estrogens conjugated synthetic (Cenestin, Enjuvia)

Dosing and uses of Cenestin, Enjuvia (estrogens conjugated synthetic)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 0.3mg
• 0.45mg
• 0.625mg
• 0.9mg
• 1.25mg

 

Menopausal Vasomotor Symptoms

0.45-1.25 mg PO qDay

 

Atrophic Vaginits, Kraurosis Vulvae, Perimenopausal Dyspareunia

PO: 0.3 mg qDay

 

Pediatric dosage forms and strengths

Safety & efficacy not established

 

Cenestin, Enjuvia (estrogens conjugated synthetic) adverse (side) effects

>10%

Abdominal pain

Back pain

Bloating

Breast enlargement

Breast tenderness

Headache

Nausea

Peripheral edema

Vomiting

 

Frequency not defined

Amenorrhea

Breakthrough bleeding

Corneal curvation change

Depression

Diarrhea

Melasma

Spotting

Weight changes

 

Postmarketing reports

Abdominal discomfort, abdominal distension

Muscle spasms

Dizziness

Insomnia

Breast pain

Alopecia

Rash

Urticaria

Deep vein thrombosis, thrombosis

 

Warnings

Black box warnings

Estrogens increase risk of endometrial cancer

• Close clinical surveillance of all women taking estrogens is important
• Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding
• There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses

Cardiovascular risks

• Estrogens with and without progestins should not be used to prevent cardiovascular disease
• Estrogens plus progestins: Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, & deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 yr) during 5.6 yr of treatment w/ daily PO conjugated estrogens (CE 0.625 mg) combined w/ medroxyprogesterone acetate (MPA 2.5 mg) compared with placebo
• Estrogens alone: A substudy of the WHI Study reported increased risk for stroke and DVT in postmenopausal women (aged 50-79 yr) during 6.8 year of treatment with oral conjugated estrogens (0.625 mg/day) alone compared with placebo

Dementia risks

• Estrogens with and without progestins should not be used to prevent dementia
• Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged 65 years or older during 4 year of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, compared with placebo
• Estrogens alone: A substudy of the WHIMS reported an increased risk of developing probable dementia in postmenopausal women aged 65 years or older during 5.2 years of treatment with conjugated estrogens 0.625 mg alone compared w/ placebo
• Unknown whether these findings apply to younger postmenopausal women

Dose & duration

• In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins
• Because of these risks, estrogens with or without progestins should be prescribed at lowest effective dose and for shortest duration consistent with treatment goals and individual risks

 

Contraindications

Documented hypersensitivity; active or history of breast cancer, arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease, protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

Uncontrolled hypertension, diabetes mellitus with vascular involvement

Jaundice with prior oral contraceptive use

History of migraine with aura

Estrogen-dependent neoplasia

Undiagnosed abnormal vaginal bleeding

Liver disease, liver tumors

Known or suspected pregnancy

 

Cautions

Caution in history of hyperlipidemias, HTN, hepatic/renal impairment, uterine leiomyomata, porphyria, patients with defects of lipoprotein metabolism, hypertriglyceridemia, ovarian cancer, SLE, and the elderly

Discontinue if the following develop jaundice, any signs of VTE, migraine with unusual severity, significant blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery

Discontinue 4 week before major surgery or prolonged immobilization

Use caution in patients with asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; exacerbations may occur

Increased risk of ovarian and endometrial cancer

Long-term postmenopausal estrogen treatment has been associated with increased risk of MI, stroke, DVT/PE, and dementia

Patients on warfarin/oral anticoagulants: Estrogens increase thromboembolic risk; increase in anticoagulant dose may be warranted

Not approved for osteoporosis prevention

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema

Estrogens increase the risk of gallbladder disease

Estrogen administration reported to lead to severe hypercalcemia in women with breast cancer and bone metastases; if hypercalcemia occurs, discontinue use and take appropriate measures to reduce serum calcium leveL

Retinal vascular thrombosis may occur; discontinue therapy, if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine, pending visual examination; permanently discontinue if examination reveals papilledema or renal vascular lesions

Consider discontinuation of therapy if pancreatitis occurs; in women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis

Monitor thyroid function in order to maintain free thyroid hormone levels in an acceptable range

Use with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur

A few cases of malignant transformation of residual endometrial implants reported in women treated post-hysterectomy with estrogen-alone therapy; consider addition of progestin in women known to have residual endometriosis post-hysterectomy

 

Pregnancy and lactation

Pregnancy category: X

Lactation: Controversial; estrogens are excreted into breast milk in small quantities, use caution

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Cenestin, Enjuvia (estrogens conjugated synthetic)

Mechanism of action

Replaces natural estrogen. Important for development and maintenance of the female reproductive system and secondary sexual characteristics.

Derived from plant sources; B but not A contains delta 8,9-dehydroestrone sulfate

 

Pharmacokinetics

Onset: 2-4 wk (menopause; PO)

Peak plasma time: 8 hr (PO)

Bioavailability: Readily absorbed from GI tract

Protein Bound: 80%

Metabolism: In liver to inactive sulfates and glucuronides which are then excreted in urine and bile

Metabolites: Estradiol, estrone, estrioL

Excretion: Mainly in urine as conjugates with small amount of unchanged drug, most estrogens are also excreted in bile and undergo enterohepatic recycling