraceptives usually are described in terms of their estrogen content. The estrogenic and progestinic dominance of oral contraceptives depends mainly on the amount of estrogen and the amount and specific progestin contained in the formulation. The estrogenic or progestinic dominance of an oral contraceptive may contribute to hormone-related adverse effects and may be useful in selecting an alternate formulation when unacceptable adverse effects occur with a given formulation.
Whenever possible, the smallest dosage of estrogen and progestin should be used. The amount of both hormones should be considered in the choice of an oral contraceptive preparation. It is prudent and in keeping with good principles of therapeutics to minimize exposure to estrogen and progestin.
The combination used should be one which contains the least amount of estrogen and progestin that is compatible with a low failure rate and with the individual needs of the woman. Common adverse effects are usually most pronounced during the first oral contraceptive cycle and generally disappear or diminish after 3 or 4 cycles; there does not appear to be any advantage in changing preparations during this period. If minor adverse effects persist after the fourth cycle, a different combination of drugs or a different dosage may be tried.
Most fixed combinations are available as 21- or 28-day dosage preparations (conventional-cycle oral contraceptives). Some 28-day preparations contain 21 hormonally active tablets and 7 inert or ferrous fumarate-containing tablets; other 28-day preparations contain 24 hormonally active tablets and 4 inert or ferrous fumarate-containing tablets. In establishing an oral contraceptive dosage cycle, the menstrual cycle is usually considered to be 28 days.
The first day of bleeding is counted as the first day of the cycle.
One fixed-combination extended-cycle oral contraceptive (e.g., Seasonale(R)) is available as a 91-day dosage preparation containing 84 hormonally active tablets and 7 inert tablets. Other extended-cycle oral contraceptive preparations (e.g., LoSeasonique(R), Seasonique(R),) are available as 91-day preparations with 84 hormonally active tablets containing estrogen/progestin and 7 tablets containing low-dose estrogen.
One fixed-combination continuous-regimen (noncyclic) oral contraceptive (i.e., Lybrel(R)) is available as a 28-day dosage preparation containing 28 hormonally active tablets.
Each vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing(R)) is intended to be used for one cycle which consists of a 3-week period of continuous use of the ring followed by a 1-week ring-free period. When the vaginal ring is used for contraception, one ring (delivering ethinyl estradiol 0.015 mg/24 hours and etonogestrel 0.12 mg/24 hours) is inserted into the vagina at the beginning of the cycle. After 3 weeks, the vaginal ring is removed on the same day of the week as it was inserted and at about the same time of day.
After a 1-week ring-free period, a new ring is inserted on the same day of the week as in the previous cycle. Withdrawal bleeding usually occurs within 2-3 days after removal of the ring. For contraceptive effectiveness, a new ring must be inserted 1 week after the previous ring was removed even if menstrual bleeding is not finished.
To initiate therapy, the vaginal ring (containing ethinyl estradiol and etonogestrel) usually is inserted on or before day 5 of the cycle (the first day of bleeding is counted as the first day of the menstrual cycle) in women who did not use hormonal contraception in the preceding month. During the first cycle, a back-up method of contraception (e.g., condom, spermicide) is recommended until the contraceptive ring has been used continuously for 7 days. The manufacturer states that women switching from estrogen-progestin oral contraceptives to the vaginal ring should insert the ring within 7 days of the last hormonally active tablet and no later than the day that a new oral contraceptive cycle would have been started; a back-up method of contraception is not needed.
Women switching from progestin-only contraceptives to the vaginal ring should insert the ring on any day of the month if they are switching from a progestin-only oral contraceptive (without skipping any day between receiving the last progestin oral contraceptive and the initial administration of the vaginal ring). In addition, women switching from a progestin-only contraceptive injection should insert the vaginal ring on the same day as the next contraceptive injection would have been due. Women who are switching from a progestin-only implant or a progestin-containing intrauterine device should insert the vaginal ring on the same day as the implant or the intrauterine device is removed.
A back-up method of contraception is recommended in all women switching from progestin-only contraceptives until the vaginal ring has been used continuously for 7 days.
When the woman forgets to insert a new vaginal ring at the start of any cycle, the ring should be inserted as soon as she remembers and back-up contraception must be employed until the ring has been used continuously for 7 days. If the vaginal ring is left in place for up to 1 extra week (up to 4 weeks total), the ring should be removed and a new ring can be inserted after a 1-week drug-free interval. If the ring is left in place for longer than 4 weeks, pregnancy should be ruled out and a back-up method of contraception must be used until a new ring has been used continuously for 7 days.
Women may start using the vaginal contraceptive ring in the first 5 days following a complete first-trimester abortion; a back-up method of contraception is not needed in these women. If the contraceptive preparation is not used within the mentioned 5 days, the woman should follow the general instructions for women who did not use hormonal contraception in the preceding month.
If a nonlactating woman chooses to initiate contraception postpartum with the contraceptive vaginal ring (NuvaRing(R)) before menstruation has started, the possibility that ovulation and conception may have occurred prior to initiation of contraceptive therapy should be considered, and back-up contraception must be employed for the first 7 days.
When the transdermal system containing ethinyl estradiol and norelgestromin (Ortho Evra(R)) is used for contraception, it is applied topically in a cyclic regimen using a 28-day cycle. One transdermal system (containing ethinyl estradiol 0.75 mg and norelgestromin 6 mg) is applied once weekly (same day each week) for 3 weeks, followed by a 1-week drug-free interval (drug-free interval should not exceed 7 days); then the regimen is repeated. Systemic exposure to estrogen is greater with the transdermal system (Ortho Evra(R)) than with oral contraceptive preparations because of differences in the pharmacokinetic profiles of the preparations.
Administration of the transdermal contraceptive system usually begins on the first day of the menstrual cycle or on the first Sunday after menstrual bleeding has started. A back-up method of contraception (condom, spermicide, diaphragm) should be employed for the first 7 days after application of the first system if therapy is started after day 1 of the menstrual cycle. A back-up method of contraception is not needed if the first system is applied on the first day of the menstrual cycle.
The manufacturer states that women switching from estrogen-progestin oral contraceptives to the estrogen-progestin transdermal system should apply the transdermal system on the first day of withdrawal bleeding. If there is no withdrawal bleeding within 5 days of the last hormonally active tablet, pregnancy must be ruled out. If therapy with the transdermal system is initiated after the first day of bleeding, a back-up method of contraception should be used for 7 days.
If more than 7 days elapse after receiving the last hormonally active tablet, the possibility of ovulation and conception should be considered.
When a woman has not adhered to the prescribed transdermal contraceptive regimen by not applying the estrogen and progestin-containing system at the initiation of any cycle (i.e., day 1/first week), the system should be applied as soon as it is remembered and a new dosage cycle started the same day; back-up contraception must be employed for the first 7 days of the new cycle. In addition, if the transdermal system has not been changed in the middle of the cycle (i.e., on day 8/week 2 or day 15/week 3) for 1-2 days (up to 48 hours), a new system should be applied as soon as it is remembered and the application schedule employed should be continued; back-up contraception is not needed. However, if the transdermal system has not been changed for more than 2 days (48 hours or more) in the middle of the cycle, a new dosage cycle should be started; back-up contraception must be employed for the first 7 days of the new cycle.
When the transdermal system is not removed at the end of the application schedule (i.e., on day 22/week 4), the system should be removed as soon as it is remembered and the application schedule employed should be continued (i.e., system applied on day 28); back-up contraception is not needed.
Women may start using the transdermal contraceptive system immediately after a first-trimester abortion; a back-up method of contraception is not needed. If the contraceptive preparation is not used within 5 days of a first-trimester abortion, the woman should follow instructions as if initiating transdermal contraception for the first time.
Several regimens employing short-course, high-dose oral combinations of ethinyl estradiol and norgestrel or levonorgestrel have been used safely and effectively for postcoital contraception+. One widely studied and used regimen (the ''Yuzpe'' regimen) consists of an oral dose of 100 mcg of ethinyl estradiol and 1 mg of norgestrel (administered as 2 tablets each containing 50 mcg and 0.5 mg of the drugs, respectively) within 72 hours after unprotected intercourse, initiating the first dose at a time when it would make convenient administering the subsequent repeat dose 12 hours later. Alternative combination regimens that have been used consist of a dose of 120 mcg of ethinyl estradiol and 1.2
mg of norgestrel or 0.5-0.6 mg of levonorgestrel (e.g., administered as 4 tablets each containing 30 mcg of ethinyl estradiol and 0.3 mg of norgestrel or 0.125-0.15 mg of levonorgestrel) within 72 hours after intercourse, repeating the dose 12 hours later.
Another combination regimen that has been used consists of a dose of 100 mcg of ethinyl estradiol and 0.5 mg of levonorgestrel (e.g., administered as 5 tablets each containing 20 mcg of ethinyl estradiol and 0.1 mg of levonorgestrel) within 72 hours after intercourse, repeating the dose 12 hours later. Because postcoital efficacy diminishes as the time between intercourse and initiation of estrogen-progestin combination therapy increases, such therapy should be initiated as soon as possible but preferably within 72 hours following unprotected intercourse.
If necessary, the first dose can be given up to 120 hours after unprotected intercourse. Women should be advised that taking more than the prescribed dose probably will not further decrease the risk of pregnancy, but will increase the risk of severe adverse GI effects.
If women are given a conventional mnemonic package of an oral estrogen-progestin combination for use in taking a postcoital contraceptive regimen, they should be instructed carefully regarding the number and color of the tablets to be taken with each dose and that only a portion of the contents of the package actually will be used.
Table 1. Dosage of estrogen-progestin combinations for postcoital contraception
Estrogen-progestin combination Number and color of tablets per dose formulation (brand name) Ethinyl estradiol (50 mcg) with 2 white tablets (any of 21 tablets) norgestrel (0.5 mg) (Ovral(R)) Ethinyl estradiol (50 mcg) with 2 white tablets (any of first 21 norgestrel (0.5 mg) (Ovral(R)-28) tablets) Ethinyl estradiol (30 mcg) with 4 white tablets (any of 21 tablets) norgestrel (0.3 mg) (Lo-Ovral(R)) Ethinyl estradiol (30 mcg) with 4 white tablets (any of first 21 norgestrel (0.3 mg) (Lo-Ovral(R)-28) tablets) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of 21 levonorgestrel (0.15 mg) tablets) (Nordette(R)) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of first levonorgestrel (0.15 mg) 21 tablets) (Nordette(R)-28) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of 21 levonorgestrel (0.15 mg) (Levlen(R) tablets) 21) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of first levonorgestrel (0.15 mg) (Levlen(R) 21 tablets) 28) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of last 10 levonorgestrel (0.125 mg) tablets) (Tri-Levlen(R) 21) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of tablets levonorgestrel (0.125 mg) 12-21) (Tri-Levlen(R) 28) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of last 10 levonorgestrel (0.125 mg) tablets) (Tri-Phasil(R) 21) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of tablets levonorgestrel (0.125 mg) 12-21) (Tri-Levlen(R) 28) Ethinyl estradiol (20 mcg) with 5 pink tablets (any of first 21 levonorgestrel (0.1 mg) (Lessina(R) tablets) 28)
Dose is administered initially and then repeated 12 hours later
For increasing folate concentrations in women using oral contraceptives, the combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz(R)) or ethinyl estradiol 30 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Safyral(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
For the treatment of acne vulgaris, the triphasic oral estrogen-progestin combination of ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.18, 0.215, or 0.25
mg (Ortho-Tri-Cyclen(R)) or norethindrone 1 mg in fixed combination with ethinyl estradiol 20, 30, or 35 mcg (Estrostep(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
For the treatment of acne vulgaris, the estrogen-progestin combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz(R)) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
For the treatment of premenstrual dysphoric disorder, the combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz(R)) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
*those monophasic preparations containing 50 mcg of estrogen,
*those monophasic preparations containing less than 50 mcg of estrogen (usually 20-35 mcg),
*those containing less than 50 mcg of estrogen with 2 sequences of progestin doses (biphasic),
*those containing less than 50 mcg of estrogen with 3 sequences of progestin doses (triphasic), and
*those containing 3 sequences of estrogen (e.g., 20, 30, 35 mcg) with a fixed dose of progestin (estrophasic).
Although the progestin content of the formulations also varies, oral contraceptives usually are described in terms of their estrogen content. The estrogenic and progestinic dominance of oral contraceptives depends mainly on the amount of estrogen and the amount and specific progestin contained in the formulation. The estrogenic or progestinic dominance of an oral contraceptive may contribute to hormone-related adverse effects and may be useful in selecting an alternate formulation when unacceptable adverse effects occur with a given formulation.
Whenever possible, the smallest dosage of estrogen and progestin should be used. The amount of both hormones should be considered in the choice of an oral contraceptive preparation. It is prudent and in keeping with good principles of therapeutics to minimize exposure to estrogen and progestin.
The combination used should be one which contains the least amount of estrogen and progestin that is compatible with a low failure rate and with the individual needs of the woman. Common adverse effects are usually most pronounced during the first oral contraceptive cycle and generally disappear or diminish after 3 or 4 cycles; there does not appear to be any advantage in changing preparations during this period. If minor adverse effects persist after the fourth cycle, a different combination of drugs or a different dosage may be tried.
Most fixed combinations are available as 21- or 28-day dosage preparations (conventional-cycle oral contraceptives). Some 28-day preparations contain 21 hormonally active tablets and 7 inert or ferrous fumarate-containing tablets; other 28-day preparations contain 24 hormonally active tablets and 4 inert or ferrous fumarate-containing tablets. In establishing an oral contraceptive dosage cycle, the menstrual cycle is usually considered to be 28 days.
The first day of bleeding is counted as the first day of the cycle.
One fixed-combination extended-cycle oral contraceptive (e.g., Seasonale(R)) is available as a 91-day dosage preparation containing 84 hormonally active tablets and 7 inert tablets. Other extended-cycle oral contraceptive preparations (e.g., LoSeasonique(R), Seasonique(R),) are available as 91-day preparations with 84 hormonally active tablets containing estrogen/progestin and 7 tablets containing low-dose estrogen.
One fixed-combination continuous-regimen (noncyclic) oral contraceptive (i.e., Lybrel(R)) is available as a 28-day dosage preparation containing 28 hormonally active tablets.
Each vaginal contraceptive ring containing ethinyl estradiol and etonogestrel (NuvaRing(R)) is intended to be used for one cycle which consists of a 3-week period of continuous use of the ring followed by a 1-week ring-free period. When the vaginal ring is used for contraception, one ring (delivering ethinyl estradiol 0.015 mg/24 hours and etonogestrel 0.12 mg/24 hours) is inserted into the vagina at the beginning of the cycle. After 3 weeks, the vaginal ring is removed on the same day of the week as it was inserted and at about the same time of day.
After a 1-week ring-free period, a new ring is inserted on the same day of the week as in the previous cycle. Withdrawal bleeding usually occurs within 2-3 days after removal of the ring. For contraceptive effectiveness, a new ring must be inserted 1 week after the previous ring was removed even if menstrual bleeding is not finished.
To initiate therapy, the vaginal ring (containing ethinyl estradiol and etonogestrel) usually is inserted on or before day 5 of the cycle (the first day of bleeding is counted as the first day of the menstrual cycle) in women who did not use hormonal contraception in the preceding month. During the first cycle, a back-up method of contraception (e.g., condom, spermicide) is recommended until the contraceptive ring has been used continuously for 7 days. The manufacturer states that women switching from estrogen-progestin oral contraceptives to the vaginal ring should insert the ring within 7 days of the last hormonally active tablet and no later than the day that a new oral contraceptive cycle would have been started; a back-up method of contraception is not needed.
Women switching from progestin-only contraceptives to the vaginal ring should insert the ring on any day of the month if they are switching from a progestin-only oral contraceptive (without skipping any day between receiving the last progestin oral contraceptive and the initial administration of the vaginal ring). In addition, women switching from a progestin-only contraceptive injection should insert the vaginal ring on the same day as the next contraceptive injection would have been due. Women who are switching from a progestin-only implant or a progestin-containing intrauterine device should insert the vaginal ring on the same day as the implant or the intrauterine device is removed.
A back-up method of contraception is recommended in all women switching from progestin-only contraceptives until the vaginal ring has been used continuously for 7 days.
When the woman forgets to insert a new vaginal ring at the start of any cycle, the ring should be inserted as soon as she remembers and back-up contraception must be employed until the ring has been used continuously for 7 days. If the vaginal ring is left in place for up to 1 extra week (up to 4 weeks total), the ring should be removed and a new ring can be inserted after a 1-week drug-free interval. If the ring is left in place for longer than 4 weeks, pregnancy should be ruled out and a back-up method of contraception must be used until a new ring has been used continuously for 7 days.
Women may start using the vaginal contraceptive ring in the first 5 days following a complete first-trimester abortion; a back-up method of contraception is not needed in these women. If the contraceptive preparation is not used within the mentioned 5 days, the woman should follow the general instructions for women who did not use hormonal contraception in the preceding month.
If a nonlactating woman chooses to initiate contraception postpartum with the contraceptive vaginal ring (NuvaRing(R)) before menstruation has started, the possibility that ovulation and conception may have occurred prior to initiation of contraceptive therapy should be considered, and back-up contraception must be employed for the first 7 days.
When the transdermal system containing ethinyl estradiol and norelgestromin (Ortho Evra(R)) is used for contraception, it is applied topically in a cyclic regimen using a 28-day cycle. One transdermal system (containing ethinyl estradiol 0.75 mg and norelgestromin 6 mg) is applied once weekly (same day each week) for 3 weeks, followed by a 1-week drug-free interval (drug-free interval should not exceed 7 days); then the regimen is repeated. Systemic exposure to estrogen is greater with the transdermal system (Ortho Evra(R)) than with oral contraceptive preparations because of differences in the pharmacokinetic profiles of the preparations.
Administration of the transdermal contraceptive system usually begins on the first day of the menstrual cycle or on the first Sunday after menstrual bleeding has started. A back-up method of contraception (condom, spermicide, diaphragm) should be employed for the first 7 days after application of the first system if therapy is started after day 1 of the menstrual cycle. A back-up method of contraception is not needed if the first system is applied on the first day of the menstrual cycle.
The manufacturer states that women switching from estrogen-progestin oral contraceptives to the estrogen-progestin transdermal system should apply the transdermal system on the first day of withdrawal bleeding. If there is no withdrawal bleeding within 5 days of the last hormonally active tablet, pregnancy must be ruled out. If therapy with the transdermal system is initiated after the first day of bleeding, a back-up method of contraception should be used for 7 days.
If more than 7 days elapse after receiving the last hormonally active tablet, the possibility of ovulation and conception should be considered.
When a woman has not adhered to the prescribed transdermal contraceptive regimen by not applying the estrogen and progestin-containing system at the initiation of any cycle (i.e., day 1/first week), the system should be applied as soon as it is remembered and a new dosage cycle started the same day; back-up contraception must be employed for the first 7 days of the new cycle. In addition, if the transdermal system has not been changed in the middle of the cycle (i.e., on day 8/week 2 or day 15/week 3) for 1-2 days (up to 48 hours), a new system should be applied as soon as it is remembered and the application schedule employed should be continued; back-up contraception is not needed. However, if the transdermal system has not been changed for more than 2 days (48 hours or more) in the middle of the cycle, a new dosage cycle should be started; back-up contraception must be employed for the first 7 days of the new cycle.
When the transdermal system is not removed at the end of the application schedule (i.e., on day 22/week 4), the system should be removed as soon as it is remembered and the application schedule employed should be continued (i.e., system applied on day 28); back-up contraception is not needed.
Women may start using the transdermal contraceptive system immediately after a first-trimester abortion; a back-up method of contraception is not needed. If the contraceptive preparation is not used within 5 days of a first-trimester abortion, the woman should follow instructions as if initiating transdermal contraception for the first time.
Several regimens employing short-course, high-dose oral combinations of ethinyl estradiol and norgestrel or levonorgestrel have been used safely and effectively for postcoital contraception+. One widely studied and used regimen (the ''Yuzpe'' regimen) consists of an oral dose of 100 mcg of ethinyl estradiol and 1 mg of norgestrel (administered as 2 tablets each containing 50 mcg and 0.5 mg of the drugs, respectively) within 72 hours after unprotected intercourse, initiating the first dose at a time when it would make convenient administering the subsequent repeat dose 12 hours later. Alternative combination regimens that have been used consist of a dose of 120 mcg of ethinyl estradiol and 1.2
mg of norgestrel or 0.5-0.6 mg of levonorgestrel (e.g., administered as 4 tablets each containing 30 mcg of ethinyl estradiol and 0.3 mg of norgestrel or 0.125-0.15 mg of levonorgestrel) within 72 hours after intercourse, repeating the dose 12 hours later.
Another combination regimen that has been used consists of a dose of 100 mcg of ethinyl estradiol and 0.5 mg of levonorgestrel (e.g., administered as 5 tablets each containing 20 mcg of ethinyl estradiol and 0.1 mg of levonorgestrel) within 72 hours after intercourse, repeating the dose 12 hours later. Because postcoital efficacy diminishes as the time between intercourse and initiation of estrogen-progestin combination therapy increases, such therapy should be initiated as soon as possible but preferably within 72 hours following unprotected intercourse.
If necessary, the first dose can be given up to 120 hours after unprotected intercourse. Women should be advised that taking more than the prescribed dose probably will not further decrease the risk of pregnancy, but will increase the risk of severe adverse GI effects.
If women are given a conventional mnemonic package of an oral estrogen-progestin combination for use in taking a postcoital contraceptive regimen, they should be instructed carefully regarding the number and color of the tablets to be taken with each dose and that only a portion of the contents of the package actually will be used.
Table 1. Dosage of estrogen-progestin combinations for postcoital contraception
Estrogen-progestin combination Number and color of tablets per dose formulation (brand name) Ethinyl estradiol (50 mcg) with 2 white tablets (any of 21 tablets) norgestrel (0.5 mg) (Ovral(R)) Ethinyl estradiol (50 mcg) with 2 white tablets (any of first 21 norgestrel (0.5 mg) (Ovral(R)-28) tablets) Ethinyl estradiol (30 mcg) with 4 white tablets (any of 21 tablets) norgestrel (0.3 mg) (Lo-Ovral(R)) Ethinyl estradiol (30 mcg) with 4 white tablets (any of first 21 norgestrel (0.3 mg) (Lo-Ovral(R)-28) tablets) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of 21 levonorgestrel (0.15 mg) tablets) (Nordette(R)) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of first levonorgestrel (0.15 mg) 21 tablets) (Nordette(R)-28) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of 21 levonorgestrel (0.15 mg) (Levlen(R) tablets) 21) Ethinyl estradiol (30 mcg) with 4 light-orange tablets (any of first levonorgestrel (0.15 mg) (Levlen(R) 21 tablets) 28) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of last 10 levonorgestrel (0.125 mg) tablets) (Tri-Levlen(R) 21) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of tablets levonorgestrel (0.125 mg) 12-21) (Tri-Levlen(R) 28) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of last 10 levonorgestrel (0.125 mg) tablets) (Tri-Phasil(R) 21) Ethinyl estradiol (30 mcg) with 4 yellow tablets (any of tablets levonorgestrel (0.125 mg) 12-21) (Tri-Levlen(R) 28) Ethinyl estradiol (20 mcg) with 5 pink tablets (any of first 21 levonorgestrel (0.1 mg) (Lessina(R) tablets) 28)
Dose is administered initially and then repeated 12 hours later
For increasing folate concentrations in women using oral contraceptives, the combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz(R)) or ethinyl estradiol 30 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Safyral(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
For the treatment of acne vulgaris, the triphasic oral estrogen-progestin combination of ethinyl estradiol 35 mcg in fixed combination with norgestimate 0.18, 0.215, or 0.25
mg (Ortho-Tri-Cyclen(R)) or norethindrone 1 mg in fixed combination with ethinyl estradiol 20, 30, or 35 mcg (Estrostep(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
For the treatment of acne vulgaris, the estrogen-progestin combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz(R)) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
For the treatment of premenstrual dysphoric disorder, the combination of ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg (Yaz(R)) or ethinyl estradiol 20 mcg in fixed combination with drospirenone 3 mg and levomefolate calcium 0.451 mg (Beyaz(R)) is used in the same dosage and administration (i.e., timing of initiation of therapy) as used in contraception.
Estrogen-progestin combination contraceptives are administered orally, intravaginally, and percutaneously by topical application of a transdermal system to the skin.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| NIKKI 3 MG-0.02 MG TABLET | Maintenance | Adults take 1 tablet by oral route once daily |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| DROSPIRENONE-EE 3-0.02 MG TAB | Maintenance | Adults take 1 tablet by oral route once daily |
The following drug interaction information is available for NIKKI (28) (ethinyl estradiol/drospirenone):
There are 6 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Selected Anti-Aromatase Agents/Estrogens SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme. CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy. DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10) |
ANASTROZOLE, ARIMIDEX, AROMASIN, EXEMESTANE, FEMARA, LETROZOLE, TESTOSTERONE-ANASTROZOLE |
| Sodium Tetradecyl Sulfate/Estrogens SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Patients taking estrogen-containing hormonal contraceptives or hormone replacement therapy have a higher risk of clotting problems.(1) CLINICAL EFFECTS: Use of sodium tetradecyl sulfate on patients taking estrogen-containing hormonal contraceptives or hormone replacement therapy may increase the risk of deep vein thrombosis.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of sodium tetradecyl sulfate states that its use in patients taking contraceptives or hormone replacement therapy is contraindicated.(2) DISCUSSION: Factors which may increase the risk of deep vein thrombosis after sclerotherapy should be avoided.(1) Therefore, its use in patients taking estrogen-containing contraceptives or hormone replacement therapy is contraindicated.(2) |
SODIUM TETRADECYL SULFATE, SOTRADECOL |
| Tranexamic Acid (Oral)/Estrogenic Agents SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Tranexamic acid is an antifibrinolytic and estrogen-containing hormonal contraceptives are known to increase the risk of venous thromboembolism and arterial thromboses, including stroke and myocardial infarction. Concurrent use may increase the risk of these events.(1) CLINICAL EFFECTS: Concurrent use of tranexamic acid in patients taking estrogen-containing agents or hormonal contraceptives may increase the risk of embolisms.(1) PREDISPOSING FACTORS: The risk of thrombosis may be even greater in women who are obese or smoke, especially smokers over age 35.(1) PATIENT MANAGEMENT: The concurrent use of oral tranexamic and and estrogen-containing hormonal contraception is contraindicated.(1) It would be prudent to follow this restriction with estrogen-replacement therapy as well. DISCUSSION: There are no clinical trial data on the risk of concurrent therapy with tranexamic acid and hormonal contraceptives. There have been postmarketing reports of venous and arterial thrombotic events in women receiving combination therapy.(1) Women taking hormonal contraception were excluded from safety and efficacy trials of tranexamic acid.(1) |
TRANEXAMIC ACID |
| Drospirenone-Ethinyl Estradiol/Atazanavir-Cobicistat SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Atazanavir and cobicistat are both inhibitors of CYP3A4 and may inhibit the metabolism of drospirenone. Drospirenone has anti-mineralocorticoid activity. CLINICAL EFFECTS: Concurrent administration may result in increased effects from the progestin (insulin resistance, dyslipidemia, acne, and venous thrombosis) and decreased effects of the estrogen component.(1) Concurrent use of atazanavir-cobicistat may result in elevated levels of and effects from drospirenone, including hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, potassium-sparing diuretics, heparin, and NSAIDs may increase potassium levels. PATIENT MANAGEMENT: The US manufacturer of cobicistat states that concurrent use of drospirenone is contraindicated when cobicistat is also administered with atazanavir.(1) DISCUSSION: Drospirenone has anti-mineralocorticoid activity comparable to a 25mg dose of spironolactone. Concurrent use of cobicistat 150 mg increased the area-under-curve (AUC) and concentration maximum (Cmax) of drospirenone (administered as drospirenone/ethinyl estradiol 3/0.02 mg single dose) by 2.3-fold and 1.12-fold, respectively. Concurrent use decreased the AUC and Cmax of ethinyl estradiol by 0.78-fold and 0.82-fold, respectively.(1) |
EVOTAZ |
| Rasagiline (Greater Than 0.5 mg)/Selected CYP1A2 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2) DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5) |
AZILECT, RASAGILINE MESYLATE |
| Fezolinetant/CYP1A2 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of fezolinetant states that concurrent use with CYP1A2 inhibitors is contraindicated.(1) DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include allopurinol, artemisinin, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, verapamil, zileuton.(2-4) |
VEOZAH |
There are 55 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Hormonal Contraceptives/Rifamycins SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Rifamycins (rifampin, rifabutin and rifapentine) induce the CYP3A4 mediated metabolism of both estrogen and progestin components of hormonal contraceptives. CLINICAL EFFECTS: Concurrent use of rifampin, rifabutin, or rifapentine may result in reduced levels and clinical effectiveness of hormone containing contraceptives. Breakthrough bleeding and contraceptive failure/pregnancy may result. Effects may be seen for several weeks after discontinuation of the rifamycin. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving rifamycins should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. It is recommended that alternative or additional contraceptive methods be used during and for several weeks after rifamycin therapy. If a combined oral contraceptive is used, the preparation should contain at least 30 mcg of ethinyl estradiol should be used. The patient should be asked to report any spotting or bleeding. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: In an open-label, randomized crossover study, 22 healthy females received oral contraceptives for 21 days, then were randomized to receive rifampin or rifabutin (300 mg/d for 10 days). Rifampin and rifabutin decreased the area-under-curve (AUC) of ethinyl estradiol by 64% and 35%, respectively, and maximum concentration (Cmax) by 42% and 20%, respectively. Rifampin and rifabutin decreased the AUC of norethindrone by 60% and 20%, respectively. Incidences of spotting were much greater in the rifampin co-administration group. In a study, a single dose of oral contraceptive (ethinyl estradiol 50 mcg and norethindrone acetate 1 mg) was administered to 7 female patients with tuberculosis, both during TB treatment and one month after stopping rifampin (450-600 mg/d). Upon cessation of rifampin therapy, the AUC for ethinyl estradiol significantly increased by 70%, and terminal plasma half-life more than doubled. A similar study design analyzed the pharmacokinetics of norethisterone (1 mg) in 8 women receiving rifampin (450-600 mg/d). Upon termination of TB treatment, it was found that rifampin reduced the AUC of a single dose of norethisterone (1 mg) by approximately 40%, with a half-life reduction of 50%. In a study, male volunteers received 50 mcg iv of ethinyl estradiol, followed by rifampin (600 mg for 6 days). Ethinyl estradiol half-life decreased by approximately 55%. The upward titration of ethinyl estradiol to 100 mcg resulted in a more than 2-fold increase in ethinyl estradiol metabolism caused by rifampicin treatment. An analytical trial evaluated liver biopsies from four patients treated with rifampin 600 mg for a period of 6-10 days. Hepatic microsomes from the biopsies were incubated with hormone substrates, including oestradiol and ethinyl estradiol. Rifampin resulted in a fourfold increase in hydroxylation. Not only did rifampin increase the rate of hydroxylation through enzyme induction, it also caused an increase in cytochrome P-450. There are reports of breakthrough bleeding and unintended pregnancy during concurrent use. A study of 118 HIV-positive females compared levonorgestrel pharmacokinetics and safety between the following groups: 1. levonorgestrel 1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2. levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin. While both levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control group, the half life of levonorgestrel was shorter, resulting in an AUC(inf) that was 53% lower in the efavirenz group and 37% lower in the rifampin group than the control group. Tolerability was similar between groups. No pregnancies were reported but it is unknown whether the correction of levonorgestrel levels early in the dosing period is sufficient to maintain overall emergency contraceptive effectiveness.(25) |
PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA |
| Selected Anticonvulsants; Barbiturates/Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Barbiturates, hydantoins, and primidone may increase the metabolism of the contraceptives via CYP3A4 induction. CLINICAL EFFECTS: May observe reduced contraceptive effects such as breakthrough bleeding, spotting, or pregnancy. Effects may be seen several days after discontinuation of the anticonvulsant or barbiturate. In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. Depo medroxyprogesterone may be an alternative, since its effectiveness is not decreased by anticonvulsants. Patients receiving perampanel at doses of 12 mg/day should use alternative contraception methods, such as an intra-uterine device or condom. Patients receiving topiramate may observe decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day. Patients taking topiramate and estrogen containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns.(20) Patients taking the combination of phentermine/topiramate for weight loss should be counseled that break-through bleeding may occur but is not expected to increase the risk of pregnancy. Instruct patients to report changes in bleeding patterns to their physician and to continue to take their hormonal contraceptive. Patients should not rely on hormonal contraceptives (other than implants or IUD) alone, but may use them in combination with a barrier contraceptive. It is necessary to use effective contraception with phentermine/topiramate, because the topiramate content of the product can cause birth defects. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: Decreased effectiveness of oral contraceptives, characterized by breakthrough bleeding and amenorrhea have been documented. Through August, 2010, Australia's Therapeutic Goods Association had received 32 reports of contraceptive failure leading to pregnancy as a result of a suspected interaction between etonogestrel implants and carbamazepine. In a randomized, open-label study in healthy women, concurrent topiramate (50 mg daily to 200 mg daily) and Ortho Novum 1/35 (ethinyl estradiol and norethindrone) resulted in no changes in levels of ethinyl estradiol or norethindrone. However, in another study, concurrent topiramate at doses of 200 mg daily, 400 mg daily, and 800 mg daily with valproic acid decreased the area-under-curve (AUC) of ethinyl estradiol by 18%, 21%, and 30%, respectively. There were no changes in norethindrone levels. The US manufacturer of topiramate states that the possibility of decreased contraceptive effectiveness should be considered. At doses of 12 mg/day, perampanel decreased the maximum concentration (Cmax) and AUC of levonorgestrel by 40% each. The Cmax of ethinyl estradiol was decreased by 18%. There were no effects on ethinyl estradiol AUC. Doses of perampanel of 4 mg/day and 8 mg/day had no effect on contraceptive levels. The combination of phentermine/topiramate (15 mg/92 mg for 15 days) increased the Cmax and AUC of norethindrone by 22% and 16%, respectively. The Cmax and AUC of ethinyl estradiol decreased 8% and 16%, respectively. Because contraceptive efficacy is primarily determined by the progestin component, no effect on contraceptive efficacy is expected, although breakthrough bleeding may occur. The effectiveness of depo medroxyprogesterone is not decreased by anticonvulsants or barbiturates. |
APTIOM, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, CEREBYX, DILANTIN, DILANTIN-125, DONNATAL, EPRONTIA, FELBAMATE, FELBATOL, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, FYCOMPA, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIMIDONE, QSYMIA, QUDEXY XR, SEZABY, TENCON, TOPAMAX, TOPIRAMATE, TOPIRAMATE ER, TROKENDI XR |
| Contraceptives/Griseofulvin SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Unknown. However, possibly due to increased metabolism of oral contraceptives. CLINICAL EFFECTS: Decreased effectiveness of oral contraceptives, producing breakthrough bleeding, amenorrhea and unintended pregnancy. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The patient should use an alternative method of contraception during and for one month after receiving griseofulvin. Increasing the dose of estrogen may be necessary in patients on low-dose estrogen. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used an inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: Loss of oral contraceptive efficacy has been reported following the addition of griseofulvin to the patient's drug therapy. Loss of efficacy was indicated by breakthrough bleeding, amenorrhea and unintended pregnancy. |
FULVICIN P-G, GRISEOFULVIN, GRISEOFULVIN MICRONIZED, GRISEOFULVIN ULTRAMICROSIZE |
| Hormonal Contraceptive Agents/Efavirenz; Nevirapine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Efavirenz(1) and nevirapine(2,3) may induce the metabolism of hormonal contraceptives via CYP3A4. CLINICAL EFFECTS: Concurrent administration of efavirenz(1) or nevirapine(2,3) with a hormonal contraceptive agent may result in decreased plasma concentrations and clinical effectiveness of the contraceptive agent. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturers of efavirenz(1) and nevirapine(2) state that hormonal contraceptives should not be used as the sole method of contraception in women taking these agents. A reliable method of barrier contraception must be used in addition to hormonal contraception in women taking efavirenz.(1) Alternative or additional methods of contraception should be considered in women taking nevirapine.(2) Because of the long half-life of efavirenz, women should continue to use a barrier method of contraception in addition to hormonal contraception for 12 weeks after discontinuing efavirenz.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.(4) Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: In a study in 21 subjects, concurrent efavirenz (600 mg daily for 14 days) and ethinyl estradiol/norgestimate (0.035/0.25 mg for 14 days) had no effect on ethinyl estradiol levels. The maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of norelgestromin decreased by 46%, 64%, and 82%, respectively. The Cmax, AUC, and Cmin of levonorgestrel decreased by 80%, 83%, and 86%, respectively.(1) There have been reports of contraceptive failure in patients with etonogestrel implants who were receiving efavirenz.(1) In a study in 10 subjects taking Ortho-Novum 1/35, nevirapine decreased the AUC of ethinyl estradiol by 20% and the AUC and Cmax of norethindrone by 19% and 16%, respectively.(2) In a study in 16 HIV-positive females, concurrent nevirapine (200 mg daily, Days 2-15; 200 mg twice daily, Days 16-29) and ethinyl estradiol with norethindrone decreased the AUCs of ethinyl estradiol and norethindrone by 29% and 18%, respectively.(3) A study of 118 HIV-positive females compared levonorgestrel pharmacokinetics and safety between the following groups: 1. levonorgestrel 1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2. levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin. While both levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control group, the half life of levonorgestrel was shorter, resulting in an AUC(inf) that was 53% lower in the efavirenz group and 37% lower in the rifampin group than the control group. Tolerability was similar between groups. No pregnancies were reported but it is unknown whether the correction of levonorgestrel levels early in the dosing period is sufficient to maintain overall emergency contraceptive effectiveness.(5) |
EFAVIRENZ, EFAVIRENZ-EMTRIC-TENOFOV DISOP, EFAVIRENZ-LAMIVU-TENOFOV DISOP, NEVIRAPINE, NEVIRAPINE ER, SYMFI, SYMFI LO |
| Armodafinil; Modafinil/Steroidal Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Modafinil may induce the CYP3A4 mediated metabolism of the steroidal contraceptive.(1-3) Armodafinil is the R-enantiomer of modafinil.(4) CLINICAL EFFECTS: Armodafinil(4) or modafinil(1-3) may result in decreased levels of steroidal contraceptives and possibly decreased effectiveness of the contraceptive agent during and one(1,4) to two(2-3) months following armodafinil or modafinil therapy. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The United Kingdom manufacturer of modafinil states that when oral contraceptives are used concurrently with modafinil, a product containing 50 mcg or more of ethinyl estradiol should be used. Adequate contraception requires continuation of the oral contraceptive two months after the discontinuation of modafinil.(2) The Australian manufacturer of modafinil states that alternative or concomitant methods of contraception are recommended for patients on modafinil until 2 months after discontinuation of modafinil.(3) The United States manufacturer of armodafinil(4) and modafinil(1) states that because the effectiveness of steroidal contraceptives may be decreased during concurrent therapy, alternative or concomitant methods of contraception are recommended during therapy and for one month following discontinuation of armodafinil or modafinil. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(5) DISCUSSION: Modafinil is contraindicated during pregnancy and may induce the metabolism of oral,(2) depot, and implantable(1) contraceptives, thus decreasing their effectiveness. A placebo-controlled, single-blind study in 41 females evaluated the effect of modafinil on the pharmacokinetics of ethinyl estradiol. The study subjects were controlled on long-term oral contraceptive treatment (0.035 mg ethinyl estradiol) and norgestimate (0.180-0.250 mg). Pharmacokinetic profiles were obtained for ethinyl estradiol on the day before initiation and on the last day of modafinil (200 mg for 7 days, then 400 mg for 21 days) or placebo (28 days). A small, but significant decrease in the ethinyl estradiol area-under-curve (AUC) by 18%, and maximum concentration (Cmax) by 11% were reported.(6) |
ARMODAFINIL, MODAFINIL, NUVIGIL, PROVIGIL |
| Selected Protease Inhibitors/Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ritonavir-boosted protease inhibitors(1-10), fosamprenavir(1), and nelfinavir(2) may induce the metabolism of estrogens. Unboosted atazanavir may inhibit the metabolism of estrogens and progestins.(3) CLINICAL EFFECTS: Concurrent use of ritonavir-boosted protease inhibitors may result in decreased levels and effectiveness of estrogen and increased levels of progestins, which may increase the risk of insulin resistance, dyslipidemia, and acne.(1-10) Additionally, concurrent use of atazanavir-cobicistat with drospirenone-containing contraceptives may result in elevated levels of and effects from drospirenone, including hyperkalemia.(4) Atazanavir alone may result in elevated levels of estrogens.(3) Hormonal contraceptives may decrease the effectiveness of fosamprenavir.(1) Elevated liver enzymes may also occur.(1) Concurrent use with tipranavir may increase the risk of rash.(5) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US Department of Health and Human Services (DHHS) HIV guidelines recommend that concurrent use of oral contraceptives with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir be done with a contraceptive product that contains at least 35 mcg ethinyl estradiol. If atazanavir is used without ritonavir, limit the dose of ethinyl estradiol to 30 mcg. Atazanavir/cobistat is contraindicated with drospirenone-containing products. No dose adjustment is needed when atazanavir/cobicistat is used with other oral contraceptives.(11) Most manufacturer recommendations differ from the DHHS guidelines. The manufacturer of atazanavir states that if an oral contraceptive agent containing either norgestimate or norethindrone is used with atazanavir without ritonavir, the contraceptive should contain no more than 30 mcg of ethinyl estradiol. These agents should be used with caution. Oral contraceptives containing progestins other than norethindrone or norgestimate and hormonal contraceptives other than oral (e.g. patches, rings, injections) have not been studied with atazanavir (boosted or unboosted), and alternative contraceptive methods are recommended.(3,4) The manufacturers of fosamprenavir,(1) darunavir,(5) and tipranavir(6) state that alternate methods of non-hormonal contraception are recommended. The manufacturers of the combination of lopinavir and ritonavir,(7) nelfinavir,(2) ritonavir,(8) and saquinavir(9) state that additional or alternate methods of contraception should be used in patients receiving these agents. The manufacturer of nirmatrelvir/ritonavir states that a non-hormonal method of contraception should be considered during nirmatrelvir/ritonavir therapy until one menstrual cycle after stopping therapy.(10) The CDC contraceptive guidelines state that intrauterine devices (copper or levonorgestrel) may be used with any antiretroviral agent.(12) DISCUSSION: Concurrent administration of unboosted amprenavir (1200 mg twice daily) with ethinyl estradiol/norethindrone (0.035 mg/1 mg daily) decreased the amprenavir area-under-curve (AUC) and minimum concentration (Cmin) by 22% and 20%, respectively. The Cmin of ethinyl estradiol was increased by 32%. The AUC and Cmin of norethindrone were increased by 18% and 45%, respectively. Fosamprenavir is a prodrug of amprenavir.(1) In contrast, a study of fosamprenavir/ritonavir (700/100 mg twice daily) with ethinyl estradiol/norethindrone (0.035/0.5 mg daily) in 25 subjects had no effect on amprenavir levels. In addition, this combination decreased the Cmax and AUC of ethinyl estradiol by 28% and 37%, respectively. The Cmax, AUC, and Cmin of norethindrone decreased by 38%, 34%, and 26%, respectively.(1) Concurrent administration of atazanavir (400 mg daily) with ethinyl estradiol-norethindrone (Ortho-Novum) increased the maximum concentration (Cmax), AUC, and Cmin of ethinyl estradiol by 15%, 48%, and 91%, respectively, and the Cmax, AUC, and Cmin of norethindrone by 67%, 210%, and 362%, respectively.(3) Concurrent administration of atazanavir/ritonavir (300/100 mg daily) with ethinyl estradiol-norgestimate (Ortho Tri-Cyclen) decreased the maximum concentration (Cmax), AUC, and Cmin of ethinyl estradiol by 16%, 19%, and 37%, respectively, and increased the Cmax, AUC, and Cmin of norgestimate by 68%, 85%, and 202%, respectively.(3) In a study in 11 subjects, concurrent administration of darunavir/ritonavir (600/100 mg twice daily) with ethinyl estradiol/norethindrone (0.035/1 mg daily) decreased ethinyl estradiol Cmax, AUC, and Cmin by 32%, 44%, and 62%, respectively. The Cmax, AUC, and Cmin, of norethindrone decreased by 10%, 14%, and 30%, respectively.(6) The concurrent administration of nelfinavir (2250 mg daily) and ethinyl estradiol (35 mcg daily) and norethindrone (0.4 mg daily) decreased the AUC, Cmax, and Cmin of ethinyl estradiol by 47%, 28%, and 62%, respectively, and decreased the AUC and Cmin of norethindrone by 18% and 46%, respectively. There was no effect on the Cmax of norethindrone.(2) Concurrent administration of lopinavir/ritonavir (400/100 mg twice daily) and Ortho Novum (once daily) decreased the Cmax, AUC, and Cmin of ethinyl estradiol by 41%, 42%, and 58%, respectively. The Cmax, AUC, and Cmin, of norethindrone decreased by 16%, 17%, and 32%, respectively.(7) Concurrent administration of ritonavir (500 mg twice daily) and ethinyl estradiol (50 mcg single dose) decreased ethinyl estradiol AUC and Cmax by 40% and 32%, respectively.(8,14) In a study in 8 healthy females, ethinyl estradiol/gestodene (0.03/0.075 mg) had no effect on the pharmacokinetics of a single dose of saquinavir (600 mg).(15) In a study in 21 subjects, concurrent ethinyl estradiol/norethindrone (0.035/1 mg) and tipranavir-ritonavir (500/100 mg twice daily) decreased tipranavir Cmin by 27%. Ethinyl estradiol AUC and Cmax decreased by 48% and 48%, respectively. There were no significant effects on norethindrone levels. In a study in 13 subjects, concurrent ethinyl estradiol/ norethindrone (0.035/1 mg) and tipranavir-ritonavir (750/200 mg twice daily) had no significant effects on tipranavir levels. Ethinyl estradiol AUC and Cmax decreased by 52% and 43%, respectively. There were no significant effects on norethindrone levels.(6) Selected protease inhibitors linked to this monograph include: amprenavir, atazanavir, darunavir, fosamprenavir, lopinavir, nelfinavir, nirmatrelvir, and ritonavir. Although not directly linked, protease inhibitor regimens containing saquinavir and tipranavir also alert. |
ATAZANAVIR SULFATE, DARUNAVIR, FOSAMPRENAVIR CALCIUM, KALETRA, LOPINAVIR-RITONAVIR, NORVIR, PAXLOVID, PREZCOBIX, PREZISTA, REYATAZ, RITONAVIR, SYMTUZA, VIRACEPT |
| Hormonal Contraceptives/Selected Anticonvulsants SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Carbamazepine is a strong inducer of CYP3A4; oxcarbazepine and rufinamide are weak inducers of CYP3A4.(1) CLINICAL EFFECTS: Concurrent use with carbamazepine, oxcarbazepine or rufinamide may result in decreased contraceptive levels, which may result in menstrual abnormalities or unintended pregnancy. PREDISPOSING FACTORS: Intermittent compliance with oral contraceptives. PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. If larger doses of hormonal contraceptives are utilized, titrating the dose against a response such as lack of spotting or breakthrough bleeding may not guarantee contraceptive efficacy. In women who wish to continue oral contraceptives with the addition of a second form of contraception, emphasize the importance of not missing doses of the oral contraceptive. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: In a study of four epileptic patients receiving an oral contraceptive containing ethinyl estradiol 50 mcg plus levonorgestrel 250 mcg carbamazepine reduced the area-under-curve (AUC) for ethinyl estradiol by 42% and for levonorgestrel by 40%. Pregnancy has been reported. Pregnancy has been reported in a woman receiving low-dose oral contraceptives six weeks after initiation of treatment with carbamazepine. In a randomized, open label study, concurrent administration of carbamazepine (600 mg daily) and Ortho Novum 1/35 (ethinyl estradiol, norethindrone) decreased the AUC of ethinyl estradiol and norethindrone by 42% and 58%, respectively. The apparent oral clearance of ethinyl estradiol and norethindrone increased by 127% and 69%, respectively. Concurrent use of rufinamide (800 mg twice daily) and ethinyl estradiol / norethindrone (35 mcg/1 mg) for 14 days decreased the AUC of ethinyl estradiol and norethindrone by 22% and 14%, respectively. The maximum concentration (Cmax) of ethinyl estradiol and norethindrone decreased by 31% and 18%, respectively. Double-blind, randomized, crossover study with 24 women (only 20 analyzed) given 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel and either carbamazepine 600 mg or a matched placebo for 4 months. Ethinyl estradiol and levonorgestrel levels were measured and mean AUC was significantly lower in those taking carbamazepine. Cmax of ethinyl estradiol was also significantly decreased. Additionally more cases of breakthrough bleeding and ovulation occurred with concurrent use of the carbamazepine. In a case report, a patient with an etonogestrel implant became pregnant while taking carbamazepine for epilepsy. Coadministration of immediate-release oxcarbazepine decreased mean ethinyl estradiol AUC levels in two different studies by 48% and 52%, respectively. Additionally, mean AUC of levonorgestrel was decreased in two different studies by 32% and 52%, respectively. |
BANZEL, CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, EPITOL, EQUETRO, OXCARBAZEPINE, OXCARBAZEPINE ER, OXTELLAR XR, RUFINAMIDE, TEGRETOL, TEGRETOL XR, TRILEPTAL |
| Hormonal Contraceptive Agents/Bosentan SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bosentan may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1,2) CLINICAL EFFECTS: Concurrent use of bosentan and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure.(1,2) Bosentan is likely to cause major birth defects if used by pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women receiving bosentan therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Consider consulting a gynecologist or similar expert for advice on adequate contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: Concurrent use of bosentan and Ortho-Novum (norethindrone and ethinyl estradiol) resulted in average decreases of norethindrone and ethinyl estradiol by 14% and 31%, respectively. However, individual subjects experienced decreases in norethindrone and ethinyl estradiol by as much as 56% and 66%, respectively. Therefore, hormonal contraceptive agents may not be reliable in patients taking bosentan.(1,2) |
BOSENTAN, TRACLEER |
| Steroidal Contraceptives/Aprepitant SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Aprepitant may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: The effectiveness of hormonal contraceptives may be reduced during and for 28 days following aprepitant use.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients taking hormonal contraceptives should be instructed to use alternative or back-up methods of contraception while using aprepitant and for 1 month after the last dose of aprepitant.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: The concurrent use of aprepitant (100 mg daily for 14 days) with an oral contraceptive (ethinyl estradiol, 35 mcg and norethindrone, 1 mg) decreased the area-under-curve (AUC) of ethinyl estradiol and norethindrone by 43% and 8%, respectively.(1) In another study, an oral contraceptive (ethinyl estradiol and norethindrone, dosages not stated) was administered on Days 1 through 21. Subjects also received aprepitant (125 mg Day 8, 80 mg daily Days 9 and 10), ondansetron (32 mg Day 8), dexamethasone (12 mg Day 8, 8 mg daily Days 9 through 11). The AUC of ethinyl estradiol decreased by 19% on Day 10 and by as much as 64% on Days 9 through 21. There was no effect on the AUC of norethindrone on Day 10, but there was as much as a 60% decrease in norethindrone minimum concentration (Cmin) during Days 9 through 21.(1) In another study, an oral contraceptive (ethinyl estradiol and norgestimate, dosages not stated) was administered on Days 1 through 21. Subjects also received aprepitant (40 mg Day 8). The AUC of ethinyl estradiol decreased by 4% and 29% on Days 8 and 12, respectively. The AUC of norelgestromin (norgestimate is converted to norelgestromin) increased by 18% on Day 8 and decreased by 10% on Day 12. Trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following aprepitant.(1) |
APONVIE, APREPITANT, CINVANTI, EMEND, FOCINVEZ, FOSAPREPITANT DIMEGLUMINE |
| Lamotrigine/Estrogen-Containing Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Estrogens increase glucuronidation mediated metabolism of lamotrigine. Lamotrigine may modestly induce the metabolism of hormonal contraceptives.(1,2) CLINICAL EFFECTS: Concurrent use of lamotrigine and estrogen-containing contraceptives may result in decreased levels and effectiveness of both agents. Increased seizure rates have been reported in patients taking lamotrigine for epilepsy.(1,2) PREDISPOSING FACTORS: Increased seizure risk is more likely in when lamotrigine is used as monotherapy for treatment of epilepsy. The risk for an increase in seizure rate is lower in patients already stabilized on a combination of lamotrigine and an enzyme inducing agent such as carbamazepine, phenytoin, phenobarbital, or primidone. The risk for contraceptive failure may be greater in patients also taking other enzyme inducing agents such as carbamazepine, phenytoin, phenobarbital, primidone, or rifampin. PATIENT MANAGEMENT: During initiation of lamotrigine therapy, no adjustments to the recommended lamotrigine dose escalation guidelines are recommended in patients taking estrogen-containing contraceptives.(1) Dose adjustments will be necessary in most patients who start or stop an estrogen-containing oral contraceptive in patients taking maintenance doses of lamotrigine. The lamotrigine dosage may need to be increased by as much as 2-fold according to clinical response when estrogen-containing contraceptives are initiated in patients NOT taking other drugs which induce glucuronidation such as carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin. If estrogen-containing contraceptives are discontinued, the dosage of lamotrigine may need to be decreased by 50%.(1) Initiate changes in lamotrigine dosage at the same time estrogen containing products are started or stopped.(1) In patients also taking carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin, no lamotrigine maintenance dosage adjustments should be necessary if estrogen-containing contraceptives are initiated or discontinued.(1) Patients should be instructed to promptly report any changes in their menstrual cycle, such as break-through bleeding.(1) DISCUSSION: In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) increased lamotrigine clearance by 2-fold, with a mean decrease in lamotrigine area-under-curve (AUC) and maximum concentration (Cmax) by 52% and 39%, respectively. Serum trough lamotrigine levels were two-fold higher at the end of the week of inactive tablets when compared to lamotrigine levels at the end of the active hormonal cycle. This effect should be expected in women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.(1) In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) had no effect on ethinylestradiol levels. Levonorgestrel AUC and Cmax decreased by 19% and 12%, respectively. Though there was no hormonal evidence of ovulation, there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.(1) In a study, mean steady-state lamotrigine levels were 13 micro mol/L in 22 women taking oral contraceptives compared to 28 micro mol/L in 30 women who were not taking oral contraceptives. The lamotrigine dose/body weight/ plasma concentration was 2.1 L/kg/day in patients taking oral contraceptives compared to 0.8 L/kg/day in patients without oral contraceptives.(3) One set of authors reported seven cases of decreased lamotrigine levels in patients receiving oral contraceptives. Lamotrigine levels were decreased by 41% to 64%, average 49%. Most patients either experienced increased seizure frequency or recurrence of seizures after the addition of the oral contraceptive, or increased lamotrigine adverse effects following the discontinuation of the oral contraceptive.(4) A study in 45 females compared lamotrigine pharmacokinetics in patients taking an ethinyl estradiol-containing contraceptive (n=11) to patients taking a progestin-only contraceptive (n=16) and to patients taking no contraceptives (n=18). The lamotrigine serum concentration to dose ratio was significantly lower in patients taking ethinyl estradiol-containing contraceptives. There was no significant difference between patients taking progestin-only contraceptives and those using no contraceptives.(5) In a double-blind, placebo-controlled study, women with epilepsy were treated with lamotrigine monotherapy, or lamotrigine plus oral contraceptive. After 21 days, the mean dose-corrected lamotrigine concentration was 84% higher in the monotherapy group verses the combined treatment group.(6) Another study in 8 epileptic females assessed the pharmacokinetics of lamotrigine in combination with hormonal contraceptives. Serum samples were drawn on days 18 and 21 of hormonal contraceptive therapy and during days 5 and 7 of the placebo week (hormonal contraceptive free week). Analysis found statistically significant elevations (approximately 27%) in lamotrigine plasma concentrations during the hormone-free week, than during cycle intake.(7) In a study, 22 enrolled females took lamotrigine titrated up to 300 mg/d for a period of 130 days and either combined it with an oral contraceptive or took lamotrigine monotherapy. Both ethinyl estradiol and lamotrigine serum levels were drawn in the presence or absence of combined therapy. Laboratory serum data showed the ratios of lamotrigine AUC (0-24h) and Cmax at 0.48 for coadministration (lamotrigine plus oral contraceptive) and a ratio of 0.61 for lamotrigine monotherapy. There were no changes in ethinyl estradiol levels. Levonorgestrel levels decreased 19% and 7 of 22 patients reported break-through bleeding; however, suppression of ovulation was maintained.(8) In an interaction study, lamotrigine decreased exposure to the progestin component (levonorgestrel) of an oral contraceptive by 19%, but suppression of ovulation was not affected. The manufacturer of lamotrigine states that the possibility of decreased contraceptive efficacy in some patients cannot be excluded.(1) The 2010 CDC and 2015 WHO contraceptive guidelines do not mention evidence of reduced contraceptive efficacy with concurrent therapy with lamotrigine.(9,10) The 2018 Faculty of Sexual and Reproductive Healthcare contraceptive guidelines state that lamotrigine is not thought to be an enzyme-inducing drug but that contraceptive efficacy may be reduced by concurrent use with lamotrigine. The clinical significance of this effect is unknown. The guideline recommends caution when administering lamotrigine and contraceptives concurrently.(11) |
LAMICTAL, LAMICTAL (BLUE), LAMICTAL (GREEN), LAMICTAL (ORANGE), LAMICTAL ODT, LAMICTAL ODT (BLUE), LAMICTAL ODT (GREEN), LAMICTAL ODT (ORANGE), LAMICTAL XR, LAMICTAL XR (BLUE), LAMICTAL XR (GREEN), LAMICTAL XR (ORANGE), LAMOTRIGINE, LAMOTRIGINE (BLUE), LAMOTRIGINE (GREEN), LAMOTRIGINE (ORANGE), LAMOTRIGINE ER, LAMOTRIGINE ODT, LAMOTRIGINE ODT (BLUE), LAMOTRIGINE ODT (GREEN), LAMOTRIGINE ODT (ORANGE), SUBVENITE, SUBVENITE (BLUE), SUBVENITE (GREEN), SUBVENITE (ORANGE) |
| Tizanidine/Estrogens SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Estrogen containing hormonal contraceptives or hormone replacement therapy may decrease the clearance of tizanidine by inhibiting CYP1A2.(1) CLINICAL EFFECTS: Concurrent use of tizanidine and estrogen containing hormonal contraceptives or hormone replacement therapy may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function. PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2) PATIENT MANAGEMENT: The manufacturer states that routine administration of tizanidine and estrogen containing hormonal contraceptives or hormone replacement therapy should be avoided.(1) If concurrent use is necessary, tizanidine should be initiated with a 2 mg dose and increased 2-4 mg daily based on patient response to therapy.(1) If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1) DISCUSSION: In a retrospective analysis of population pharmacokinetic data, women taking oral contraceptives with tizanidine has a 50% lower clearance compared to women not on oral contraceptives.(1) In fifteen women using oral contraceptives, tizanidine (4 mg) increased the area-under-curve (AUC) and peak plasma tizanidine concentration, 3.9-fold and 3.0-fold respectively, compared to placebo. In one patient, the AUC of tizanidine exceeded twenty times the AUC of the placebo group.(3) |
TIZANIDINE HCL, ZANAFLEX |
| Hormonal Contraceptives/Mycophenolate SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of mycophenolate may result in decreased levels and effectiveness of hormonal contraceptives. The use of mycophenolate in pregnancy has been associated with an increased risk for first trimester pregnancy loss and and congenital malformations.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients should be informed that mycophenolate may reduce the effectiveness of hormonal contraceptives and that the use of mycophenolate in pregnancy has been associated with an increased risk for first trimester pregnancy loss and congenital malformations.(1,2) Female patients of childbearing potential should use two forms of contraception four weeks prior to initiating mycophenolate, during therapy, and for six weeks after completing mycophenolate therapy.(1,2) DISCUSSION: In a study in 18 female patients, concurrent mycophenolate mofetil (1 gram twice daily) and oral contraceptives containing ethinyl estradiol (0.02 to 0.04 mg) with levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg), or gestodene (0.05 mg to 0.10 mg) decreased the area-under-curve (AUC) of levonorgestrel by 15%. There was large inter-patient variability in the data, especially for ethinyl estradiol. Mean serum levels of LH, FSH, and progesterone were not significantly affected. (1) |
CELLCEPT, MYCOPHENOLATE MOFETIL, MYCOPHENOLIC ACID, MYFORTIC, MYHIBBIN |
| Contraceptives/Chloramphenicol SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Estrogens and progesterones are extensively excreted in bile, principally as glycuronide conjugates. Subsequently, they undergo enterohepatic circulation where bacterial hydrolysis occurs, allowing for reabsorption of the oral contraceptives through the bowel wall and eventual urinary excretion. Treatment with antibiotics destroys the gut flora and prevents steroid reabsorption, resulting in lower than normal concentrations of the contraceptive and excretion via the feces rather than the urine. Chloramphenicol may also induce hepatic enzymes, resulting in increased metabolism of the contraceptive agent. CLINICAL EFFECTS: May observe reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy. Reduced effects may be seen for several days after discontinuation of antibiotic therapy. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: It is recommended that additional forms of birth control be used during concurrent administration of short courses of chloramphenicol. For longer courses, use another method of birth control. The patient should be asked to report any spotting or bleeding. DISCUSSION: The manufacturer states that lower estrogen reabsorption and reduced efficacy may result in women taking oral contraceptives and chloramphenicol. |
CHLORAMPHENICOL, CHLORAMPHENICOL PALMITATE, CHLORAMPHENICOL SOD SUCCINATE |
| Sugammadex/Hormonal Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sugammadex may bind to hormonal contraceptives.(1,2) CLINICAL EFFECTS: Use of sugammadex may result in decreased levels of hormonal contraceptive similar to those seen with a missed dose of an oral contraceptive, which may result in decreased hormonal contraceptive effectiveness.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sugammadex recommends that all patients using hormonal contraceptives use an additional non-hormonal contraceptive method for 7 days following the administration of sugammadex.(1) The UK manufacturer of sugammadex recommends that patients taking oral hormonal contraceptives should be instructed to follow the missed dose instructions for their oral hormonal contraceptive on the day they receive sugammadex. Patients taking non-oral hormonal contraceptives should use an additional non-hormonal contraceptive method for 7 days following the administration of sugammadex and should refer to the advice in the package leaflet of their non-oral hormonal contraceptive.(2) DISCUSSION: Use of sugammadex may result in decreased levels of hormonal contraceptive similar to those seen with a missed dose of an oral contraceptive, which may result in decreased hormonal contraceptive effectiveness.(1,2) |
BRIDION, SUGAMMADEX SODIUM |
| Progestin-Containing Contraceptives/Ulipristal SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity.(1)(2) CLINICAL EFFECTS: Concurrent use of ulipristal may make hormonal contraception (including combined hormonal products, progestin-only products, and levonorgestrel emergency contraception) ineffective.(1,2) These agents may also make ulipristal ineffective. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal recommends that patients who have received ulipristal use a reliable barrier method of contraception for subsequent acts of intercourse until the next menstrual cycle begins.(1)(2) The US manufacturer of ulipristal states that if a woman wishes to start or resume hormonal contraception after taking ulipristal, she should do so no sooner than 5 days afterwards. The UK manufacturer of ulipristal states that concurrent use with levonorgestrel emergency contraception is not recommended.(1) DISCUSSION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity, thus it may interfere with the efficacy of hormonal contraception (including combined hormonal products, progestin-only products, and levonorgestrel emergency contraception) and progestin products.(1-2) These products may also make ulipristal ineffective. |
ELLA |
| Hormonal Contraceptive Agents/Clobazam SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Clobazam may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of clobazam and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. While there are no adequate studies in pregnant women, animal data suggests that clobazam use in pregnancy may result in development toxicity and fetal abnormalities.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women receiving clobazam therapy should not rely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Women taking clobazam should use additional, non-hormonal forms of contraception during and for 28 days after discontinuing clobazam.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Clobazam decreased the maximum concentration (Cmax) and area-under-curve (AUC) of midazolam, a CYP3A4 substrate by 24% and 27%, respectively. Because some hormonal contraceptives are metabolized by CYP3A4, clobazam use may decrease their effectiveness.(1) |
CLOBAZAM, ONFI, SYMPAZAN |
| Hormonal Contraceptives/Mifepristone SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Mifepristone is a progesterone-receptor antagonist, which will interfere mechanism of action of hormonal contraceptives (including oral, implantable, injectable, or transdermal agents).(1) CLINICAL EFFECTS: Concurrent use of mifepristone may decrease the effectiveness of hormonal contraceptives. Mifepristone will result in the loss of any pregnancy that results from decreased hormonal contraceptive efficacy.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Females of reproductive age maintained on mifepristone for hyperglycemia secondary to hypercortisolism should use a non-hormonal form of contraception during and for 1 month after mifepristone therapy unless they have been surgically sterilized.(1) DISCUSSION: Mifepristone is a progesterone-receptor antagonist, which will interfere mechanism of action of hormonal contraceptives. Mifepristone will result in the loss of any pregnancy that results from decreased hormonal contraceptive efficacy. Therefore, females of reproductive age maintained on mifepristone for hyperglycemia secondary to hypercortisolism should use a non-hormonal form of contraception during and for 1 month after mifepristone therapy unless they have been surgically sterilized.(1) |
KORLYM, MIFEPRISTONE |
| Hormonal Contraceptives/Elvitegravir-Cobicistat SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent administration may result in increased effects from the progestin (insulin resistance, dyslipidemia, acne, and venous thrombosis) and decreased effects of the estrogen component.(1,2) Concurrent use of cobicistat-containing products may result in elevated levels of and adverse effects from drospirenone, including hyperkalemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of cobicistat-elvitegravir-emtricitabine-tenofovir recommends the use of non-hormonal methods of contraception.(1) The manufacturer of cobicistat-elvitegravir-emtricitabine-tenofovir alafenamide recommends clinical monitoring due to the potential for hyperkalemia when administered concurrently with drospirenone-ethinyl estradiol.(2) DISCUSSION: Concurrent administration of cobicistat-elvitegravir-emtricitabine-tenofovir increased Cmax, AUC, and minimum concentration (Cmin) of norgestimate by 2.08-fold, 2.26-fold, and 2.67-fold, respectively. The Cmax, AUC, and Cmin of ethinyl estradiol decreased by 6%, 25%, and 44%, respectively.(1) Drospirenone has anti-mineralocorticoid activity comparable to a 25mg dose of spironolactone. |
GENVOYA, STRIBILD |
| Hormonal Contraceptives/Artemether SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Artemether may increase the metabolism of hormonal contraceptives. CLINICAL EFFECTS: Concurrent use of artemether may result in reduced levels and clinical effectiveness of hormonal contraceptives. In the case of contraceptives, breakthrough bleeding and pregnancy may result. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving artemether should be alerted to the possibility of decreased effectiveness of their hormonal contraceptive. It is recommended that alternative or additional non-hormonal contraceptive methods be used during artemether therapy(1) and for 28 days after completing therapy.(2) The patient should be asked to report any spotting or bleeding. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant. DISCUSSION: Artemether has been shown to weakly induce CYP2C19, CYP2B6, and CYP3A and may reduce the efficacy of hormonal contraceptives.(1) |
COARTEM |
| Hormonal Contraceptive Agents/Dabrafenib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Dabrafenib may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of dabrafenib and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. Dabrafenib may cause birth defects and/or miscarriage if used by pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women receiving dabrafenib therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Women should be advised to use a highly effective non-hormonal method of contraception during and for 2 weeks after dabrafenib mono-therapy.(1-3) The Canadian and UK manufacturers of dabrafenib also state that an effective method of contraception should be continued for 16 weeks after the last dose of trametinib when given in combination dabrafenib.(2-3) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(4) DISCUSSION: Dabrafenib is a moderate inducer of CYP3A4. In a clinical trial in 12 subjects, dabrafenib decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of midazolam, a sensitive CYP3A4 substrate) by 61% and 74%, respectively. Hormonal contraceptives are also metabolized by CYP3A4, therefore, hormonal contraceptive agents may not be reliable in patients taking dabrafenib.(1) |
TAFINLAR |
| Hormonal Contraceptive Agents/Lumacaftor SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lumacaftor, a strong inducer of CYP3A4, may induce the metabolism of hormonal contraceptive agents.(1) CLINICAL EFFECTS: Concurrent use of lumacaftor and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. In addition, menstrual related adverse effects such as such as amenorrhea, dysmenorrhea, menorrhagia and irregular menses are common.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women receiving lumacaftor therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. The manufacturer recommends avoiding concomitant use unless the benefit outweighs the risk.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Lumacaftor is a strong inducer of CYP3A4. Hormonal contraceptives are metabolized by CYP3A4, therefore, hormonal contraceptive agents may not be reliable in patients taking lumacaftor.(1) Menstrual irregularities, e.g. amenorrhea, dysmenorrhea, menorrhagia and irregular menses were reported in 27% of lumacaftor patients also taking hormonal contraceptives vs. 3% of female patients not using hormonal contraceptives.(1) |
ORKAMBI |
| Hormonal Contraceptives/Lesinurad SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lesinurad may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of lesinurad may reduce the effectiveness of hormonal contraceptives.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during lesinurad therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Lesinurad may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during lesinurad therapy.(1) |
DUZALLO |
| Lomitapide (Less Than or Equal To 40 mg)/Hormonal Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Hormonal contraceptives are weak inhibitors of CYP3A4 and may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve). CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1) PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1) PATIENT MANAGEMENT: The maximum lomitapide dose should be 40 mg daily for patients taking hormonal contraceptives. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction. When initiating a hormonal contraceptive in patients taking lomitapide 10 mg daily or more, decrease the dose of lomitapide by 50%. In patients taking lomitapide 5 mg daily, continue current dose. DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1) |
JUXTAPID |
| Hormonal Contraceptives/Enasidenib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Enasidenib may increase or decrease the metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of enasidenib may increase side effect from or reduce the effectiveness of hormonal contraceptives. Enasidenib may cause birth defects if used by pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during enasidenib therapy. Women of reproductive potential should use effective non-hormonal methods of contraception during enasidenib therapy and for at least 2 months after the final dose.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Enasidenib may increase or decrease metabolism of hormonal contraceptives. Enasidenib may increase or decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during enasidenib therapy and for at least 1 month after the final dose.(1) |
IDHIFA |
| Hormonal Contraceptives/Bexarotene SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Bexarotene may induce the CYP3A4 mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1,2) CLINICAL EFFECTS: Concurrent use of bexarotene may result in reduced levels and clinical effectiveness of hormone containing contraceptives. Breakthrough bleeding and contraceptive failure/pregnancy may result.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving bexarotene should be alerted to the risk for decreased effectiveness (e.g. contraceptive failure) of their hormonal contraceptive therapy and should be advised to use a reliable non-hormonal contraceptive option.(1) Due to bexarotene being teratogenic in animal studies and may cause fetal harm, the US prescribing information recommends that two reliable forms of contraception be used simultaneously one month before, during, and at least one month after bexarotene therapy. Females of reproductive potential should be advised to avoid becoming pregnant. If treatment with bexarotene is intended in a female with reproductive potential, it is strongly recommended that one of the two reliable forms of contraception should be non-hormonal. The patient should be asked to report any spotting or bleeding.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3) DISCUSSION: In a study of bexarotene 400 mg/m2 was administered orally with atorvastatin (another CYP3A4 substrate), the area-under-curve (AUC) of atorvastatin was decreased by 50%.(1) No studies have been conducted looking specifically at hormonal contraceptive use with bexarotene. However, due to the possibility of intended pregnancy the use of non-hormonal contraception needs to be considered.(1) |
BEXAROTENE, TARGRETIN |
| Cosyntropin/Agents Affecting Plasma Cortisol Levels SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1) CLINICAL EFFECTS: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of cosyntropin states accuracy of diagnosis using the cosyntropin diagnostic test may be complicated by concomitant medications affecting plasma cortisol levels.(1) Agents affecting plasma cortisol levels and recommendation to stop prior to cosyntropin diagnostic test include: - Glucocorticoids: May elevate plasma cortisol levels. Stop these drugs on the day of testing. Long-acting glucocorticoids may need to be stopped for a longer period before testing. - Spironolactone: May elevate plasma cortisol levels. Stop spironolactone on the day of testing. - Estrogen: May elevate plasma total cortisol levels. Discontinue estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.(1) DISCUSSION: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1) |
CORTROSYN, COSYNTROPIN |
| Hormonal Contraceptive Agents/Encorafenib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Encorafenib may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of encorafenib and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. Encorafenib may cause birth defects and/or miscarriage if used by pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women receiving encorafenib therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Women should be advised to use a highly effective non-hormonal method of contraception during and for 2 weeks after the final dose of encorafenib.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Based on in vitro data, encorafenib is an inducer of CYP3A4 at clinically relevant plasma concentrations.(1) Hormonal contraceptives are also metabolized by CYP3A4, therefore, hormonal contraceptive agents may not be reliable in patients taking encorafenib.(1) |
BRAFTOVI |
| Hormonal Contraceptives/Selected Strong & Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may increase the CYP3A4-mediated metabolism of hormonal contraceptives.(1-2) CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may reduce the effectiveness of hormonal contraceptives.(1-2) Apalutamide, enzalutamide, ivosidenib, and mitotane may cause birth defects and/or miscarriage if used by pregnant women. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during therapy with a CYP3A4 inducer. Women of reproductive potential should use effective non-hormonal methods of contraception during therapy with a CYP3A4 inducer. Continuation of an effective non-hormonal contraceptive after discontinuation of the CYP3A4 inducer is also advised for the period of time indicated below.(1-3) There is no specific recommendation for contraception in women on apalutamide or enzalutamide. Male patients with female partners of reproductive age are advised to continue effective contraception for 3 months after discontinuation of apalutamide or enzalutamide.(4,5) The manufacturer of mitotane recommends continuing effective contraception after discontinuation of mitotane for as long as mitotane plasma levels are detectable. Mitotane half life ranges from 18 to 159 days (median 53 days).(3) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(6) DISCUSSION: Strong and moderate CYP3A4 inducers may increase the CYP3A4-mediated metabolism of hormonal contraceptives and decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during and after CYP3A4 inducer therapy.(1-3) An in vivo mechanism static model predicted strong interactions between ulipristal combined with enzalutamide or mitotane. Enzalutamide was predicted to lower ulipristal area-under-curve (AUC) by 85%, and mitotane was predicted to lower ulipristal AUC by 93%.(2) Strong and moderate CYP3A4 inducers linked include: apalutamide, enzalutamide, ivosidenib, mitotane, nafcillin, sotorasib, telotristat, and thioridazine.(7,8) |
ERLEADA, LUMAKRAS, LYSODREN, MITOTANE, NAFCILLIN, NAFCILLIN SODIUM, THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE, TIBSOVO, XERMELO, XTANDI |
| Hormonal Contraceptives/Elagolix SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Based on the mechanism of action of elagolix, estrogen containing contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on elagolix is unknown.(1) Elagolix is a weak to moderate inducer of CYP3A4 and may increase the metabolism of progestins. The mechanism of elagolix's interaction with estrogens is unknown.(1) CLINICAL EFFECTS: Concurrent use of hormonal contraceptives may reduce the effectiveness of elagolix.(1) Elagolix 200 mg twice daily may increase the levels and toxicity of estrogens, including thromboembolic disorders and vascular events, while decreasing the levels and efficacy of progestin-containing hormonal contraceptives. Elagolix may cause birth defects and/or miscarriage if used by pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive potential should use effective non-hormonal methods of contraception during elagolix therapy and for 28 days after discontinuing elagolix. Women of reproductive age should be counseled not to use hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) DISCUSSION: Hormonal contraceptives may decrease the effectiveness of elagolix. Women should use a non-hormonal method of birth control during elagolix therapy.(1) Coadministration of elagolix 200 mg twice daily for 14 days with ethinyl estradiol 20 mcg-levonorgestrel 0.1 mg resulted in a 2.2-fold increase in ethinyl estradiol exposure and a 27% decrease in levonorgestrel exposure.(1) Coadministration of elagolix 150 mg daily did not affect exposure to norethindrone 0.35 mg once daily nor to ethinyl estradiol 35 mcg-triphasic norgestimate 0.18/0.215/0.25 mg once daily.(1) |
ORIAHNN, ORILISSA |
| Tranexamic Acid (Injectable)/Estrogenic Agents SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Tranexamic acid is an antifibrinolytic and estrogen-containing hormonal contraceptives are known to increase the risk of venous thromboembolism and arterial thromboses, including stroke and myocardial infarction. Concurrent use may increase the risk of these events.(1,2) CLINICAL EFFECTS: Concurrent use of tranexamic acid in patients taking estrogen-containing agents or hormonal contraceptives may increase the risk of embolisms.(1,2) PREDISPOSING FACTORS: The risk of thrombosis may be even greater in women who are obese or smoke, especially smokers over age 35.(1) PATIENT MANAGEMENT: The concurrent use of injectable tranexamic and and estrogen-containing hormonal contraception or estrogen replacement therapy should be approached with caution.(1) DISCUSSION: There are no clinical trial data on the risk of concurrent therapy with tranexamic acid and hormonal contraceptives. There have been postmarketing reports of venous and arterial thrombotic events in women receiving combination therapy with oral tranexamic acid.(2) Women taking hormonal contraception were excluded from safety and efficacy trials of oral tranexamic acid.(2) |
CYKLOKAPRON, TRANEXAMIC ACID, TRANEXAMIC ACID-NACL |
| Hormonal Contraceptives/Lorlatinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lorlatinib may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of lorlatinib may reduce the effectiveness of hormonal contraceptives.(1) Lorlatinib may cause birth defects and/or miscarriage if used by pregnant women. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during lorlatinib therapy and for at least 6 months after the final dose. Women of reproductive potential should use effective non-hormonal methods of contraception during lorlatinib therapy and for at least 6 months after the final dose.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Lorlatinib may induce the CYP3A4 mediated metabolism of hormonal contraceptives. Lorlatinib may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during lorlatinib therapy and for at least 6 months after the final dose.(1) |
LORBRENA |
| Hormonal Contraceptives/Pitolisant SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Pitolisant may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1,2) CLINICAL EFFECTS: Concurrent use of pitolisant may reduce the effectiveness of hormonal contraceptives.(1,2) Pitolisant may cause birth defects and/or miscarriage if used by pregnant women. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during pitolisant therapy and for at least 21 days after the final dose. Women of reproductive potential should use effective non-hormonal methods of contraception during pitolisant therapy and for at least 21 days after the final dose.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3) DISCUSSION: Pitolisant may induce the CYP3A4 mediated metabolism of hormonal contraceptives. Pitolisant may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during pitolisant therapy and for at least 21 days after the final dose.(1,2) |
WAKIX |
| Hormonal Contraceptives/Cladribine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cladribine may lower the efficacy of hormonal contraceptives. The mechanism of this potential interaction is unknown.(1) CLINICAL EFFECTS: Concurrent use of cladribine may reduce the effectiveness of hormonal contraceptives.(1) Cladribine may cause birth defects and/or miscarriage if used by pregnant women. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should add a back-up method of birth control during cladribine therapy and for at least 4 weeks after the final dose of each treatment course.(1) DISCUSSION: It is unknown whether cladribine reduces the effectiveness of hormonal contraceptives. Cladribine is teratogenic and contraindicated in pregnancy.(1) |
CLADRIBINE, MAVENCLAD |
| Tofacitinib (Greater Than or Equal To 20 mg daily)/Estrogens SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Estrogens increase the risk of thrombosis, and combining estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may place patients at high risk of thromboembolism.(1-3) CLINICAL EFFECTS: Concurrent use of estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may increase the incidence of pulmonary embolism and death.(1-3) PREDISPOSING FACTORS: Additional risk factors include advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.(1) PATIENT MANAGEMENT: The European manufacturer states that the 10 mg twice daily dose of tofacitinib is not recommended in patients who are on combined hormonal contraceptives or hormone replacement therapy, or who are otherwise at high risk of pulmonary embolism, unless there are no suitable alternatives.(4) Patients at high risk of pulmonary embolism should be switched to alternative therapies. For the treatment of rheumatoid arthritis and psoriatic arthritis, the dose of tofacitinib should be limited to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4) The US FDA and Health Canada have not placed use restrictions specifically on concurrent use of tofacitinib with hormonal contraceptives or hormone replacement therapy. Both agencies advise avoiding tofacitinib in patients at increased risk of thrombosis. The US and Canadian manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile idiopathic arthritis. For the treatment of ulcerative colitis, the lowest effective dose for the shortest duration possible is recommended. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis and discontinue tofacitinib in patients with symptoms of thrombosis.(5-7) There is currently no use restriction on the combination of estrogens with lower doses of tofacitinib (less than 20 mg daily). DISCUSSION: In an ongoing open-label study comparing the safety of tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5 mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123 patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years, respectively). All-cause mortality was also higher in the tofacitinib 10 mg twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28 deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9 deaths/3,323 patient-years, respectively).(3) |
TOFACITINIB CITRATE, XELJANZ, XELJANZ XR |
| Hormonal Contraceptives/Deferasirox SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Deferasirox may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of deferasirox may reduce the effectiveness of hormonal contraceptives.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a non-hormonal method of birth control during deferasirox therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2) DISCUSSION: Deferasirox may induce the CYP3A4 mediated metabolism of hormonal contraceptives. Deferasirox may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a non-hormonal method of birth control during deferasirox therapy.(1) |
DEFERASIROX, EXJADE, JADENU, JADENU SPRINKLE |
| Hormonal Contraceptives/Cenobamate SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Cenobamate may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of cenobamate may reduce the effectiveness of hormonal contraceptives.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives for contraception. According to the US manufacturer, women should use additional or alternative non-hormonal methods of birth control during cenobamate therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2) DISCUSSION: Cenobamate may induce the CYP3A4 mediated metabolism of hormonal contraceptives. The effectiveness of hormonal contraceptives may be reduced when administered concomitantly with cenobamate. Women should use additional or alternative non-hormonal birth control.(1) |
XCOPRI |
| Hormonal Contraceptives/Tazemetostat SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Tazemetostat is a weak CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1) CLINICAL EFFECTS: Coadministration of tazemetostat with hormonal contraceptives can result in decreased concentrations and reduced efficacy.(1) Breakthrough bleeding and contraceptive failure/pregnancy may result. Tazemetostat may cause fetal harm if administered to pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of tazemetostat recommends that female patients of reproductive potential use effective non-hormonal contraception during treatment with tazemetostat and for 6 months after the final dose.(1) Patients should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD).(2) DISCUSSION: Coadministration of tazemetostat 800 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 40% and maximum concentration (Cmax) by 21%.(1) |
TAZVERIK |
| Hormonal Contraceptives/Pexidartinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Pexidartinib is a moderate CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1) CLINICAL EFFECTS: Coadministration of pexidartinib with hormonal contraceptives can result in decreased concentrations and reduced efficacy.(1) Breakthrough bleeding and contraceptive failure/pregnancy may result. Pexidartinib may cause fetal harm if administered to pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of pexidartinib recommends that female patients of reproductive potential use effective non-hormonal contraception during treatment with pexidartinib and for 1 month after the final dose.(1) Patients should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD).(2) DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1) |
TURALIO |
| Hormonal Contraceptives/Ixazomib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ixazomib does not interact with hormonal contraceptives, but the dexamethasone used with ixazomib is a weak to moderate CYP3A4 inducer and may increase the CYP3A4 mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of ixazomib with dexamethasone may reduce the effectiveness of hormonal contraceptives.(1) Ixazomib may cause birth defects and/or miscarriage if used by pregnant women. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal back-up method of birth control during and for 90 days after ixazomib-dexamethasone therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Ixazomib-dexamethasone has not been studied with hormonal contraceptives. Dexamethasone may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during ixazomib-dexamethasone therapy.(1) |
NINLARO |
| Thalidomide Analogues/Estrogen-Containing Contraceptives SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Both the thalidomide analogues and estrogen-containing contraceptives are associated with an increased risk of thromboembolic disorders.(1-9) The US manufacturer of thalidomide states that it is unknown if these risks are additive.(1) CLINICAL EFFECTS: Use of lenalidomide, pomalidomide, or thalidomide in patients taking estrogen-containing hormonal contraceptives may increase the risk of venous or arterial thromboembolism, including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), and stroke.(1-9) PREDISPOSING FACTORS: Previous history of thromboembolic events or concomitant administration of erythropoietic agents may increase the thrombotic risk. Modifiable risk factors (e.g., diabetes, hyperlipidemia, hypertension, smoking) should be minimized.(1-9) PATIENT MANAGEMENT: The Canadian manufacturer of the thalidomide analogues states that use of hormonal contraceptives is not recommended.(2-4) The UK manufacturer of the thalidomide analogues states that concurrent combined hormonal contraceptives is not recommended and that patients should be switched to a progesterone-only or non-hormonal contraceptive (e.g., progestin-only pills, progestin implant or intrauterine device, depot medroxyprogesterone acetate, tubal sterilization).(5-7) The US manufacturer of the thalidomide analogues does not recommend against use of hormonal contraceptives but instead includes them as an option for highly effective contraception. Estrogen-containing therapies should be used with caution after assessment of their risks and benefits.(1,8-9) The risk of venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception.(5-7) If the estrogen-containing contraceptive is not used, two other simultaneous, effective methods of contraception are still required in the US and Canada.(1-4,8,9) In the UK, at least one effective method of contraception is required.(5-7) DISCUSSION: Lenalidomide, pomalidomide, and thalidomide can all cause thromboembolism. Concurrent use of other agents that may increase the risk of thrombosis, like estrogen-containing therapies, may result in an increased risk of thrombosis. |
LENALIDOMIDE, POMALYST, REVLIMID, THALOMID |
| Hormonal Contraceptives/Belzutifan SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Belzutifan is a weak to moderate CYP3A4 inducer. Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1) CLINICAL EFFECTS: Concurrent use of belzutifan can lead to ineffective hormonal contraceptive and cause fetal harm when administered to a pregnant woman.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Pregnant women and females of reproductive potential should be counseled on the potential risk to the fetus.(1) Advise females of reproductive potential to use effective non-hormonal contraception during treatment with belzutifan and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with belzutifan and for 1 week after the last dose.(1) Verify the pregnancy status of females of reproductive potential prior to initiating treatment with belzutifan.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Belzutifan has not been studied with hormonal contraceptives. It can render some hormonal contraceptives ineffective and cause embryo-fetal harm. Women should use non-hormonal contraception during therapy.(1) In an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures greater than or equal to 0.2 times the human exposure (AUC) at the recommended dose of 120 mg daily.(1) |
WELIREG |
| Hormonal Contraceptives/Mitapivat SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Mitapivat is a moderate CYP3A4 inducer. Coadministration of mitapivat with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1) CLINICAL EFFECTS: Concurrent use of mitapivat can lead to ineffective hormonal contraceptive and cause unintended pregnancy.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Pregnant women and females of reproductive potential should be counseled on the potential risk to the fetus.(1) Advise females of reproductive potential to use effective non-hormonal contraception during treatment with mitapivat.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Mitapivat is a moderate CYP3A4 inducer. Mitapivat has not been studied with hormonal contraceptives. It can render some hormonal contraceptives ineffective and may cause unintended pregnancy. Women should use non-hormonal contraception during therapy.(1) In an animal reproduction study, oral administration of mitapivat to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 13 and 3 times the maximum recommended ose.(1) |
PYRUKYND |
| Hormonal Contraceptives/Mavacamten SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Mavacamten is a moderate CYP3A4 inducer. Coadministration of mavacamten with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1) CLINICAL EFFECTS: Concurrent use of mavacamten can lead to ineffective hormonal contraceptive and cause unintended pregnancy. Mavacamten may cause fetal harm when administered to a pregnant woman.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant use of hormonal contraceptives with mavacamten. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with mavacamten and for 4 months after the last dose.(1) Hormonal contraceptives containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten.(1) Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Pregnant women and females of reproductive potential should be counseled on the potential risk to the fetus.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(3) DISCUSSION: Mavacamten is a moderate CYP3A4 inducer.(1) Concurrent use of a 16-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) resulted in a decrease in midazolam area-under-curve (AUC) and concentration maximum (Cmax) by 13% and 7%, respectively, in healthy CYP2C19 normal metabolizers. Concurrent use of mavacamten once daily in patients with hypertrophic cardiomyopathy, midazolam AUC and Cmax are predicted to decrease by 21 to 64% and 13 to 48%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.(1) Mavacamten has not been studied with hormonal contraceptives. It can render some hormonal contraceptives ineffective and may cause unintended pregnancy. Women should use non-hormonal contraception during therapy.(1) In an animal reproduction study, mavacamten administration resulted in decreases in mean fetal body weight, reductions in fetal ossification of bones, and increases in post-implantation loss as well as increases in skeletal malformations at doses similar to maximum recommended human doses.(1) |
CAMZYOS |
| Oral Contraceptives/Tirzepatide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Tirzepatide delays gastric emptying, which may result in decreased oral contraceptive absorption.(1,2) CLINICAL EFFECTS: Tirzepatide may result in decreased levels and effectiveness of oral contraceptives.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of tirzepatide states patients should be advised to switch from oral hormonal contraceptives to a non-oral contraceptive method or to add a barrier method of contraception. Patients should use a non-oral contraceptive or barrier method of contraception for 4 weeks after starting tirzepatide and for 4 weeks after each dose escalation of tirzepatide.(1,2) Hormonal contraceptives that are not administered orally are not expected to be affected by tirzepatide.(1) DISCUSSION: In a pharmacokinetic study, a single dose of tirzepatide 5 mg with combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) decreased the mean concentration maximum (Cmax) of ethinyl estradiol, norgestimate, and norelgestromin by 59%, 66%, and 55%, respectively, while mean area-under-curve (AUC) was reduced by 20%, 21%, and 23%, respectively.(1,2) A study in pregnant rats, tirzepatide caused fetal growth restrictions and fetal abnormalities at clinical exposure. A study in pregnant rabbits, tirzepatide caused fetal growth restrictions at clinically relevant exposures.(1) |
MOUNJARO, ZEPBOUND |
| Oral Contraceptives/Exenatide Microsphere SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Exenatide delays gastric emptying, which may result in decreased oral contraceptive absorption.(1,2) CLINICAL EFFECTS: Exenatide may result in decreased levels and effectiveness of oral contraceptives.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of oral contraceptives with extended-release exenatide is not recommended. No recommendations are available for the timing of administration of extended-release exenatide and oral contraceptives.(1) Consider using non-sustained release exenatide. If using non-sustained release exenatide, oral contraceptives should be taken one hour before administering exenatide non-sustained release.(2) DISCUSSION: In a study in 32 healthy females, administration of an oral contraceptive 30 minutes after exenatide (5 mcg BID) decreased the maximum concentration (Cmax) of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively. Time to Cmax (Tmax) of ethinyl estradiol and levonorgestrel increased by 3 hours and 3.5 hours, respectively. Administering the oral contraceptive one hour before exenatide decreased the Cmax of ethinyl estradiol by 15%, but there was no effect on levonorgestrel. There was no significant effect on bioavailability with either regimen.(1-3) |
BYDUREON BCISE |
| Hormonal Contraceptives/Omaveloxolone SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Omaveloxolone is a weak CYP3A4 inducer. Coadministration of omaveloxolone with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1) CLINICAL EFFECTS: Concurrent use of omaveloxolone may reduce the effectiveness of hormonal contraceptives.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant use of hormonal contraceptives with omaveloxolone. Advise females of reproductive potential to use effective non-hormonal contraception (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during treatment with omaveloxolone and for 28 days after the last dose. Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2) DISCUSSION: Coadministration of omaveloxolone with midazolam (a CYP3A substrate) decreased the area-under-curve (AUC) of midazolam by 45%.(1) |
SKYCLARYS |
| Hormonal Contraceptives/Pegaspargase SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: An indirect interaction may occur due to pegaspargase hepatotoxicity resulting in decreased hepatic clearance of hormonal contraceptives.(1,2) Both medicines may also cause thromboembolic events. CLINICAL EFFECTS: Concurrent use of pegaspargase may result in increased levels and effects of hormonal contraceptives and increase the risk of venous thromboembolism.(3) PREDISPOSING FACTORS: Patients with risk factors for thrombosis include those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery. PATIENT MANAGEMENT: The Australian and UK manufacturers of pegaspargase state that hormonal contraceptives are not considered to be sufficiently safe in patients on pegaspargase. Concurrent use of hormonal contraceptives and pegaspargase is not recommended.(1,2) The US manufacturer of pegaspargase states that females of reproductive potential should be counseled to use an effective non-hormonal contraceptive method during and for 3 months after therapy with pegaspargase.(4) The UK manufacturer of pegaspargase recommends using non-oral contraceptives during and for 6 months after therapy with pegaspargase.(2) DISCUSSION: Hepatotoxicity caused by pegaspargase may result in increased exposure to hormonal contraceptives and increase the risk of thromboembolism. Concurrent use of hormonal contraceptives is not recommended.(1-4) |
ONCASPAR |
| Ethinyl Estradiol (Less Than or Equal To 20 mcg)/Glecaprevir-Pibrentasvir SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The mechanism of action has not been described. CLINICAL EFFECTS: Coadministration of greater than 20 mcg of ethinyl estradiol with glecaprevir-pibrentasvir may increase the risk of ALT elevations.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Due to the added risk for ALT elevations, the US manufacturer of glecaprevir-pibrentasvir states that medications which contain more than 20 mcg of ethinyl estradiol such as oral contraceptives are not recommended to be administered with glecaprevir-pibrentasvir. No dose adjustment is required when glecaprevir-pibrentasvir is coadministered with products containing 20 mcg or less of ethinyl estradiol.(1) The Canadian and UK manufacturers of glecaprevir-pibrentasvir state that ethinyl estradiol-containing products are contraindicated.(2,3) Alternative methods of contraception, such as progestin only or non-hormonal methods may be recommended during glecaprevir-pibrentasvir therapy. DISCUSSION: Simultaneous administration of glecaprevir-pibrentasvir may increase the risk of ALT elevations.(1) |
MAVYRET |
| Hormonal Contraceptives/Repotrectinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Repotrectinib may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of repotrectinib may reduce the blood concentrations and effectiveness of hormonal contraceptives. Repotrectinib may cause fetal harm when administered to pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled to avoid hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women should use an effective non-hormonal method of contraception during and for 2 months after repotrectinib therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: Repotrectinib is a moderate CYP3A4 inducer. In a study, repotrectinib decreased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a sensitive CYP3A4 substrate) by 69% and 48%, respectively. It may also decrease estrogen or progestin concentrations and reduce the effectiveness of hormonal contraceptives. Repotrectinib may cause fetal harm when administered to pregnant women.(1) |
AUGTYRO |
| Hormonal Contraceptives/Tovorafenib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Tovorafenib may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of tovorafenib may reduce the blood concentrations and effectiveness of hormonal contraceptives. Tovorafenib may cause fetal harm when administered to pregnant women.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled to avoid hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women should use an effective non-hormonal method of contraception during and for 28 days after tovorafenib therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: A pharmacokinetic model predicted tovorafenib to decrease midazolam Cmax and AUC by at least 20%. Tovorafenib may also decrease estrogen or progestin concentrations and reduce the effectiveness of hormonal contraceptives and/or an increase in breakthrough bleeding. Tovorafenib may cause fetal harm when administered to pregnant women.(1) |
OJEMDA |
| Hormonal Contraceptives/Elafibranor SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Elafibranor is a weak CYP3A4 inducer. Coadministration of elafibranor with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1) CLINICAL EFFECTS: Concurrent use of elafibranor may reduce the effectiveness of hormonal contraceptives.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant use of hormonal contraceptives with elafibranor. Advise females of reproductive potential to use effective non-hormonal contraception (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during treatment with elafibranor and for 21 days after the last dose. Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2) DISCUSSION: Elafibranor is a weak CYP3A4 inducer.(1) Coadministration of elafibranor with simvastatin (a CYP3A, OATP1B1, and OATP1B3 substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of simvastatin beta-hydroxyacid by 26% and 32%, respectively.(1) |
IQIRVO |
| Hormonal Contraceptives/Vorasidenib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Vorasidenib may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1) Hormonal contraceptives may inhibit the CYP1A2-mediated metabolism of vorasidenib.(1,2) CLINICAL EFFECTS: Concurrent use of vorasidenib may reduce the blood concentrations and effectiveness of hormonal contraceptives. Vorasidenib may cause fetal harm when administered to pregnant women.(1) Concurrent use of moderate CYP1A2 inhibitors such as hormonal contraceptives may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of vorasidenib states that concurrent use of moderate CYP1A2 inhibitors should be avoided. If concurrent use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased risk of adverse reactions and modify the dose of vorasidenib as recommended in the prescribing information.(1) Women of reproductive age should be counseled to avoid hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women should use an effective non-hormonal method of contraception during and for 3 months after vorasidenib therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3) DISCUSSION: Vorasidenib is an inducer of CYP3A4 in vitro. Concomitant use of multiple doses of vorasidenib is predicted to decrease the concentration of CYP3A4 substrates, including hormonal contraceptives. Vorasidenib may cause fetal harm when administered to pregnant women.(1) Vorasidenib is primarily metabolized by CYP1A2. In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1) |
VORANIGO |
| Hormonal Contraceptives/Pacritinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Pacritinib is a moderate CYP3A4 inducer. Coadministration of pacritinib with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1) CLINICAL EFFECTS: Concurrent use of pacritinib may reduce the effectiveness of hormonal contraceptives, except for intrauterine systems containing levonorgestrel.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of pacritinib states to avoid concomitant use with hormonal contraceptives except for intrauterine systems containing levonorgestrel. If contraception is needed or desired, an alternate contraceptive that is not affected by CYP3A4 inducers (e.g., an intrauterine system) or additional non-hormonal contraceptives (e.g., condoms) should be used when treated concomitantly with pacritinib and for 30 days after the last dose of pacritinib.(1) Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2) DISCUSSION: Pacritinib is a moderate CYP3A4 inducer.(1) Coadministration of pacritinib (200 mg twice daily at steady state) with a single dose of oral midazolam (2 mg) (a CYP3A4 substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 60% and 60%, respectively.(1) |
VONJO |
| Selected Hormonal Contraceptives/Suzetrigine SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Suzetrigine may induce the metabolism of hormonal contraceptives containing progestins other than levonorgestrel and norethindrone.(1) CLINICAL EFFECTS: Concurrent use of suzetrigine and hormonal contraceptives containing progestins other than levonorgestrel or norethindrone may result in decreased levels and effectiveness of the contraceptive.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of suzetrigine advises that suzetrigine-treated patients using hormonal contraceptives containing progestins other than levonorgestrel and norethindrone should either: - Use additional non-hormonal contraceptives, - Use alternative contraceptives such as a combined oral contraceptive containing ethinyl estradiol as the estrogen and levonorgestrel or norethindrone as the progestin, or - Use an intrauterine system The alternative birth control method should be used during treatment with suzetrigine and for 28 days after discontinuation of suzetrigine.(1) DISCUSSION: Suzetrigine did not result in clinically significant changes in the pharmacokinetics of ethinyl estradiol and levonorgestrel when used concomitantly with an oral contraceptive containing ethinyl estradiol and levonorgestrel.(1) Suzetrigine administered 50 mg every 12 hours at steady state decreased the area-under-curve (AUC) of midazolam (a CYP3A4 substrate) by 48% and maximum concentration (Cmax) by 37%.(1) |
JOURNAVX |
| Hormonal Contraceptives/Zanubrutinib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Zanubrutinib is a weak CYP3A4 inducer. Coadministration of zanubrutinib with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1,2) CLINICAL EFFECTS: Concurrent use of zanubrutinib may reduce the effectiveness of hormonal contraceptives.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled to use highly effective contraception due to the risk of fetal harm with zanubrutinib. Women of reproductive age should not rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women who use hormonal methods of birth control must add a barrier method.(1) Advise females of reproductive potential to use effective non-hormonal contraception (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during treatment with zanubrutinib and for 7 days after the last dose.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(3) DISCUSSION: Zanubrutinib is a weak CYP3A4 inducer.(1,2) Coadministration of zanubrutinib with midazolam (a CYP3A substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 30% and 47%, respectively.(1,2) |
BRUKINSA |
There are 23 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Corticosteroids/Hormonal Contraceptives; Estrogens SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: It is speculated that hormonal contraceptives and estrogens inhibit hepatic metabolism of some corticosteroids as well as endogenous cortisol. Competitive protein binding may also contribute to elevations in serum corticosteroids. CLINICAL EFFECTS: Concurrent use of hormonal contraceptives or estrogens may result in an increase in the therapeutic and toxic effects of corticosteroids. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving concurrent hormonal contraceptives or estrogen should be observed for symptoms of corticosteroid toxicity. A lower corticosteroid dose may be required. DISCUSSION: In a study in 6 healthy females controlled on long-term oral contraceptives, subjects received either a placebo or high and low-dose prednisolone (0.53 and 0.14 mg/Kg iv). Both dosages of prednisolone decreased the total clearance, unbound clearance, and volume of distribution (Vd) at maximum concentration (Cmax) of total drug. Significant increases in half-life for free and unbound prednisolone and hydrocortisone concentrations were also observed in comparison to the placebo group. In a study in 8 females controlled on oral contraceptive therapy, 8 females not receiving contraceptive therapy, and 8 males, each subject received prednisolone 40 mg iv. The plasma clearance of total prednisolone in females on OC was 96 ml/min, which was significantly lower than those in both the male and female (205 and 187 ml/min, respectively) control groups. Prednisolone half-life and mean residence times were increased. The oral contraceptive group had a significantly higher (2-fold) concentration of transcortin, resulting in lower clearance, decreased Vd, and a 2-fold increase in the area-under-curve (AUC) for prednisolone. A clinical trial demonstrated the interaction between prednisolone (20 mg) and oral contraceptives containing ethinyl estradiol (30 mcg). The oral contraceptive users had an average plasma concentration of prednisolone 131% higher compared to the control group, and plasma cortisol levels were suppressed by approximately 90%. No differences were reported for ethinyl estradiol levels. In a study in 8 females taking oral contraceptives and 8 females who were were not, subjects received IV doses of prednisolone at 0.1 mg/Kg and 1.0 mg/Kg. Free prednisolone clearance was reduced by approximately 30% in the contraceptive receiving subjects compared to the control group, and plasma cortisol concentrations were reduced 2-fold compared to the control group. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ALDOSTERONE, ALKINDI SPRINKLE, ANUCORT-HC, ANUSOL-HC, BECLOMETHASONE DIPROPIONATE, BETA 1, BETALOAN SUIK, BETAMETHASONE ACETATE MICRO, BETAMETHASONE ACETATE-SOD PHOS, BETAMETHASONE DIPROPIONATE, BETAMETHASONE SOD PHOS-ACETATE, BETAMETHASONE SOD PHOS-WATER, BETAMETHASONE SODIUM PHOSPHATE, BETAMETHASONE VALERATE, BSP 0820, BUDESONIDE, BUDESONIDE DR, BUDESONIDE EC, BUDESONIDE ER, BUDESONIDE MICRONIZED, BUPIVACAINE-DEXAMETH-EPINEPHRN, CELESTONE, CLOBETASOL PROPIONATE MICRO, CORTEF, CORTENEMA, CORTIFOAM, CORTISONE ACETATE, DEFLAZACORT, DEPO-MEDROL, DESONIDE MICRONIZED, DESOXIMETASONE, DESOXYCORTICOSTERONE ACETATE, DEXABLISS, DEXAMETHASONE, DEXAMETHASONE ACETATE, DEXAMETHASONE ACETATE MICRO, DEXAMETHASONE INTENSOL, DEXAMETHASONE ISONICOTINATE, DEXAMETHASONE MICRONIZED, DEXAMETHASONE SOD PHOS-WATER, DEXAMETHASONE SODIUM PHOSPHATE, DEXAMETHASONE-0.9% NACL, DEXONTO, DMT SUIK, DOUBLEDEX, EMFLAZA, EOHILIA, FLUDROCORTISONE ACETATE, FLUNISOLIDE, FLUOCINOLONE ACETONIDE, FLUOCINOLONE ACETONIDE MICRO, FLUOCINONIDE MICRONIZED, FLUTICASONE PROPIONATE, FLUTICASONE PROPIONATE MICRO, HEMADY, HEMMOREX-HC, HEXATRIONE, HYDROCORTISONE, HYDROCORTISONE ACETATE, HYDROCORTISONE SOD SUCCINATE, HYDROCORTISONE-PRAMOXINE, KENALOG-10, KENALOG-40, KENALOG-80, LIDOCIDEX-I, MAS CARE-PAK, MEDROL, MEDROLOAN II SUIK, MEDROLOAN SUIK, METHYLPREDNISOLONE, METHYLPREDNISOLONE AC MICRO, METHYLPREDNISOLONE ACETATE, METHYLPREDNISOLONE SODIUM SUCC, MILLIPRED, MILLIPRED DP, MOMETASONE FUROATE, ORAPRED ODT, ORTIKOS, PEDIAPRED, PREDNISOLONE, PREDNISOLONE ACETATE MICRONIZE, PREDNISOLONE MICRONIZED, PREDNISOLONE SODIUM PHOS ODT, PREDNISOLONE SODIUM PHOSPHATE, PREDNISONE, PREDNISONE INTENSOL, PREDNISONE MICRONIZED, PRO-C-DURE 5, PRO-C-DURE 6, PROCTOCORT, RAYOS, SOLU-CORTEF, SOLU-MEDROL, TAPERDEX, TARPEYO, TRIAMCINOLONE, TRIAMCINOLONE ACETONIDE, TRIAMCINOLONE DIACETATE, TRIAMCINOLONE DIACETATE MICRO, TRILOAN II SUIK, TRILOAN SUIK, UCERIS, VERIPRED 20, ZCORT |
| Estrogens/Xanthine Derivatives SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Estrogens may inhibit the hepatic microsomal enzymes responsible for the metabolism of the theophyllines. CLINICAL EFFECTS: Concurrent use of estrogens may result in an increase in the pharmacologic effects of xanthine derivatives as a result of elevated serum levels. Signs and symptoms of theophylline toxicity including anorexia, nausea, vomiting, nervousness, agitation, headache, tachycardia, arrhythmias, and convulsions. PREDISPOSING FACTORS: Smoking. PATIENT MANAGEMENT: Patients receiving concurrent estrogens should be monitored for elevated xanthine levels and signs of toxicity. Adjust dosages accordingly. DISCUSSION: Although there are no reports of toxicity due to concurrent administration of oral contraceptives and theophylline, use of this combination has been associated with a decrease in the plasma clearance and an increase in the elimination half-life of theophylline. One study involving a small number of patients found that low dose oral contraceptive administration (i.e., 35 mcg) for up to 9 months, did not alter the pharmacokinetics of theophylline. Other studies demonstrate the effect of caffeine, a xanthine alkaloid chemically similar to theophylline, when administered to patients taking oral contraceptives or hormone replacement. Concomitant administration resulted in decreased caffeine metabolism by ethinyl estradiol's metabolic inhibition. A study of 20 healthy women evaluated the effect of caffeine elimination prior to and during one cycle of oral contraception. Compared to pretreatment values, it was determined that clearance of caffeine was reduced by approximately 55%. Another study evaluated the pharmacokinetics of caffeine in seven women receiving an oral depot contraceptive containing ethinyl estradiol. After six months, the oral contraceptive was found to significantly decrease the elimination half-life of caffeine: half-life prior to therapy was 4.9h, and after oral contraceptive therapy, the half-life of caffeine increased to 8.0h. |
AMINOPHYLLINE, ELIXOPHYLLIN, THEO-24, THEOPHYLLINE, THEOPHYLLINE ANHYDROUS, THEOPHYLLINE ER, THEOPHYLLINE ETHYLENEDIAMINE |
| Oral Contraceptives/Penicillins SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Estrogens and progesterones are extensively excreted in bile, principally as glycuronide conjugates. Subsequently, they undergo enterohepatic circulation where bacterial hydrolysis occurs, allowing for reabsorption of the oral contraceptives through the bowel wall and eventual urinary excretion. Treatment with antibiotics destroys the gut flora and prevents steroid reabsorption, resulting in lower than normal concentrations of the contraceptive and excretion via the feces rather than the urine. CLINICAL EFFECTS: May observe reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy. Reduced effects may be seen for several days after discontinuation of antibiotic therapy. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception. DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Reports of breakthrough bleeding and loss of contraceptive protection leading to unwanted pregnancies have occurred in women taking oral contraceptive agents who received concurrent ampicillin, amoxicillin, penicillin G, or oxacillin. Several studies have shown that the administration of ampicillin or penicillin to pregnant and nonpregnant women resulted in lowered urinary estrogen excretion, in some women as soon as three days after ampicillin therapy began. However in one small prospective study, plasma ethinyl estradiol concentrations showed a tendency to decrease during ampicillin administration on the third, fourth, and fifth morning of ampicillin administration, but were never lower than pretreatment values. In another small prospective study of women taking low dose combination contraceptives, concurrent ampicillin therapy neither altered the plasma levels nor the AUC of norethisterone and ethinyl estradiol. In addition, progesterone levels were in an anovulatory range. In another prospective study of 13 women taking long term oral contraceptive steroids, concurrent ampicillin was not associated with any significant changes in plasma concentrations of ethinyl estradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyl estradiol were noted in two women. |
AMOXICILLIN, AMOXICILLIN TRIHYDRATE, AMOXICILLIN-CLAVULANATE POT ER, AMOXICILLIN-CLAVULANATE POTASS, AMPICILLIN SODIUM, AMPICILLIN TRIHYDRATE, AMPICILLIN-SULBACTAM, AUGMENTIN, AUGMENTIN ES-600, AUGMENTIN XR, BICILLIN C-R, BICILLIN L-A, DICLOXACILLIN SODIUM, EXTENCILLINE, LANSOPRAZOL-AMOXICIL-CLARITHRO, LENTOCILIN S, MOXATAG, OMECLAMOX-PAK, OXACILLIN, OXACILLIN SODIUM, PENICILLIN G POTASSIUM, PENICILLIN G SODIUM, PENICILLIN GK-ISO-OSM DEXTROSE, PENICILLIN V POTASSIUM, PFIZERPEN, PIPERACILLIN-TAZOBACTAM, TALICIA, UNASYN, VOQUEZNA DUAL PAK, VOQUEZNA TRIPLE PAK, ZOSYN |
| Contraceptives/Tetracyclines; Tigecycline SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not established. CLINICAL EFFECTS: Reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy may occur. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception. DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Pregnancy has been reported following the addition of tetracycline to oral contraceptive therapy.(1) In contrast, a study in 7 healthy women found no effect of tetracycline on ethinyl estradiol or norethindrone levels.(2) A study in 24 healthy women found no significant effects of doxycycline on ethinyl estradiol, norethindrone, or progesterone levels. However, the authors noted that there large inter-patient and inter-patient variability in these levels and that the interaction may just manifest itself in a small proportion of women.(3) |
AVIDOXY, AVIDOXY DK, BENZODOX 30, BENZODOX 60, BISMUTH-METRONIDAZOLE-TETRACYC, DEMECLOCYCLINE HCL, DORYX, DORYX MPC, DOXY 100, DOXYCYCLINE HYCLATE, DOXYCYCLINE IR-DR, DOXYCYCLINE MONOHYDRATE, EMROSI, MINOCIN, MINOCYCLINE ER, MINOCYCLINE HCL, MINOCYCLINE HCL ER, MONDOXYNE NL, MORGIDOX, ORACEA, OXYTETRACYCLINE HCL, PYLERA, TARGADOX, TETRACYCLINE HCL, TIGECYCLINE, TYGACIL, XERAVA, XIMINO |
| Raloxifene/Estrogen SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Raloxifene binds to estrogen receptors and activates certain estrogenic pathways while blocking others.(1) CLINICAL EFFECTS: Concurrent use of raloxifene and estrogen may result in an unpredictable response. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of raloxifene does not recommend the use of systemic estrogen or hormone replacement therapy with raloxifene.(1) DISCUSSION: Information on the interaction between raloxifene and estrogen is lacking and the manufacturer of raloxifene states that the concurrent use of these medications has not been studied in prospective clinical trials.(1) |
EVISTA, RALOXIFENE HCL |
| Drospirenone/ACE Inhibitors; ARBs SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. ACE inhibitors and angiotensin II receptor antagonists may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and ACE inhibitors or angiotensin II receptor antagonists may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, potassium-sparing diuretics, heparin, and NSAIDs may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with either an ACE inhibitor or an angiotensin II receptor antagonist should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of ACE inhibitors or angiotensin II receptor antagonists may also increase potassium levels.(1) In a study in 24 mildly hypertensive postmenopausal women who received concurrent drospirenone/estradiol (3 mg/1 mg) with enalapril (10 mg), mean serum potassium levels were 0.22 mEq/L higher than in the placebo group. On day 14 of concurrent therapy, the ratios for serum potassium maximum concentration (Cmax) and area-under-curve (AUC) were 0.955 and 1.010, respectively. No patient developed hyperkalemia.(1) |
ACCUPRIL, ACCURETIC, ALTACE, AMLODIPINE BESYLATE-BENAZEPRIL, AMLODIPINE-OLMESARTAN, AMLODIPINE-VALSARTAN, AMLODIPINE-VALSARTAN-HCTZ, ARBLI, ATACAND, ATACAND HCT, AVALIDE, AVAPRO, AZOR, BENAZEPRIL HCL, BENAZEPRIL-HYDROCHLOROTHIAZIDE, BENICAR, BENICAR HCT, CANDESARTAN CILEXETIL, CANDESARTAN-HYDROCHLOROTHIAZID, CAPTOPRIL, CAPTOPRIL-HYDROCHLOROTHIAZIDE, COZAAR, DIOVAN, DIOVAN HCT, EDARBI, EDARBYCLOR, ENALAPRIL MALEATE, ENALAPRIL-HYDROCHLOROTHIAZIDE, ENALAPRILAT, ENTRESTO, ENTRESTO SPRINKLE, EPANED, EPROSARTAN MESYLATE, EXFORGE, EXFORGE HCT, FILSPARI, FOSINOPRIL SODIUM, FOSINOPRIL-HYDROCHLOROTHIAZIDE, HYZAAR, IRBESARTAN, IRBESARTAN-HYDROCHLOROTHIAZIDE, LISINOPRIL, LISINOPRIL-HYDROCHLOROTHIAZIDE, LOSARTAN POTASSIUM, LOSARTAN-HYDROCHLOROTHIAZIDE, LOTENSIN, LOTENSIN HCT, LOTREL, MICARDIS, MICARDIS HCT, MOEXIPRIL HCL, OLMESARTAN MEDOXOMIL, OLMESARTAN-AMLODIPINE-HCTZ, OLMESARTAN-HYDROCHLOROTHIAZIDE, PERINDOPRIL ERBUMINE, PRESTALIA, QBRELIS, QUINAPRIL HCL, QUINAPRIL-HYDROCHLOROTHIAZIDE, RAMIPRIL, TELMISARTAN, TELMISARTAN-AMLODIPINE, TELMISARTAN-HYDROCHLOROTHIAZID, TRANDOLAPRIL, TRANDOLAPRIL-VERAPAMIL ER, TRIBENZOR, VALSARTAN, VALSARTAN-HYDROCHLOROTHIAZIDE, VASERETIC, VASOTEC, ZESTORETIC, ZESTRIL |
| Drospirenone/Potassium Sparing Diuretics SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. Potassium sparing diuretics may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and potassium sparing diuretics may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, heparin, and NSAIDs may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with a potassium sparing diuretic should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of potassium sparing diuretics may also increase potassium levels.(1) |
ALDACTONE, AMILORIDE HCL, AMILORIDE-HYDROCHLOROTHIAZIDE, CAROSPIR, DYRENIUM, EPLERENONE, INSPRA, KERENDIA, SPIRONOLACTONE, SPIRONOLACTONE-HCTZ, TRIAMTERENE, TRIAMTERENE-HYDROCHLOROTHIAZID |
| Drospirenone/NSAIDs; Salicylates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. NSAIDs may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and NSAIDs may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, heparin, and potassium-sparing diuretics may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with a NSAID should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of NSAIDs may also increase potassium levels.(1) Occasional or chronic use of NSAIDs was not restricted in clinical trials of drospirenone.(1) |
ACETYL SALICYLIC ACID, ANAPROX DS, ANJESO, ARTHROTEC 50, ARTHROTEC 75, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, BISMUTH SUBSALICYLATE, BROMFENAC SODIUM, BUTALBITAL-ASPIRIN-CAFFEINE, CALDOLOR, CAMBIA, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CELEBREX, CELECOXIB, CHOLINE MAGNESIUM TRISALICYLAT, COMBOGESIC, COMBOGESIC IV, CONSENSI, COXANTO, DAYPRO, DICLOFENAC, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, DIFLUNISAL, DISALCID, DOLOBID, EC-NAPROSYN, ELYXYB, ETODOLAC, ETODOLAC ER, FELDENE, FENOPROFEN CALCIUM, FENOPRON, FLURBIPROFEN, HYDROCODONE-IBUPROFEN, IBU, IBUPAK, IBUPROFEN, IBUPROFEN LYSINE, IBUPROFEN-FAMOTIDINE, INDOCIN, INDOMETHACIN, INDOMETHACIN ER, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), KETOPROFEN, KETOPROFEN MICRONIZED, KETOROLAC TROMETHAMINE, KIPROFEN, LODINE, LOFENA, LURBIPR, MECLOFENAMATE SODIUM, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NABUMETONE MICRONIZED, NALFON, NAPRELAN, NAPROSYN, NAPROTIN, NAPROXEN, NAPROXEN SODIUM, NAPROXEN SODIUM CR, NAPROXEN SODIUM ER, NAPROXEN-ESOMEPRAZOLE MAG, NEOPROFEN, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, OXAPROZIN, PHENYL SALICYLATE, PHENYLBUTAZONE, PIROXICAM, RELAFEN DS, SALSALATE, SODIUM SALICYLATE, SULINDAC, SUMATRIPTAN SUCC-NAPROXEN SOD, SYMBRAVO, TOLECTIN 600, TOLMETIN SODIUM, TORONOVA II SUIK, TORONOVA SUIK, TRESNI, TREXIMET, URELLE, URETRON D-S, URIBEL TABS, URIMAR-T, URO-MP, URO-SP, VIMOVO, VIVLODEX, ZIPSOR, ZORVOLEX, ZYNRELEF |
| Drospirenone/Potassium Supplements SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. Potassium supplements also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and potassium supplements may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, heparin, and NSAIDs may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with a potassium supplement should have their serum potassium level checked during the first treatment cycle.(1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of potassium-supplements also increase potassium levels.(1) |
CLINIMIX E, DEXTROSE 5%-ELECTROLYTE #48, EFFER-K, K-PHOS NO.2, K-PHOS ORIGINAL, KABIVEN, KCL-D5W-0.2% NACL, KCL-D5W-0.225% NACL, KCL-D5W-0.45% NACL, KCL-D5W-0.9% NACL, KLOR-CON, KLOR-CON 10, KLOR-CON 8, KLOR-CON M10, KLOR-CON M15, KLOR-CON M20, KLOR-CON-EF, POKONZA, POTASSIUM ACETATE, POTASSIUM CHLORIDE, POTASSIUM CHLORIDE IN D5LR, POTASSIUM CHLORIDE-0.45% NACL, POTASSIUM CHLORIDE-0.9% NACL, POTASSIUM CHLORIDE-DEXTROSE 5%, POTASSIUM CHLORIDE-WATER, POTASSIUM CITRATE, POTASSIUM CITRATE ER, POTASSIUM CL-LIDOCAINE-NS, POTASSIUM GLUCONATE, POTASSIUM PHOSPHATE, POTASSIUM PHOSPHATE-0.9% NACL, POTASSIUM PHOSPHATES, UROCIT-K |
| Drospirenone/Heparin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Drospirenone has antimineralocorticoid activity and may cause hyperkalemia. Heparin may also increase potassium levels.(1) CLINICAL EFFECTS: Concurrent use of drospirenone and heparin may result in hyperkalemia.(1) PREDISPOSING FACTORS: Renal insufficiency, hepatic dysfunction, adrenal insufficiency, and use of potassium supplements, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs, and potassium-sparing diuretics may increase potassium levels.(1) PATIENT MANAGEMENT: Patients receiving drospirenone with heparin should have their serum potassium level checked during the first treatment cycle. (1) DISCUSSION: Drospirenone has antimineralocorticoid activity comparable to 25 mg of spironolactone and may result in hyperkalemia. Concurrent use of heparin may also increase potassium levels.(1) |
HEPARIN SODIUM, HEPARIN SODIUM IN 0.45% NACL, HEPARIN SODIUM-0.45% NACL, HEPARIN SODIUM-0.9% NACL, HEPARIN SODIUM-D5W |
| Rasagiline (Less Than or Equal To 0.5 mg)/Selected CYP1A2 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2) DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5) |
AZILECT, RASAGILINE MESYLATE |
| Oral Contraceptives/Colesevelam SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Colesevelam may bind to oral contraceptives in the gastrointestinal track, preventing their absorption.(1,2) CLINICAL EFFECTS: Simultaneous administration of colesevelam may result in decreased levels and effectiveness of oral contraceptives.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Oral contraceptives should be administered four hours before colesevelam.(1) DISCUSSION: When administered with colesevelam (3.75 g), the area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol (0.035 mg) decreased by 24% and by 24%, respectively, and the AUC and Cmax of norethindrone (1 mg) decreased by 1% and 20%, respectively. When administered 1 hour prior to colesevelam, the AUC and Cmax of ethinyl estradiol decreased by 18% and 1%, respectively, the AUC of norethindrone increased by 5%, and the Cmax of norethindrone decreased by 3%. When administered 4 hours prior to colesevelam, the AUC of ethinyl decreased by 12% and the AUC and Cmax of norethindrone increased by 6% and 7%, respectively.(1,2) |
COLESEVELAM HCL, WELCHOL |
| Selected Human Immunoglobulins/Estrogens SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Concurrent use of human immunoglobulin with estrogens may have additive effects on clotting mechanisms.(1) CLINICAL EFFECTS: Concurrent use of human immunoglobulin with estrogens may increase the risk of thrombosis. Thrombosis may occur regardless of the route of administration of the immunoglobulin.(1) PREDISPOSING FACTORS: Additional risk factors include advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes).(1) PATIENT MANAGEMENT: For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1) DISCUSSION: Thrombosis has been associated with the use of human immunoglobulin and may occur without the presence of risk factors and regardless of the route of administration of the immunoglobulin. Risk factors known to increase the risk of thrombosis include the use of estrogens, advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes). For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1) |
ALYGLO, ASCENIV, BIVIGAM, CUTAQUIG, CUVITRU, FLEBOGAMMA DIF, GAMASTAN, GAMMAGARD LIQUID, GAMMAGARD S-D, GAMMAKED, GAMMAPLEX, GAMUNEX-C, HIZENTRA, HYQVIA, HYQVIA IG COMPONENT, OCTAGAM, PANZYGA, PRIVIGEN, XEMBIFY |
| Pirfenidone/Moderate CYP1A2 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1) Inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1) CLINICAL EFFECTS: Concurrent pirfenidone use with moderate inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1) PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).(1) The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1) PATIENT MANAGEMENT: The manufacturer of pirfenidone states that for concurrent use with moderate inhibitors of CYP1A2, dose reduction is recommended. Reduce the dose of pirfenidone to two-267 mg capsules three times a day (total daily dose of 1602 mg/day).(1) Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should be discontinued prior to and avoided during pirfenidone treatment.(1) DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(1) In a single-dose study in 27 healthy subjects, coadministration of 801 mg of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2) |
ESBRIET, PIRFENIDONE |
| Oral Contraceptives/Exenatide; Lixisenatide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Exenatide and lixisenatide delay gastric emptying, which may result in decreased oral contraceptive absorption.(1,2) CLINICAL EFFECTS: Exenatide and lixisenatide may result in decreased levels and effectiveness of oral contraceptives.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Oral contraceptives should be taken one hour before administering exenatide non-sustained release.(1) No recommendations are available for the timing of administration of extended-release exenatide and oral contraceptives.(3) Oral contraceptives should be taken one hour before or 11 hours after administering lixisenatide.(2) DISCUSSION: In a study in 32 healthy females, administration of an oral contraceptive 30 minutes after exenatide (5 mcg BID) decreased the maximum concentration (Cmax) of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively. Time to Cmax (Tmax) of ethinyl estradiol and levonorgestrel increased by 3 hours and 3.5 hours, respectively. Administering the oral contraceptive one hour before exenatide decreased the Cmax of ethinyl estradiol by 15%, but there was no effect on levonorgestrel. There was no significant effect on bioavailability with either regimen.(1,3,4) Administration of an oral contraceptive 1 hour before or 11 hours after lixisenatide had no effect on the pharmacokinetics of ethinyl estradiol or levonorgestrel. Administration of an oral contraceptive 1 hour or 4 hours after lixisenatide did not affect the area-under-curve (AUC) of ethinyl estradiol or levonorgestrel; however, the Cmax of ethinyl estradiol was decreased by 52% and 39%, respectively, and the Cmax of levonorgestrel decreased by 46% and 20%, respectively. Tmax was delayed by 1-3 hours.(2) |
EXENATIDE, SOLIQUA 100-33 |
| Thyroid Preparations/Estrogens SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Estrogens increase thyroxine-binding globulin (TBG) levels by increasing its biosynthesis and decreasing its clearance.(1) Hypothyroid patients who start estrogens may be unable to compensate for this increase and may have decreased serum free T4 (FT4) concentrations and increased TSH.(1,2) CLINICAL EFFECTS: The coadministration of thyroid preparations and estrogens may result in decreased levels and clinical effects of thyroid hormones.(1-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients taking thyroid preparations and who start or stop estrogens should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased.(1-4) DISCUSSION: In a prospective observational study, 25 post-menopausal women with hypothyroidism on stable levothyroxine therapy for at least 9 months started on estrogen replacement therapy. After 12 weeks, mean serum FT4 levels decreased significantly from 1.7 +/- 0.4 ng/dL to 1.4 +/-0.3 mg/dL and TSH increased significantly from 0.9 +/-1.1 to 3.2 +/- 3.1 milli-units/L.(1) |
ADTHYZA, ARMOUR THYROID, CYTOMEL, ERMEZA, EUTHYROX, LEVO-T, LEVOTHYROXINE SODIUM, LEVOTHYROXINE SODIUM DILUTION, LEVOXYL, LIOTHYRONINE SODIUM, NIVA THYROID, NP THYROID, PCCA T3 SODIUM DILUTION, PCCA T4 SODIUM DILUTION, SYNTHROID, THYQUIDITY, THYROID, TIROSINT, TIROSINT-SOL, UNITHROID |
| Tofacitinib (Less Than 20 mg daily)/Estrogens SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Estrogens increase the risk of thrombosis, and combining estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may place patients at high risk of thromboembolism.(1-3) CLINICAL EFFECTS: Concurrent use of estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may increase the incidence of pulmonary embolism and death.(1-3) PREDISPOSING FACTORS: Additional risk factors include advanced age, obesity (BMI greater than 30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.(1) PATIENT MANAGEMENT: The European manufacturer states that the 10 mg twice daily dose of tofacitinib is not recommended in patients who are on combined hormonal contraceptives or hormone replacement therapy, or who are otherwise at high risk of pulmonary embolism.(4) Patients at high risk of pulmonary embolism should be switched to alternative therapies. For the treatment of rheumatoid arthritis and psoriatic arthritis, the dose of tofacitinib should be limited to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4) The US FDA and Health Canada have not placed use restrictions specifically on concurrent use of tofacitinib with hormonal contraceptives or hormone replacement therapy. Both agencies advise avoiding tofacitinib in patients at increased risk of thrombosis. The US and Canadian manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile idiopathic arthritis. For the treatment of ulcerative colitis, the lowest effective dose for the shortest duration possible is recommended. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis and discontinue tofacitinib in patients with symptoms of thrombosis.(5-7) There is currently no use restriction on the combination of estrogens with lower doses of tofacitinib (less than 20 mg daily). DISCUSSION: In an ongoing open-label study comparing the safety of tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5 mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123 patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years, respectively). All-cause mortality was also higher in the tofacitinib 10 mg twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28 deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9 deaths/3,323 patient-years, respectively).(3) |
XELJANZ, XELJANZ XR |
| Tacrolimus/Moderate and Weak CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1) CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant assoc ation between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ration 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) Moderate CYP3A4 inhibitors linked to this monograph include: aprepitant, berotralstat, clofazimine, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: alprazolam, avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, estrogens, flibanserin, fosaprepitant, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, remdesivir, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, suvorexant, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6) |
ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL |
| Hormonal Contraceptives/Cannabidiol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cannabidiol (CBD) may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1) CLINICAL EFFECTS: Concurrent use of CBD may reduce the effectiveness of hormonal contraceptives.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal method of contraception or a back-up method of birth control during CBD therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: An in vitro, CYP induction study showed that CBD may increase expression of CYP3A4. The effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs may be decreased. Women should use a back-up method of birth control during CBD or THC therapy.(1) |
EPIDIOLEX |
| Ethinyl Estradiol (less than or equal to 30 mcg)/Fostemsavir SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The mechanism of action has not been described. CLINICAL EFFECTS: Coadministration of ethinyl estradiol and fostemsavir may increase the plasma concentrations and toxicities of ethinyl estradiol.(1) PREDISPOSING FACTORS: Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery. PATIENT MANAGEMENT: The manufacturer of fostemsavir states that the daily dose of ethinyl estradiol should not exceed 30 mcg when used in patients concurrently on fostemsavir.(1) DISCUSSION: In a study, coadministration of ethinyl estradiol 30 mcg/norethindrone 1.5 mg once daily and fostemsavir 600 mg twice daily increased the area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol by 1.4-fold and 1.39-fold, respectively. The exposure to norethindrone was not significantly different.(1) |
RUKOBIA |
| Hormonal Contraceptives/Tecovirimat SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Tecovirimat may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1,2) CLINICAL EFFECTS: Concurrent use of tecovirimat may reduce the effectiveness of hormonal contraceptives.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal method of contraception or a back-up method of birth control during and for 28 days after tecovirimat therapy.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3) DISCUSSION: In a pharmacokinetic study, tecovirimat decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam (a CYP3A4 substrate) by 39% and 32%, respectively. The effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs may be decreased. Women should use a back-up method of birth control during and for 28 days after tecovirimat therapy.(1) |
TPOXX (NATIONAL STOCKPILE) |
| Hormonal Contraceptives/Meropenem-Vaborbactam SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Meropenem-vaborbactam may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1,2) CLINICAL EFFECTS: Concurrent use of meropenem-vaborbactam may reduce the blood concentrations and effectiveness of hormonal contraceptives.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal method of contraception or an additional method of birth control during and for 28 days after meropenem-vaborbactam therapy.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2) DISCUSSION: There have been no studies evaluating the potential of meropenem-vaborbactam to interact with other drugs. In vitro data suggest that both meropenem and vaborbactam are weak CYP3A4 inducers.(1,2) |
VABOMERE |
| Ethinyl Estradiol (<= 20 mcg)/Avapritinib SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The mechanism of action has not been described. CLINICAL EFFECTS: Coadministration of ethinyl estradiol and avapritinib may increase the plasma concentrations and toxicities of ethinyl estradiol.(1) PREDISPOSING FACTORS: Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery. PATIENT MANAGEMENT: The manufacturer of avapritinib states that the daily dose of ethinyl estradiol should not exceed 20 mcg unless a higher dose is necessary.(1) DISCUSSION: In a study, coadministration of ethinyl estradiol 30 mcg/levonorgestrel 0.15 mg once daily and avapritinib 25 mg once daily increased the area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol by 1.15-fold and 1.46-fold, respectively.(1) |
AYVAKIT |
The following contraindication information is available for NIKKI (28) (ethinyl estradiol/drospirenone):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 19 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acute myocardial infarction |
| Adrenocortical insufficiency |
| Carcinoma of breast |
| Cerebrovascular accident |
| Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min |
| Chronic kidney disease stage 5 (failure) GFr<15 ml/min |
| Coronary artery disease |
| Deep venous thrombosis |
| Estrogen-dependent neoplasm |
| Malignant neoplasm of liver |
| Migraine with aura |
| Nephrotic syndrome |
| Porphyria |
| Predisposition to thrombosis |
| Pulmonary thromboembolism |
| Sickle cell disease |
| Thromboembolic disorder |
| Thrombophilia |
| Thrombophlebitis |
There are 16 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Benign hepatic cell adenoma |
| Cardiomyopathy |
| Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min |
| Diabetes mellitus |
| Disease of liver |
| Hereditary angioedema |
| History of deep vein thrombosis |
| History of pulmonary embolism |
| History of roux-en-Y gastric bypass |
| Hyperlipidemia |
| Hypertension |
| Invasive surgical procedure |
| Obesity |
| Retinal thrombosis |
| Tobacco smoker |
| Valvular heart disease |
There are 4 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Chloasma |
| Gallbladder disease |
| Hypertriglyceridemia |
| Kidney disease with likely reduction in glomerular filtration rate (GFr) |
The following adverse reaction information is available for NIKKI (28) (ethinyl estradiol/drospirenone):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 25 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abnormal vaginal bleeding Obstructive hyperbilirubinemia |
Hypertension |
| Rare/Very Rare |
|---|
|
Acute myocardial infarction Angioedema Arterial thrombosis Benign hepatic cell adenoma Carcinoma of breast Cerebral thrombosis Cerebrovascular accident Dysplasia of cervix Erythema multiforme Erythema nodosum Gallbladder disease Hemorrhagic stroke Hepatitis Hyperkalemia Hyperlipidemia Inflammatory bowel disease Malignant neoplasm of liver Pulmonary thromboembolism Retinal vascular occlusion Systemic lupus erythematosus Thromboembolic disorder Thrombotic disorder |
There are 19 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal distension Amenorrhea Breast engorgement Headache disorder Irregular menstrual periods Mastalgia |
Abdominal pain with cramps Fatigue Irritability Libido changes Migraine Mood changes Nausea Vomiting Weight gain |
| Rare/Very Rare |
|---|
|
Body fluid retention Chloasma Depression Hypertriglyceridemia |
The following precautions are available for NIKKI (28) (ethinyl estradiol/drospirenone):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
Although preliminary evidence suggested that oral contraceptives could cause serious fetal toxicity when administered to pregnant women, current evidence does not suggest an association between inadvertent use of oral contraceptives in early pregnancy and teratogenic effects (including cardiovascular and limb defects, which have been reported following use of sex hormones). In addition, extensive epidemiologic studies have revealed no increased risk of birth defects in neonates born to women who used estrogen-progestin contraceptives prior to pregnancy. However, since the risks of estrogen-progestin contraceptive use clearly outweigh any possible benefit in women who are pregnant, these agents are contraindicated in such women.
Although estrogens and/or progestins were previously used to treat threatened or habitual abortion, there is considerable evidence that estrogens are ineffective and no evidence from well-controlled studies that progestins are effective for these uses. Progestin-only or estrogen-progestin contraceptives should not be used to induce withdrawal bleeding as a test of pregnancy. Data concerning pregnancy outcomes following unsuccessful emergency postcoital contraception with estrogen-progestin combinations are limited, in part because such women may choose abortion following failure of postcoital contraception.
Pooled data from several controlled trials that followed pregnancies that occurred despite postcoital estrogen-progestin combinations indicate delivery of 45 healthy neonates, 1 neonate with absent left kidney, and 2 neonates with minor anomalies. In addition, numerous studies evaluating teratologic risk of conception during cyclic (routine) oral contraceptive regimens (for both currently available low-dose oral contraceptive regimens and older, high-dose preparations (e.g., 150 mcg of ethinyl estradiol daily) that are no longer available) indicate no increased fetal risks. Exposure to the amount of estrogen-progestin in postcoital contraceptive regimens is not large when compared with the total amount of the estrogen-progestin cyclic (routine) oral contraceptive regimens, and there currently is no evidence of substantial risk to the fetus with such short-term exposure.
Estrogen-progestin postcoital contraceptive regimens are contraindicated in pregnancy because of lack of efficacy, not because of adverse effects on the fetus. In women who have missed 2 consecutive menstrual periods during estrogen-progestin conventional-cycle contraceptive use, the drug should be withheld until pregnancy has been ruled out. In women using a fixed-combination extended-cycle oral contraceptive (e.g., LoSeasonique(R), Seasonale(R), Seasonique(R)), the possibility of pregnancy should be considered after one missed menstrual period.
When the woman has not adhered to the prescribed oral contraceptive regimen, the possibility of pregnancy should be considered after one missed menstrual period and the drug should be withheld until pregnancy has been ruled out. A back-up method of contraception should be instituted until the possibility of pregnancy has been eliminated. If pregnancy is confirmed, the woman should be informed of the potential hazard to the fetus and the advisability of continuing the pregnancy should be weighed against the risks of exposure of the fetus to the drugs.
Although estrogens and/or progestins were previously used to treat threatened or habitual abortion, there is considerable evidence that estrogens are ineffective and no evidence from well-controlled studies that progestins are effective for these uses. Progestin-only or estrogen-progestin contraceptives should not be used to induce withdrawal bleeding as a test of pregnancy. Data concerning pregnancy outcomes following unsuccessful emergency postcoital contraception with estrogen-progestin combinations are limited, in part because such women may choose abortion following failure of postcoital contraception.
Pooled data from several controlled trials that followed pregnancies that occurred despite postcoital estrogen-progestin combinations indicate delivery of 45 healthy neonates, 1 neonate with absent left kidney, and 2 neonates with minor anomalies. In addition, numerous studies evaluating teratologic risk of conception during cyclic (routine) oral contraceptive regimens (for both currently available low-dose oral contraceptive regimens and older, high-dose preparations (e.g., 150 mcg of ethinyl estradiol daily) that are no longer available) indicate no increased fetal risks. Exposure to the amount of estrogen-progestin in postcoital contraceptive regimens is not large when compared with the total amount of the estrogen-progestin cyclic (routine) oral contraceptive regimens, and there currently is no evidence of substantial risk to the fetus with such short-term exposure.
Estrogen-progestin postcoital contraceptive regimens are contraindicated in pregnancy because of lack of efficacy, not because of adverse effects on the fetus. In women who have missed 2 consecutive menstrual periods during estrogen-progestin conventional-cycle contraceptive use, the drug should be withheld until pregnancy has been ruled out. In women using a fixed-combination extended-cycle oral contraceptive (e.g., LoSeasonique(R), Seasonale(R), Seasonique(R)), the possibility of pregnancy should be considered after one missed menstrual period.
When the woman has not adhered to the prescribed oral contraceptive regimen, the possibility of pregnancy should be considered after one missed menstrual period and the drug should be withheld until pregnancy has been ruled out. A back-up method of contraception should be instituted until the possibility of pregnancy has been eliminated. If pregnancy is confirmed, the woman should be informed of the potential hazard to the fetus and the advisability of continuing the pregnancy should be weighed against the risks of exposure of the fetus to the drugs.
Estrogen-progestin contraceptives may decrease the quantity and quality of milk if given in the immediate postpartum period. Small amounts of the hormonal agents in estrogen-progestin contraceptives are distributed into milk and adverse effects such as jaundice and breast enlargement have been reported in nursing infants of women receiving cyclic regimens; therefore, because of the theoretical risk, some clinicians recommend that lactating women receiving high-dose postcoital contraceptive regimens use alternative milk sources for their infants for at least 24 hours after completion of the regimen. When possible, the use of cyclic estrogen-progestin contraceptives should be deferred until the infant has been weaned. Long-term follow-up after oral contraceptive use showed no apparent clinical effect on breast-feeding mothers or children whose mothers were breast-feeding and using oral contraceptives.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for NIKKI (28) (ethinyl estradiol/drospirenone):
WARNING: Do not use this medication if you smoke cigarettes/use tobacco and are over 35 years old. Smoking raises your risk of stroke, heart attack, blood clots, and high blood pressure from hormonal birth control (such as the pill, patch, ring). The risk of these serious problems increases with age and with the number of cigarettes you smoke. Do not smoke or use tobacco.
WARNING: Do not use this medication if you smoke cigarettes/use tobacco and are over 35 years old. Smoking raises your risk of stroke, heart attack, blood clots, and high blood pressure from hormonal birth control (such as the pill, patch, ring). The risk of these serious problems increases with age and with the number of cigarettes you smoke. Do not smoke or use tobacco.
The following icd codes are available for NIKKI (28) (ethinyl estradiol/drospirenone)'s list of indications:
| Acne vulgaris | |
| L70.0 | Acne vulgaris |
| Pregnancy contraception | |
| Z30 | Encounter for contraceptive management |
| Z30.01 | Encounter for initial prescription of contraceptives |
| Z30.011 | Encounter for initial prescription of contraceptive pills |
| Z30.013 | Encounter for initial prescription of injectable contraceptive |
| Z30.014 | Encounter for initial prescription of intrauterine contraceptive device |
| Z30.015 | Encounter for initial prescription of vaginal ring hormonal contraceptive |
| Z30.016 | Encounter for initial prescription of transdermal patch hormonal contraceptive device |
| Z30.017 | Encounter for initial prescription of implantable subdermal contraceptive |
| Z30.018 | Encounter for initial prescription of other contraceptives |
| Z30.019 | Encounter for initial prescription of contraceptives, unspecified |
| Z30.4 | Encounter for surveillance of contraceptives |
| Z30.40 | Encounter for surveillance of contraceptives, unspecified |
| Z30.41 | Encounter for surveillance of contraceptive pills |
| Z30.42 | Encounter for surveillance of injectable contraceptive |
| Z30.43 | Encounter for surveillance of intrauterine contraceptive device |
| Z30.430 | Encounter for insertion of intrauterine contraceptive device |
| Z30.431 | Encounter for routine checking of intrauterine contraceptive device |
| Z30.433 | Encounter for removal and reinsertion of intrauterine contraceptive device |
| Z30.44 | Encounter for surveillance of vaginal ring hormonal contraceptive device |
| Z30.45 | Encounter for surveillance of transdermal patch hormonal contraceptive device |
| Z30.46 | Encounter for surveillance of implantable subdermal contraceptive |
| Z30.49 | Encounter for surveillance of other contraceptives |
| Z30.8 | Encounter for other contraceptive management |
| Z30.9 | Encounter for contraceptive management, unspecified |
| Z79.3 | Long term (current) use of hormonal contraceptives |
| Z97.5 | Presence of (intrauterine) contraceptive device |
| Premenstrual dysphoric disorder | |
| F32.81 | Premenstrual dysphoric disorder |
Formulary Reference Tool