Angeliq (drospirenone and estradiol) is a female hormone that is commonly used to reduce the symptoms associated with menopause such as hot flashes and other vasomotor symptoms.

Angeliq (Drospirenone and estradiol) Uses:

• Vasomotor symptoms associated with menopause:

  • Treatment of moderate to severe vasomotor symptoms associated with menopause in women with a uterus.

• Vulvar and vaginal atrophy associated with menopause:

  • Treatment of moderate to severe vulvar and vaginal because of menopause in women with a uterus.
• Limitations of use:
  • When used as monotherapy for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.

Note:

• The International Society for the Study of Women’s Sexual Health and The North American Menopause Society has endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy.
• The term GSM includes all genital and urinary signs and symptoms associated with a loss of estrogen because of menopause.

Adult dose:

Angeliq (drospirenone and estradiol) General dosing guidelines:

• When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient according to treatment goals, risk factors, and overall health.

Angeliq (drospirenone and estradiol) Dose in the treatment of Vasomotor symptoms associated with menopause:

• Oral: Drospirenone 0.25 mg/estradiol 0.5 mg or drospirenone 0.5 mg/estradiol 1 mg per tablet: One tablet daily.

Angeliq (drospirenone and estradiol) Dose in the treatment of Vulvar and vaginal atrophy associated with menopause:

• Oral: Drospirenone 0.5 mg/estradiol 1 mg per tablet: One tablet daily.

Use in Children:

Not indicated. 

Pregnancy Risk Category: X

• Contraindicated for pregnant women

Breastfeeding: Drospirenone or estradiol

• Breast milk contains drospirone.
• The infant received a maximum dose of 3 mg/day of drospirenone after being administered an oral contraceptive drug containing drospirenone. 
• Breast milk quality and quantity may be affected by estrogens.

Dose in Kidney disease:

Use is contraindicated.

Dose in Liver disease:

Use is contraindicated.

Common Side Effects of Angeliq (Drospirenone and estradiol):

• Genitourinary:

  • Mastalgia
  • Genital bleeding

Less Common Side Effects of Angeliq (Drospirenone and estradiol):

• Central nervous system:

  • Emotional lability
  • Migraine

• Gastrointestinal:

  • Abdominal pain
  • Gastrointestinal pain

• Genitourinary:

  • Cervical polyp

Contraindications to Angeliq (Drospirenone and estradiol):

• Angioedema, angioedema or anaphylactic reaction to drospirenone or estradiol or any component of formulation.
• Undiagnosed abnormal Genital Bleeding;
• DVT or PE (current and/or historical of);
• Active or past history of arterial embombolic disease (eg stroke, MI)
• Breast carcinoma (known, suspected or history of);
• An estrogen-dependent tumor (known, suspected)
• Hepatic impairment or disease
• Renal impairment
• Insufficiency of adrenal;
• Protein C, protein S, and other known thrombophilic conditions;
• Confirmed or suspected pregnancy

Canadian labeling: Additional contraindications not in US labeling

• Progestin-dependent malignant Neoplasia (current and/or history of);
• Malignant or benign liver tumors (currently or in the past);
• Endometrial hyperplasia
• severe hypertriglyceridemia;
• Classic migraine
• Ophthalmic vascular disease can cause vision loss, partial or total.
• Breastfeeding

Warnings and precautions

• [US Boxed Warning] Breast Cancer

  • Data from the Women's Health Initiative (WHI), shows that postmenopausal women who use conjugated estrogens (CE) and medroxyprogesterone (MPA) have a higher risk of developing invasive breast cancer.
  • Studies have shown that stopping therapy reduces the risk.
  • The WHI study didn't report an increase in breast cancer risk for women who had a hysterectomy with CE.
  • Postmenopausal women receiving hormone therapy could be at greater risk for breast cancer due to their estrogen or progestin doses, timing of therapy initiation, length of therapy, route of administration and patient characteristics.
  • Increased breast density may be caused by hormone therapy.
  • An increase in abnormal mammogram findings that require further evaluation has been reported using estrogen alone or in combination.
  • Patients with breast cancer or bone metastases may experience severe hypercalcemia from estrogen use. If this happens, discontinue estrogen.

• Dementia: [US Boxed Warning]

  • To prevent dementia, it is not a good idea to use estrogens without or with progestin.
  • The Women's Health Initiative Memory Study, (WHIMS), found that women aged >=65 years were more likely to develop dementia if they took CE either alone or in combination.
  • The WHI memory studies were performed on women aged >=65 years. It is not known if the findings can be applied to younger postmenopausal females.
  • Hormone therapy is not recommended for any age in order to treat or prevent cognitive decline or dementia.

• Endometrial Cancer: [US Boxed Warn]

  • Endometrial cancer is more likely to occur in women who use unopposed estrogen.
  • A progestin may be added to estrogen therapy to reduce the chance of endometrial hyperplasia. This is a precursor for endometrial carcinoma.
  • To rule out malignancy in women who have undiagnosed abnormal vaginal blood flow, it is important to perform appropriate diagnostic tests, including endometrial sampling, if necessary.
  • Estrogens may exacerbate endometriosis.
  • Post-hysterectomy with estrogen therapy unopposed has led to malignant transformation of the remaining endometrial implants.
  • Women with endometrium after hysterectomy should consider adding a progestin.
  • There is no evidence to suggest that natural estrogens have a different risk profile than synthetic estrogens of equivalent estrogen doses.
  • Endometrial cancer risk appears to be dependent on the duration and dose of treatment. It is highest for patients who have been using therapy for more than 5 years. This may continue even after discontinuation.
  • A progestin should not be used if low doses are being administered locally to treat vaginal atrophy. However, there are insufficient long-term data (>1 years) to support this recommendation.

• Endometriosis:

  • Estrogens may exacerbate endometriosis.
  • Post-hysterectomy with estrogen therapy unopposed has led to malignant transformation of the remaining endometrial implants.
  • Women with endometriosis after hysterectomy should consider adding a progestin.

• Hyperkalemia:

  • Drospirenone may cause hyperkalemia by its anti-mineralocorticoid activity.
  • Patients with hyperkalemia-predisposing conditions (eg, renal dysfunction, hepatic dysfunction or adrenal insufficiency) should not use this medication.

• Hyponatremia:

  • Hyponatremia may be increased by Drospirenone in high-risk patients.

• The Lipid Effects

  • Estrogen compounds have lipid effects, such as higher HDL-cholesterol or decreased LDL cholesterol.
  • Triglycerides may also be increased in women with preexisting hypertriglyceridemia; cease if pancreatitis occurs.
  • Patients with familial lipoprotein metabolism defects should be cautious.

• Ovarian cancer:

  • The information available regarding the risk of ovarian carcinoma and the use of estrogen/progestin therapy or menopausal estrogen is not consistent.
  • An association may exist, but the risk of developing a serious condition is unlikely. The duration of therapy can also influence the likelihood of developing a severe reaction.

• Retinal vascular embolism:

  • Estrogens can cause retinal vein thrombosis. Discontinue use if you experience migraines, vision loss, proptosis or diplopia. If retinal vascular or papilledema on examination, discontinue use permanently.

• Asthma

  • Patients with asthma should exercise caution as it can worsen the condition.

• Carbohydrate intolerance:

  • Patients with diabetes may experience impaired glucose tolerance.
  • Take into account the age, cardiovascular and metabolic risk factors of patients with diabetes.

• Cardiovascular disease: [US-Boxed Warning]

  • To prevent heart disease, estrogens should not be combined with or without progestin.
  • Data from the Women's Health Initiative's (WHI) studies has shown that CE has an increased risk for stroke and deep vein thrombosis. There has also been an increase in DVT, stroke, and pulmonary emboli (PE) in postmenopausal females between 50 and 79 years old.
  • Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE).
  • It is important to manage risk factors properly. If adverse cardiovascular events are suspected or occur, it is best to stop immediately.
  • Transdermal administration is preferred to treat vasomotor symptoms associated with menopause in patients at high risk for developing thrombotic events.
  • Women with an active DVT, PE, or arterial thromboembolic diseases (stroke and MI) are not recommended.

• Chorea minor:

  • Chorea minor should be used with caution as it can exacerbate the condition.

• Fluid retention can lead to more severe diseases

  • Patients with fluid retention-related diseases, such as cardiac or renal dysfunction, should be cautious.

• Epilepsy:

  • Epilepsy can be exacerbated by caution.

• Gallbladder disease

  • Postmenopausal estrogen use may increase the risk of gallbladder diseases that require surgery.

• Hepatic dysfunction

  • Patients with hepatic dysfunction are less likely to be able to metabolize estrogens.
  • Be cautious if you have a history of cholestatic jaundice due to previous estrogen use or pregnancy.
  • If jaundice occurs or if there are acute or chronic hepatic disorders, discontinue use.
  • Hepatic impairment and disease are reasons for the contraindication of using this medication.

• Hepatic hemomangiomas

  • Patients with hepatic hemomangiomas should be cautious; it may worsen the condition.

• Hereditary angioedema:

  • Women with hereditary angioedema may experience angioedema symptoms from exogenous estrogens.

• Hypoparathyroidism:

  • Hypoparathyroidism patients should be cautious; estrogen-induced hypocalcemia can occur.

• Migraine

  • Patients suffering from migraines should be cautious. It may worsen the condition.

• Otosclerosis

  • Be cautious with otosclerosis. It can worsen the condition.

• Porphyria

  • Patients with porphyria should be cautious; it may worsen the condition.

• SLE:

  • Patients with SLE should be cautious; it may worsen the condition.

Drospirenone and estradiol: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Before therapy, baseline risk for breast cancer and CVD.
• During therapy, age-appropriate breast, and pelvic exams;
• blood pressure;
• unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer);
• serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL);
• TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement).
• Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate.
• The duration of treatment should be evaluated at least yearly.
• Serum potassium during the first month of therapy in patients at risk for hyperkalemia and who are on chronic strong CYP3A4 inhibitors

Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or GSM

How to administer Angeliq (Drospirenone and estradiol)?

• Tablets should be swallowed whole with some liquid with or without meals and taken at the same time every day.
• Bleeding may occur if several doses are missed. Women who are not taking estrogen or who are changing from a continuous combination product may begin therapy at any time.
• Women who are switching from sequential or cyclic hormone therapy should complete the current cycle before switching to this product.
• A forgotten dose should be taken as soon as possible. If more than 24 hours have elapsed, the missed tablet should not be taken.

Mechanism of action of Angeliq (Drospirenone and estradiol):

Drospirenone is a synthetic progestin and spironolactone analog with anti-mineralocorticoid and antiandrogenic activity. It counteracts estrogen-induced endometrial thinning. Estrogens are responsible to the development and maintenance the female reproductive system as well as secondary sexual characteristics.

Estradiol is the principal intracellular human estrogen and is stronger than estrone and estriol at the receptor level; it is the primary estrogen secreted before menopause. Estrone and estrone-sulfate become more abundant after menopause. 

Through a negative feedback mechanism, estrogens regulate the pituitary secretion gonadotropins,luteinizing hormone and follicle stimulating hormone. Postmenopausal women with high levels of estrogen replace these hormones.

Protein binding:

• Drospirenone: 97%;
• does not bind to sex hormone-binding globulin or corticosteroid-binding globulin
• Estradiol: 37% bound to sex hormone-binding globulin;
• 61% bound to albumin

Metabolism:

• Hepatic
• Drospirenone forms two metabolites (inactive)
• Estradiol: Converted to estrone and estriol; also undergoes enterohepatic recirculation; estrone sulfite is the main metabolite in postmenopausal women

Bioavailability:

• Drospirenone: 76% to 85%

Half-life elimination:

• Drospirenone: ~36-42 hours

Time to peak, plasma:

• Drospirenone: 1 hour;
• Estradiol: ~2 hours (range: 0.3-10 hours)

Excretion:

• Drospirenone: Urine and feces;
• Estradiol: Urine

International Brand Names of Drospirenone and estradiol:

• Angeliq
• Angelica
• Angemin
• AST
• Astarte

Drospirenone and estradiol Brand Names in Pakistan:

No Brands Available in Pakistan.