Side Effects of Alora (estradiol)

Alora (estradiol) is a form of estrogen, a female hormone, used to treat symptoms of menopause, to prevent bone fractures (osteoporosis), painful uterine bleeding, vaginal pain, dryness and atrophy associated with menopause. Alora is also prescribed to treat breast cancer, and some cases of prostate cancer. 

Estrogens occur in nature in several chemical forms. In women with active menstrual cycles, the ovaries produce between 70 and 500 micrograms of estradiol daily. This is converted to estrone and to a lesser extent estriol. 

After menopause, estrone made in the adrenal glands, is the most active circulating estrogen. Estrogens cause growth and development of female sex organs and maintain sex characteristics, including underarm and pubic hair and the shape of body contours and skeleton. Estrogens also increase secretions from the cervix and growth of the inner lining of the uterus (endometrium). 

Estrogens reduce LDL-cholesterol ("bad" cholesterol) and increase HDL-cholesterol ("good" cholesterol) concentrations in the blood. Estrogens, when taken alone or in combination with a progestin (progesterone), have been shown to reduce the risk for hip fracture due to osteoporosis by 25%.

Common side effects of Alora include

• break-through bleeding or spotting,
• loss of periods or excessively prolonged periods,
• breast pain,
• breast enlargement, and
• changes in sex drive. 

Serious side effects of Alora include

• gallstones,
• hepatitis,
• migraine headaches,
• fluid retention (edema),
• melasma (tan or brown patches) on the forehead, cheeks, or temples that may persist even after the estrogen is stopped;
• increased curvature of the cornea that may cause intolerance to contact lenses,
• blood clots (occasional and dose-related,
• increased risk of endometrial cancer, and
• increased risk of developing breast cancer.

Drug interactions of Alora include cyclosporine, because Alora can inhibit the metabolism of cyclosporine, resulting in increased cyclosporine blood levels. Such increased blood levels can result in kidney and/or liver damage.

• Estrogens appear to increase the risk of liver disease in patients receiving dantrolene through an unknown mechanism.
• Estrogens increase the liver's ability to manufacture clotting factors.
• Because of this, patients receiving warfarin need to be monitored for loss of anticoagulant effect if Alora is added when warfarin is already being taken.
• Rifampin, barbiturates, carbamazepine, griseofulvin, phenytoin, primidone and St. John's wort preparations can all increase the elimination of Alora by enhancing the liver's ability to metabolize it.
• Concurrent use may result in reduction of the beneficial effects of Alora.
• On the other hand, drugs such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and grapefruit juice can decrease the liver's ability to metabolize and eliminate estrogens and may increase the side effects of Alora.
• Alora may increase the levels and effects of exogenous corticosteroids, ropinirole, tipranavir and medications that contain theophylline.
• Alora may reduce the levels and the effects of anastrozole, aripiprazole, axitinib, hyaluronidase, saxagliptin, somatropin, ibrutinib, and ursodiol.
• Estrogen levels and effects may be decreased by dabrafenib, deferasirox, peginterferon Alfa-2b, P-glycoprotein inducers, tocilizumab and herbs that belong to a class of medications called CYP3A4 inducers.
• Herbs with contents similar to estrogens may increase the side effects of Alora.
• Estrogen levels and effects may be increased by dehydroepiandrosterone, P-glycoprotein inhibitors, nonsteroidal anti-inflammatory drugs called COX-2 inhibitors such as celecoxib and ascorbic acid (vitamin C). 

Alora should not be used during pregnancy due to an increased risk of fetal abnormalities. 

Estrogens are secreted in milk and cause unpredictable effects in the infant. Alora generally should not be used by women if they are breastfeeding.

• Among the most common endocrine side effects are:
  • break-through bleeding or spotting,
  • loss of periods or excessively prolonged periods,
  • breast pain,
  • breast enlargement, and
  • changes in sexuality (increase or decrease in libido).
• Abdominal pain may indicate the development of gallstones or occasionally hepatitis.
• Migraine headaches have been associated with estrogen therapy.
• Estrogens can cause sodium and fluid retention leading to edema.
• Melasma, tan or brown patches, may develop on the forehead, cheeks, or temples. These may persist even after the estrogen is stopped.
• Conjugated estrogens may cause an increase in the curvature of the cornea. Patients with contact lenses may develop intolerance to their lenses.
• Blood clots are an occasional but serious adverse effect and are dose-related. (The higher the dose of estradiol, the more likely blood clots are to form.) Cigarette smokers are at a higher risk for clots, and, therefore, patients requiring estrogen therapy are strongly encouraged to quit smoking.
• Estrogens can increase the risk of endometrial cancer. This risk may be decreased if estrogens are combined with progestin.
• Some people also have a higher chance of developing breast cancer while taking estrogens. Sometimes people who have breast cancer when they are taking estrogens may have increased calcium in the blood. If this happens, the estrogen should be stopped.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Cardiovascular Disorders
• Malignant Neoplasms

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions for Alora 0.025 mg/day, 0.05 mg/day, and 0.075 mg/day transdermal systems versus placebo, each applied twice weekly, were evaluated in a 2-year randomized, parallel-group, double-blind, double-dummy, placebo-controlled multicenter trial for the prevention of osteoporosis in 355 hysterectomized postmenopausal women. Adverse reactions with an incidence greater than 2% and greater than placebo, are shown in Table 1

Table 1 : Adverse Reactions for Alora 0.025 mg/day, 0.05 mg/day, and 0.075 mg/day Transdermal Systems, Occurring at Greater than 2% (and greater than Placebo) in a Two-Year Prevention of Osteoporosis Trial (data are expressed as N and (%) of treatment group).

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Alora. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Genitourinary system: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, dysmenorrhea, metrorrhagia, menorrhagia, amenorrhea, vaginitis, including vaginal candidiasis, vulvovaginal dryness, vulvovaginal pruritus, endometrial cancer.
• Breast: Pain, tenderness, enlargement, swelling, breast cancer, nipple pain, galactorrhea.
• Cardiovascular: Hot flushes, palpitations, tachycardia, increase in blood pressure, deep venous thrombosis, pulmonary embolism.
• Gastrointestinal: Nausea, vomiting, abdominal pain, abdominal distention, flatulence, diarrhea, gallbladder disease, pancreatitis.
• Skin: Rash, pruritus, alopecia, erythema nodosum, hemorrhagic eruption, hyperhidrosis, hirsutism, application site reaction.
• Eyes: Blurred vision, visual impairment.
• Central nervous system: Headache, migraine, dizziness, insomnia, anxiety, mental depression, nervousness, mood swings, irritability, hypoaesthesia, paresthesia, somnolence, loss of libido.
• Miscellaneous: Increase or decrease in weight, reduced carbohydrate tolerance, arthalgias, back pain, increased triglycerides, increased cholesterol, exacerbation of asthma, vertigo.

• In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.
• Inducers of CYP3A4 such as St. John's Wort preparations (Hypericum perforatum), phenobarbital, phenytoin, carbamazepine, rifampin and dexamethasone may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile.
• Inhibitors of CYP3A4 such as cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in adverse reactions.