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Drug overview for COMBIPATCH (estradiol/norethindrone acetate):
Generic name: ESTRADIOL/NORETHINDRONE ACETATE (ES-tra-DYE-ol/nor-ETH-in-drone AS-e-tate)
Drug class: Estrogens
Therapeutic class: Endocrine
Estrogen-progestin combinations are contraceptive combinations containing estrogenic and progestinic steroids.
No enhanced Uses information available for this drug.
Generic name: ESTRADIOL/NORETHINDRONE ACETATE (ES-tra-DYE-ol/nor-ETH-in-drone AS-e-tate)
Drug class: Estrogens
Therapeutic class: Endocrine
Estrogen-progestin combinations are contraceptive combinations containing estrogenic and progestinic steroids.
No enhanced Uses information available for this drug.
DRUG IMAGES
COMBIPATCH 0.05-0.14 MG PTCH
COMBIPATCH 0.05-0.25 MG PTCH
The following indications for COMBIPATCH (estradiol/norethindrone acetate) have been approved by the FDA:
Indications:
Atrophic vaginitis associated with menopause
Atrophy of vulva
Female hypogonadism
Hypoestrogenism due to bilateral oophorectomy
Primary ovarian failure
Vasomotor symptoms associated with menopause
Professional Synonyms:
Female hypogonadism syndrome
Senile vaginitis
Vaginitis senilis
Indications:
Atrophic vaginitis associated with menopause
Atrophy of vulva
Female hypogonadism
Hypoestrogenism due to bilateral oophorectomy
Primary ovarian failure
Vasomotor symptoms associated with menopause
Professional Synonyms:
Female hypogonadism syndrome
Senile vaginitis
Vaginitis senilis
The following dosing information is available for COMBIPATCH (estradiol/norethindrone acetate):
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 |
|---|---|---|
| COMBIPATCH 0.05-0.14 MG PTCH | Maintenance | Adults apply 1 patch by transdermal route twice weekly |
| COMBIPATCH 0.05-0.25 MG PTCH | Maintenance | Adults apply 1 patch by transdermal route twice weekly |
No generic dosing information available.
The following drug interaction information is available for COMBIPATCH (estradiol/norethindrone acetate):
There are 5 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 |
| 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 6 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 |
|---|---|
| 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 |
| Lamotrigine/Estrogen Replacement Therapy 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 estrogens.(1,2) CLINICAL EFFECTS: Concurrent use of lamotrigine and estrogens 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. PATIENT MANAGEMENT: During initiation of lamotrigine therapy, no adjustments to the recommended lamotrigine dose escalation guidelines are recommended in patients taking estrogen.(1) Dose adjustments will be necessary in most patients who start or stop an estrogen 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 or 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 is 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 is initiated or discontinued.(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.(8) |
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) |
| Progestin Replacement Therapy/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 progesterone products ineffective.(1,2) These agents may also make ulipristal ineffective.(3) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Products containing progestin should not be used within 12 days of ulipristal discontinuation.(3) DISCUSSION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity, thus it may interfere with the efficacy of progestin products.(1-3) These products may also make ulipristal ineffective.(3) |
ELLA |
| 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 |
| 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 |
| 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 |
There are 11 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 |
| Selected Anticonvulsants; Barbiturates/Estrogens SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Enzyme induction, causing increased hepatic metabolism of estrogens. CLINICAL EFFECTS: Decreased effectiveness of estrogens may lead to spotting, breakthrough bleeding, vaginitis and may increase the risk for osteoporosis. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Increasing the dose of estrogen may be sufficient. DISCUSSION: Decreased effectiveness of estrogens characterized by spotting, breakthrough bleeding or vaginitis have been documented during concurrent administration of barbiturates and hydantoins. Primidone is metabolized to phenobarbital. Additionally, lowered estrogen levels may increase the risk of osteoporosis. Often, patients are receiving multiple anticonvulsant drugs making it difficult to quantify the frequency of this interaction. However, decreases in the area under the plasma concentration-time curves for ethinyl estradiol and levonorgestrel have been documented during concurrent administration of phenytoin. |
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, FIORICET, FIORICET WITH CODEINE, FOSPHENYTOIN SODIUM, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIMIDONE, SEZABY, TENCON |
| 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 |
| 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 |
| 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 |
| Estrogen Replacement Therapy/Rifamycins SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Rifamycins (rifampin, rifabutin and rifapentine) induce the the CYP3A4 mediated metabolism of estrogens and progestins. CLINICAL EFFECTS: Concurrent use of rifampin, rifabutin, or rifapentine may result in reduced levels and clinical effectiveness of hormone replacement therapy. 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 of their hormone replacement therapy. The patient should be asked to report any spotting or bleeding. 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 ethinyloestradiol. 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. |
PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA |
| 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, RENTHYROID, 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 |
The following contraindication information is available for COMBIPATCH (estradiol/norethindrone acetate):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 13 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| 30 day risk period post-myocardial infarction |
| Abnormal uterine bleeding |
| Acute myocardial infarction |
| Carcinoma of breast |
| Cerebrovascular accident |
| Deep venous thrombosis |
| Disease of liver |
| Endometrial carcinoma |
| Estrogen-dependent neoplasm |
| Porphyria |
| Pregnancy |
| Thromboembolic disorder |
| Thrombotic disorder |
There are 17 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Acute myocardial infarction |
| Cerebrovascular accident |
| Coronary artery disease |
| Deep venous thrombosis |
| Disease of liver |
| Edema |
| Hereditary angioedema |
| Migraine |
| Obesity |
| Papilledema |
| Predisposition to thrombosis |
| Pulmonary thromboembolism |
| Systemic lupus erythematosus |
| Thromboembolic disorder |
| Thrombophlebitis |
| Tobacco smoker |
| Valvular heart disease |
There are 15 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Chronic heart failure |
| Depression |
| Diabetes mellitus |
| Family history of malignant tumor of breast |
| Gallbladder disease |
| Hypercholesterolemia |
| Hyperlipidemia |
| Hypertension |
| Hypertriglyceridemia |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Mammography abnormal |
| Migraine |
| Obesity |
| Seizure disorder |
| Unspecified lump in breast |
The following adverse reaction information is available for COMBIPATCH (estradiol/norethindrone acetate):
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 48 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal distension Abnormal vaginal bleeding Irregular menstrual periods |
Endometrial hyperplasia Gastroenteritis |
| Rare/Very Rare |
|---|
|
Abnormal hepatic function tests Acute myocardial infarction Acute pancreatitis Anaphylaxis Angina Angioedema Asthma exacerbation Cerebrovascular accident Chorea Deep venous thrombosis Dementia Depression Ectopic pregnancy Endometrial carcinoma Endometrial hyperplasia Epithelial ovarian cancer Erythema multiforme Erythema nodosum Fibrocystic breast disease Galactorrhea not associated with childbirth Gallbladder obstruction Hepatitis Hypercalcemia Hypersensitivity drug reaction Hypertension Hypertriglyceridemia Hypocalcemia Malignant neoplasm of the ovary Menorrhagia Neoplasm of breast Nipple discharge Obstructive hyperbilirubinemia Optic neuritis Ovarian cyst Pancreatitis Pharyngeal edema Pruritus of skin Pulmonary thromboembolism Purpura Retinal thrombosis Thromboembolic disorder Thrombophlebitis Ventricular premature beats |
There are 92 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal distension Abnormal vaginal bleeding Back pain Edema Fatigue Headache disorder Infection Mastalgia Myalgia Peripheral edema Pharyngitis Pruritus of skin Upper respiratory infection Vaginitis Weight gain Weight loss |
Back pain Bronchitis Cervical discharge Constipation Dizziness Dyspepsia Ectropion of cervix Hypertonia Libido changes Migraine Nausea Neck pain Pain in extremities Palpitations Sinusitis Skin irritation Vaginal discharge Vaginitis Vomiting Vulvovaginal candidiasis |
| Rare/Very Rare |
|---|
|
Abdominal pain with cramps Acne vulgaris Alopecia Amenorrhea Arthralgia Body fluid retention Cervical discharge Chloasma Constipation Cramps in legs Cystitis Depression Diarrhea Drowsy Dry skin Dyspnea Erythema Fallopian tube disorder Fatigue Fever Fibrocystic breast disease Flatulence Flu-like symptoms Galactorrhea not associated with childbirth General weakness Gynecomastia Hirsutism Hyperglycemia Hyperhidrosis Insomnia Irritability Malaise Mastalgia Menorrhagia Migraine Mood changes Muscle spasm Nausea Nervousness Oral hypoesthesia Ovarian cyst Pain in extremities Palpitations Paresthesia Pelvic pain Skin pigmentation enhancement Skin rash Tachycardia Tongue swelling Urinary incontinence Urticaria Uterine cramps Uterine leiomyoma Varicose veins Vertigo Weight gain |
The following precautions are available for COMBIPATCH (estradiol/norethindrone acetate):
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 COMBIPATCH (estradiol/norethindrone acetate):
WARNING: Estrogens, either used alone or with a progestin, have rarely caused very serious side effects. Discuss the risks and benefits of hormone treatment with your doctor. Estrogens and progestins should not be used to prevent heart disease or dementia.
In postmenopausal women, estrogen when used with a progestin can increase the risk of heart disease (such as heart attacks), stroke, serious blood clots in the lungs/legs, dementia, and cancer of the breast/ovaries. The risk for serious side effects may depend on the dose of estrogen and the length of time it is used. This medication should be used at the lowest effective dose and for the shortest amount of time.
Discuss the use of this medication with your doctor regularly (for example, every 3 to 6 months) to see if you still need to use it. If you will be using this medication long-term, you should have regular complete physical exams (for example, once a year) as directed by your doctor. See also Notes section.
WARNING: Estrogens, either used alone or with a progestin, have rarely caused very serious side effects. Discuss the risks and benefits of hormone treatment with your doctor. Estrogens and progestins should not be used to prevent heart disease or dementia.
In postmenopausal women, estrogen when used with a progestin can increase the risk of heart disease (such as heart attacks), stroke, serious blood clots in the lungs/legs, dementia, and cancer of the breast/ovaries. The risk for serious side effects may depend on the dose of estrogen and the length of time it is used. This medication should be used at the lowest effective dose and for the shortest amount of time.
Discuss the use of this medication with your doctor regularly (for example, every 3 to 6 months) to see if you still need to use it. If you will be using this medication long-term, you should have regular complete physical exams (for example, once a year) as directed by your doctor. See also Notes section.
The following icd codes are available for COMBIPATCH (estradiol/norethindrone acetate)'s list of indications:
| Atrophic vaginitis associated with menopause | |
| N95.2 | Postmenopausal atrophic vaginitis |
| Atrophy of vulva | |
| N90.5 | Atrophy of vulva |
| Female hypogonadism | |
| E28.39 | Other primary ovarian failure |
| Hypoestrogenism due to bilateral oophorectomy | |
| E89.4 | Postprocedural ovarian failure |
| E89.40 | Asymptomatic postprocedural ovarian failure |
| E89.41 | Symptomatic postprocedural ovarian failure |
| Primary ovarian failure | |
| E28.3 | Primary ovarian failure |
| E28.31 | Premature menopause |
| E28.310 | Symptomatic premature menopause |
| E28.319 | Asymptomatic premature menopause |
| E28.39 | Other primary ovarian failure |
| Vasomotor symptoms associated with menopause | |
| N95.1 | Menopausal and female climacteric states |
| N95.9 | Unspecified menopausal and perimenopausal disorder |
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