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Drug overview for ELESTRIN (estradiol):
Generic name: ESTRADIOL (ES-tra-DYE-ol)
Drug class: Estrogens
Therapeutic class: Endocrine
Estradiol (a principal endogenous estrogen) is a steroidal estrogen.
No enhanced Uses information available for this drug.
Generic name: ESTRADIOL (ES-tra-DYE-ol)
Drug class: Estrogens
Therapeutic class: Endocrine
Estradiol (a principal endogenous estrogen) is a steroidal estrogen.
No enhanced Uses information available for this drug.
DRUG IMAGES
ELESTRIN 0.06% GEL
The following indications for ELESTRIN (estradiol) have been approved by the FDA:
Indications:
Vasomotor symptoms associated with menopause
Professional Synonyms:
None.
Indications:
Vasomotor symptoms associated with menopause
Professional Synonyms:
None.
The following dosing information is available for ELESTRIN (estradiol):
Dosage of estradiol, estradiol acetate, estradiol cypionate, estradiol valerate, and ethinyl estradiol must be individualized according to the condition being treated and the tolerance and therapeutic response of the patient. To minimize the risk of adverse effects, the lowest possible effective dosage should be used. When short-term estrogen therapy is indicated (e.g., for the management of vasomotor symptoms associated with menopause; vulvar and vaginal atrophy), therapy should be discontinued as soon as possible; attempts to reduce dosage or discontinue the drug should be made at 3- to 6-month intervals.
Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, estrogen and estrogen/progestin therapy should be limited to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman. Estrogen and estrogen/progestin therapy should be periodically reevaluated.
Estrogen therapy is administered continuously or cyclically. While estrogen therapy alone may be appropriate in women who have undergone a hysterectomy, many clinicians currently recommend that a progestin be added to estrogen therapy in women with an intact uterus. Addition of progestin therapy for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen reduces the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in women with an intact uterus.
Morphologic and biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hyperplastic changes. The manufacturer of Menostar(R) recommends that women with an intact uterus receive a progestin for 14 days every 6-12 months. When a progestin is used in conjunction with an estrogen, the usual precautions associated with progestin therapy should be observed.
Clinicians prescribing progestins should be aware of the risks associated with these drugs and the manufacturers' labeling should be consulted. The choice and dosage of a progestin may be important factors in minimizing adverse effects.
When long-acting parenteral preparations are used in the management of conditions associated with estrogen deficiency, the drugs are usually administered once every 3-4 weeks.
For the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial oral dosage of estradiol is 1 or 2 mg daily in a cyclic regimen. For replacement therapy in female hypogonadism, female castration, or primary ovarian failure, the usual initial oral dosage of estradiol is 1 or 2 mg daily. Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective maintenance dosage.
For the prevention of osteoporosis, an oral dosage of estradiol 0.5 mg daily in a cyclic regimen has been used. The lowest effective dosage of estradiol for this indication has not been determined.
When estradiol is used in fixed combination with norethindrone acetate (Activella(R)) for the management of moderate to severe vasomotor symptoms associated with menopause, the management of vulvar and vaginal atrophy associated with menopause, or prevention of postmenopausal osteoporosis, the usual dosage is 1 mg of estradiol combined with 0.5 mg of norethindrone acetate daily.
When estradiol is used in fixed combination with drospirenone (Angeliq(R)) for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy associated with menopause, the usual dosage is 1 mg of estradiol combined with 0.5 mg of drospirenone daily.
When estradiol is used with norgestimate (Prefest(R)) for the management of moderate to severe vasomotor symptoms associated with menopause, the management of vulvar and vaginal atrophy associated with menopause, or prevention of postmenopausal osteoporosis, the usual dosage is 1 mg of estradiol daily for 3 days followed by 1 mg of estradiol with 0.09 mg of norgestimate daily for 3 days; the regimen is continued without interruption.
For the palliative treatment of advanced, metastatic carcinoma of the breast in appropriately selected men and postmenopausal women, the usual oral dosage of estradiol is 10 mg 3 times daily. Estrogen therapy is usually continued in these patients for at least 3 months.
For the palliative treatment of advanced carcinoma of the prostate, the usual oral dosage of estradiol is 1-2 mg 3 times daily.
Transdermal estradiol is commercially available as systems that are applied once or twice weekly. Estradiol transdermal systems that are applied twice weekly include Alora(R) (available as a system delivering 0.025 mg/24 hours, 0.05 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours), Estraderm(R) (available as a system delivering 0.05 mg/24 hours or 0.1 mg/24 hours), and Vivelle(R) and Vivelle-Dot(R) (available as a system delivering 0.025 mg/24 hours, 0.0375 mg/24 hours, 0.05 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours). Estradiol transdermal systems that are applied once weekly include Climara(R) (available as a system delivering 0.025 mg/24 hours, 0.0375 mg/24 hours, 0.05 mg/24 hours, 0.06 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours) and Menostar(R) (available as a system delivering 0.014 mg/24 hours).
In addition, transdermal estradiol/norethindrone (CombiPatch(R)) is commercially available as a system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate and as a system delivering 0.05
mg/24 hours of estradiol and 0.25 mg/24 hours of norethindrone acetate. Transdermal estradiol/levonorgestrel (Climara Pro(R)) is commercially available as a system delivering 0.045
mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel.
When Alora(R) or Estraderm(R) is used for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial dosage of transdermal estradiol is one system delivering 0.05 mg/24 hours applied twice weekly in a continuous regimen in women who have undergone a hysterectomy or a cyclic regimen (3 weeks on drug followed by 1 week without the drug, and then the regimen is repeated as necessary) in women with an intact uterus.
When Climara(R) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the usual initial dosage of transdermal estradiol is one system delivering 0.025 mg/24 hours applied once weekly in a continuous regimen. Subsequent dosage should be adjusted according to the severity of the symptoms and the patient's therapeutic response, using the lowest possible effective maintenance dosage.
When Vivelle(R) or Vivelle-Dot(R) is used for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial dosage of transdermal estradiol is one system delivering 0.0375 mg/24 hours applied twice weekly in a cyclic or continuous regimen. Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective maintenance dosage.
In women who have undergone hysterectomy, transdermal estradiol Vivelle-Dot(R) may be applied twice a week in a continuous regimen.
When estradiol/levonorgestrel (Climara Pro(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus, one system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel is applied once weekly in a continuous regimen.
When estradiol/norethindrone acetate (CombiPatch(R)) is used for the management of moderate to severe vasomotor systems associated with menopause, for the management of vulvar and vaginal atrophy, or for the treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure, CombiPatch(R) may be administered as a continuous combined regimen or as a continuous sequential regimen. In the continuous combined regimen, one CombiPatch(R) system delivering 0.05 mg/24 hours of estradiol and 0.14
mg/24 hours of norethindrone acetate is applied twice weekly in a continuous regimen. If necessary, the dosage of norethindrone acetate may be increased by using the dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.
In the continuous sequential regimen, one system of transdermal estradiol delivering 0.05 mg/24 hours (i.e., Vivelle(R)) is applied twice weekly for the first 14 days of a 28-day cycle then one estradiol/norethindrone acetate (CombiPatch(R)) system delivering 0.05 mg/24 hours of estradiol and 0.14
mg/24 hours of norethindrone acetate is applied twice weekly for the remaining 14 days of the cycle. If necessary, the dosage of norethindrone acetate may be increased by using the dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.
When Alora(R) is used for the prevention of postmenopausal osteoporosis, the minimum dose that has been shown to be effective is one system delivering 0.025 mg/24 hours applied twice weekly in a continuous regimen.
When Climara(R) is used for the prevention of postmenopausal osteoporosis, the minimum dose that has been shown to be effective is one system delivering 0.025 mg/24 hours applied once weekly in a continuous regimen.
For the prevention of osteoporosis, the usual initial dosage of transdermal estradiol (Estraderm(R)) is one system delivering 0.05 mg/24 hours applied twice weekly in a cyclic regimen in women with an intact uterus. In women who have undergone hysterectomy, one Estraderm(R) system is applied twice weekly in a continuous regimen.
Subsequent dosage can be adjusted according to the patient's response.
For the prevention of osteoporosis, the usual dosage of transdermal estradiol (Menostar(R)) is one system delivering 0.014 mg/24 hours applied once weekly in a continuous regimen.
When Vivelle(R) or Vivelle-Dot(R) is used for the prevention of postmenopausal osteoporosis, the usual dosage is one system delivering 0.025 mg/24 hours applied twice weekly.
When estradiol/levonorgestrel (Climara Pro(R)) is used for the prevention of postmenopausal osteoporosis in women with an intact uterus, one system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel is applied once weekly in a continuous regimen.
In women who are currently not receiving an oral estrogen, transdermal estradiol therapy can be initiated immediately. In women who are currently receiving an oral estrogen, transdermal estradiol therapy can be initiated 1 week after discontinuance of oral therapy or sooner if symptoms reappear before the week has passed.
Commercially available estradiol 0.06% topical gel (Elestrin(R)) is supplied in a non-aerosol metered-dose pump. Each depression of the pump delivers 0.87
g of gel containing 0.52 mg of estradiol. When estradiol gel (Elestrin(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the usual initial dosage is 0.87
g of gel (0.52 mg of estradiol) applied topically once daily. Prior to using the pump for the first time, the pump must be primed by fully depressing the pump 10 times; this gel should be discarded in a manner that avoids accidental exposure or ingestion by household members or pets.
Commercially available estradiol 0.06% topical gel (EstroGel(R)) is supplied in a non-aerosol metered-dose pump. Each depression of the pump delivers 1.25
g of gel containing 0.75 mg of estradiol. When estradiol gel (EstroGel(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause or the treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause, 1.25
g of gel (0.75 mg of estradiol) is applied topically once daily. Prior to using the pump for the first time, the pump must be primed by fully depressing the 93-g pump twice or depressing the 25-g pump 3 times; this gel should be discarded in a manner that avoids accidental exposure or ingestion by household members or pets.
Commercially available estradiol hemihydrate 0.25% topical emulsion (Estrasorb(R)) is supplied in foil-laminated pouches. Each pouch contains 1.74
g of emulsion. When estradiol topical emulsion (Estrasorb(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the contents of 2 pouches (delivering a total of 0.05 mg of estradiol/24 hours) are applied topically once daily.
Commercially available estradiol transdermal spray (Evamist(R)) is supplied in a metered-dose pump. The metered pump delivers a metered 90-mcL spray that contains 1.53 mg of estradiol per actuation.
When estradiol transdermal spray is used for the management of moderate to severe vasomotor symptoms associated with menopause, the recommended initial dose is one spray to the inner forearm once daily. Subsequent dosage is based on clinical response. One, two, or three sprays may be administered each morning to adjacent, non-overlapping areas of the inner forearm.
For the management of symptoms of vulvar and vaginal atrophy associated with menopause, 2-4 g of estradiol vaginal cream may be administered intravaginally once daily for 1-2 weeks, then gradually reduced to one-half the initial dosage for a similar period. Maintenance dosages of 1 g of estradiol vaginal cream administered intravaginally 1-3 times weekly may be used after restoration of the vaginal mucosa has occurred.
When estradiol vaginal ring (Estring(R)) is used for the management of postmenopausal urogenital symptoms, one ring (delivering estradiol 0.0075 mg/24 hours) is inserted into the upper third of the vaginal vault; the ring is to remain in place for 3 months. After 3 months, the ring should be removed and, if appropriate, replaced with a new ring. If the ring is expelled, the ring should be rinsed in lukewarm water and reinserted.
For the management of atrophic vaginitis, one vaginal tablet containing 25 mcg of estradiol (Vagifem(R)) is inserted intravaginally once daily (preferably at the same time each day) for 2 weeks (initial dosage). For maintenance therapy for this condition, one vaginal tablet containing 25 mcg of the drug is inserted intravaginally twice weekly.
Because of the potential increased risk of cardiovascular events, breast cancer, and venous thromboembolic events, estrogen and estrogen/progestin therapy should be limited to the lowest effective doses and shortest duration of therapy consistent with treatment goals and risks for the individual woman. Estrogen and estrogen/progestin therapy should be periodically reevaluated.
Estrogen therapy is administered continuously or cyclically. While estrogen therapy alone may be appropriate in women who have undergone a hysterectomy, many clinicians currently recommend that a progestin be added to estrogen therapy in women with an intact uterus. Addition of progestin therapy for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen reduces the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in women with an intact uterus.
Morphologic and biochemical studies of the endometrium suggest that 10-13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hyperplastic changes. The manufacturer of Menostar(R) recommends that women with an intact uterus receive a progestin for 14 days every 6-12 months. When a progestin is used in conjunction with an estrogen, the usual precautions associated with progestin therapy should be observed.
Clinicians prescribing progestins should be aware of the risks associated with these drugs and the manufacturers' labeling should be consulted. The choice and dosage of a progestin may be important factors in minimizing adverse effects.
When long-acting parenteral preparations are used in the management of conditions associated with estrogen deficiency, the drugs are usually administered once every 3-4 weeks.
For the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial oral dosage of estradiol is 1 or 2 mg daily in a cyclic regimen. For replacement therapy in female hypogonadism, female castration, or primary ovarian failure, the usual initial oral dosage of estradiol is 1 or 2 mg daily. Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective maintenance dosage.
For the prevention of osteoporosis, an oral dosage of estradiol 0.5 mg daily in a cyclic regimen has been used. The lowest effective dosage of estradiol for this indication has not been determined.
When estradiol is used in fixed combination with norethindrone acetate (Activella(R)) for the management of moderate to severe vasomotor symptoms associated with menopause, the management of vulvar and vaginal atrophy associated with menopause, or prevention of postmenopausal osteoporosis, the usual dosage is 1 mg of estradiol combined with 0.5 mg of norethindrone acetate daily.
When estradiol is used in fixed combination with drospirenone (Angeliq(R)) for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy associated with menopause, the usual dosage is 1 mg of estradiol combined with 0.5 mg of drospirenone daily.
When estradiol is used with norgestimate (Prefest(R)) for the management of moderate to severe vasomotor symptoms associated with menopause, the management of vulvar and vaginal atrophy associated with menopause, or prevention of postmenopausal osteoporosis, the usual dosage is 1 mg of estradiol daily for 3 days followed by 1 mg of estradiol with 0.09 mg of norgestimate daily for 3 days; the regimen is continued without interruption.
For the palliative treatment of advanced, metastatic carcinoma of the breast in appropriately selected men and postmenopausal women, the usual oral dosage of estradiol is 10 mg 3 times daily. Estrogen therapy is usually continued in these patients for at least 3 months.
For the palliative treatment of advanced carcinoma of the prostate, the usual oral dosage of estradiol is 1-2 mg 3 times daily.
Transdermal estradiol is commercially available as systems that are applied once or twice weekly. Estradiol transdermal systems that are applied twice weekly include Alora(R) (available as a system delivering 0.025 mg/24 hours, 0.05 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours), Estraderm(R) (available as a system delivering 0.05 mg/24 hours or 0.1 mg/24 hours), and Vivelle(R) and Vivelle-Dot(R) (available as a system delivering 0.025 mg/24 hours, 0.0375 mg/24 hours, 0.05 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours). Estradiol transdermal systems that are applied once weekly include Climara(R) (available as a system delivering 0.025 mg/24 hours, 0.0375 mg/24 hours, 0.05 mg/24 hours, 0.06 mg/24 hours, 0.075 mg/24 hours, or 0.1 mg/24 hours) and Menostar(R) (available as a system delivering 0.014 mg/24 hours).
In addition, transdermal estradiol/norethindrone (CombiPatch(R)) is commercially available as a system delivering 0.05 mg/24 hours of estradiol and 0.14 mg/24 hours of norethindrone acetate and as a system delivering 0.05
mg/24 hours of estradiol and 0.25 mg/24 hours of norethindrone acetate. Transdermal estradiol/levonorgestrel (Climara Pro(R)) is commercially available as a system delivering 0.045
mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel.
When Alora(R) or Estraderm(R) is used for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial dosage of transdermal estradiol is one system delivering 0.05 mg/24 hours applied twice weekly in a continuous regimen in women who have undergone a hysterectomy or a cyclic regimen (3 weeks on drug followed by 1 week without the drug, and then the regimen is repeated as necessary) in women with an intact uterus.
When Climara(R) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the usual initial dosage of transdermal estradiol is one system delivering 0.025 mg/24 hours applied once weekly in a continuous regimen. Subsequent dosage should be adjusted according to the severity of the symptoms and the patient's therapeutic response, using the lowest possible effective maintenance dosage.
When Vivelle(R) or Vivelle-Dot(R) is used for the management of moderate to severe vasomotor symptoms associated with menopause or for the management of vulvar and vaginal atrophy, the usual initial dosage of transdermal estradiol is one system delivering 0.0375 mg/24 hours applied twice weekly in a cyclic or continuous regimen. Subsequent dosage should be adjusted according to the patient's therapeutic response, using the lowest possible effective maintenance dosage.
In women who have undergone hysterectomy, transdermal estradiol Vivelle-Dot(R) may be applied twice a week in a continuous regimen.
When estradiol/levonorgestrel (Climara Pro(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus, one system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel is applied once weekly in a continuous regimen.
When estradiol/norethindrone acetate (CombiPatch(R)) is used for the management of moderate to severe vasomotor systems associated with menopause, for the management of vulvar and vaginal atrophy, or for the treatment of hypoestrogenism secondary to hypogonadism, castration, or primary ovarian failure, CombiPatch(R) may be administered as a continuous combined regimen or as a continuous sequential regimen. In the continuous combined regimen, one CombiPatch(R) system delivering 0.05 mg/24 hours of estradiol and 0.14
mg/24 hours of norethindrone acetate is applied twice weekly in a continuous regimen. If necessary, the dosage of norethindrone acetate may be increased by using the dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.
In the continuous sequential regimen, one system of transdermal estradiol delivering 0.05 mg/24 hours (i.e., Vivelle(R)) is applied twice weekly for the first 14 days of a 28-day cycle then one estradiol/norethindrone acetate (CombiPatch(R)) system delivering 0.05 mg/24 hours of estradiol and 0.14
mg/24 hours of norethindrone acetate is applied twice weekly for the remaining 14 days of the cycle. If necessary, the dosage of norethindrone acetate may be increased by using the dosage system that delivers 0.25 mg/24 hours of norethindrone acetate.
When Alora(R) is used for the prevention of postmenopausal osteoporosis, the minimum dose that has been shown to be effective is one system delivering 0.025 mg/24 hours applied twice weekly in a continuous regimen.
When Climara(R) is used for the prevention of postmenopausal osteoporosis, the minimum dose that has been shown to be effective is one system delivering 0.025 mg/24 hours applied once weekly in a continuous regimen.
For the prevention of osteoporosis, the usual initial dosage of transdermal estradiol (Estraderm(R)) is one system delivering 0.05 mg/24 hours applied twice weekly in a cyclic regimen in women with an intact uterus. In women who have undergone hysterectomy, one Estraderm(R) system is applied twice weekly in a continuous regimen.
Subsequent dosage can be adjusted according to the patient's response.
For the prevention of osteoporosis, the usual dosage of transdermal estradiol (Menostar(R)) is one system delivering 0.014 mg/24 hours applied once weekly in a continuous regimen.
When Vivelle(R) or Vivelle-Dot(R) is used for the prevention of postmenopausal osteoporosis, the usual dosage is one system delivering 0.025 mg/24 hours applied twice weekly.
When estradiol/levonorgestrel (Climara Pro(R)) is used for the prevention of postmenopausal osteoporosis in women with an intact uterus, one system delivering 0.045 mg/24 hours of estradiol and 0.015 mg/24 hours of levonorgestrel is applied once weekly in a continuous regimen.
In women who are currently not receiving an oral estrogen, transdermal estradiol therapy can be initiated immediately. In women who are currently receiving an oral estrogen, transdermal estradiol therapy can be initiated 1 week after discontinuance of oral therapy or sooner if symptoms reappear before the week has passed.
Commercially available estradiol 0.06% topical gel (Elestrin(R)) is supplied in a non-aerosol metered-dose pump. Each depression of the pump delivers 0.87
g of gel containing 0.52 mg of estradiol. When estradiol gel (Elestrin(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the usual initial dosage is 0.87
g of gel (0.52 mg of estradiol) applied topically once daily. Prior to using the pump for the first time, the pump must be primed by fully depressing the pump 10 times; this gel should be discarded in a manner that avoids accidental exposure or ingestion by household members or pets.
Commercially available estradiol 0.06% topical gel (EstroGel(R)) is supplied in a non-aerosol metered-dose pump. Each depression of the pump delivers 1.25
g of gel containing 0.75 mg of estradiol. When estradiol gel (EstroGel(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause or the treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause, 1.25
g of gel (0.75 mg of estradiol) is applied topically once daily. Prior to using the pump for the first time, the pump must be primed by fully depressing the 93-g pump twice or depressing the 25-g pump 3 times; this gel should be discarded in a manner that avoids accidental exposure or ingestion by household members or pets.
Commercially available estradiol hemihydrate 0.25% topical emulsion (Estrasorb(R)) is supplied in foil-laminated pouches. Each pouch contains 1.74
g of emulsion. When estradiol topical emulsion (Estrasorb(R)) is used for the management of moderate to severe vasomotor symptoms associated with menopause, the contents of 2 pouches (delivering a total of 0.05 mg of estradiol/24 hours) are applied topically once daily.
Commercially available estradiol transdermal spray (Evamist(R)) is supplied in a metered-dose pump. The metered pump delivers a metered 90-mcL spray that contains 1.53 mg of estradiol per actuation.
When estradiol transdermal spray is used for the management of moderate to severe vasomotor symptoms associated with menopause, the recommended initial dose is one spray to the inner forearm once daily. Subsequent dosage is based on clinical response. One, two, or three sprays may be administered each morning to adjacent, non-overlapping areas of the inner forearm.
For the management of symptoms of vulvar and vaginal atrophy associated with menopause, 2-4 g of estradiol vaginal cream may be administered intravaginally once daily for 1-2 weeks, then gradually reduced to one-half the initial dosage for a similar period. Maintenance dosages of 1 g of estradiol vaginal cream administered intravaginally 1-3 times weekly may be used after restoration of the vaginal mucosa has occurred.
When estradiol vaginal ring (Estring(R)) is used for the management of postmenopausal urogenital symptoms, one ring (delivering estradiol 0.0075 mg/24 hours) is inserted into the upper third of the vaginal vault; the ring is to remain in place for 3 months. After 3 months, the ring should be removed and, if appropriate, replaced with a new ring. If the ring is expelled, the ring should be rinsed in lukewarm water and reinserted.
For the management of atrophic vaginitis, one vaginal tablet containing 25 mcg of estradiol (Vagifem(R)) is inserted intravaginally once daily (preferably at the same time each day) for 2 weeks (initial dosage). For maintenance therapy for this condition, one vaginal tablet containing 25 mcg of the drug is inserted intravaginally twice weekly.
No enhanced Administration information available for this drug.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| ELESTRIN 0.06% GEL | Maintenance | Adults apply 1 pump (0.87 gram) to upper arm by topical route once daily |
No generic dosing information available.
The following drug interaction information is available for ELESTRIN (estradiol):
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 5 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) |
| 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 ELESTRIN (estradiol):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 12 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 |
| Thromboembolic disorder |
| Thrombotic disorder |
There are 6 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Coronary artery disease |
| Hereditary angioedema |
| Migraine |
| Predisposition to thrombosis |
| Tobacco smoker |
| Valvular heart disease |
There are 10 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Diabetes mellitus |
| Family history of malignant tumor of breast |
| Gallbladder disease |
| Hypercholesterolemia |
| Hypertension |
| Hypertriglyceridemia |
| Mammography abnormal |
| Obesity |
| Seizure disorder |
| Unspecified lump in breast |
The following adverse reaction information is available for ELESTRIN (estradiol):
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 33 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Gastroenteritis |
| Rare/Very Rare |
|---|
|
Acute myocardial infarction Acute pancreatitis Anaphylaxis Angina Angioedema Asthma exacerbation Cerebrovascular accident Chorea Deep venous thrombosis Dementia Endometrial carcinoma Endometrial hyperplasia Epithelial ovarian cancer Erythema multiforme Erythema nodosum Fibrocystic breast disease Gallbladder obstruction Hepatitis Hypercalcemia Hypertension Hypertriglyceridemia Hypocalcemia Malignant neoplasm of the ovary Neoplasm of breast Nipple discharge Obstructive hyperbilirubinemia Pharyngeal edema Pulmonary thromboembolism Purpura Retinal thrombosis Thromboembolic disorder Ventricular premature beats |
There are 69 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Abdominal distension Abnormal vaginal bleeding Headache disorder Infection Mastalgia Peripheral edema Pharyngitis Pruritus of skin Upper respiratory infection Weight gain |
Back pain Bronchitis Cervical discharge Constipation Dizziness Dyspepsia Libido changes Migraine Nausea Neck pain Pain in extremities Sinusitis Skin irritation Vaginal discharge Vaginitis Vomiting Vulvovaginal candidiasis |
| Rare/Very Rare |
|---|
|
Abdominal pain with cramps Alopecia Amenorrhea Arthralgia Body fluid retention Chloasma Cramps in legs Depression Diarrhea Dry skin Dyspnea Erythema Fallopian tube disorder Fatigue Flatulence Flu-like symptoms Galactorrhea not associated with childbirth General weakness Gynecomastia Hirsutism Hyperhidrosis Insomnia Irritability Malaise Menorrhagia Mood changes Muscle spasm Nervousness Oral hypoesthesia Ovarian cyst Palpitations Paresthesia Pelvic pain Skin pigmentation enhancement Skin rash Tachycardia Tongue swelling Urticaria Uterine cramps Uterine leiomyoma Varicose veins Vertigo |
The following precautions are available for ELESTRIN (estradiol):
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 |
No enhanced Pregnancy information available for this drug.
No enhanced Lactation information available for this drug.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for ELESTRIN (estradiol):
WARNING: Estrogens, either used alone or with another hormone (progestin), have rarely caused very serious side effects. Discuss the risks and benefits of hormone treatment with your doctor. Estrogens should not be used to prevent heart disease or dementia.
Estrogens can increase the risk of cancer of the uterus (endometrial cancer). Taking a progestin as directed by your doctor can help decrease this risk. Tell your doctor right away if you have any unusual vaginal bleeding.
In postmenopausal women, estrogens, taken with or without a progestin, increase the risk of cancer of the breast/ovaries, stroke, dementia, and serious blood clots. When used along with a progestin, estrogens also increase the risk of heart disease (such as heart attacks). 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 taking 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 another hormone (progestin), have rarely caused very serious side effects. Discuss the risks and benefits of hormone treatment with your doctor. Estrogens should not be used to prevent heart disease or dementia.
Estrogens can increase the risk of cancer of the uterus (endometrial cancer). Taking a progestin as directed by your doctor can help decrease this risk. Tell your doctor right away if you have any unusual vaginal bleeding.
In postmenopausal women, estrogens, taken with or without a progestin, increase the risk of cancer of the breast/ovaries, stroke, dementia, and serious blood clots. When used along with a progestin, estrogens also increase the risk of heart disease (such as heart attacks). 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 taking 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 ELESTRIN (estradiol)'s list of indications:
| Vasomotor symptoms associated with menopause | |
| N95.1 | Menopausal and female climacteric states |
| N95.9 | Unspecified menopausal and perimenopausal disorder |
Formulary Reference Tool