Vivelle

Estradiol is a form of estrogen, a female sex hormone produced by the ovaries. Estrogen is necessary for many processes in the body.

Estradiol transdermal skin patches are used to treat certain symptoms of menopause such as hot flashes, and vaginal dryness, burning, and irritation. This medicine is also used to prevent postmenopausal osteoporosis, or to treat ovarian disorders.

Estradiol transdermal may also be used for purposes not listed in this medication guide.

Apply a skin patch as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra patches to make up the missed dose.

In the U.S.

• Alora
• Cenestin
• Climara
• Divigel
• Elestrin
• Emcyt
• Enjuvia
• Esclim
• Estinyl
• EstroGel
• Evamist
• Femtrace
• Gynodiol
• Menest
• Menostar
• Minivelle
• Ogen .625
• Ogen 1.25
• Ogen 2.5
• Premarin
• Vivelle
• Vivelle-Dot

In Canada

• Estraderm
• Estradot Transdermal
• Estradot Transdermal Therapeutic System
• Estradot Transdermal Therapeutic System
• Estrogel
• Oesclim
• Rhoxal-Estradiol Derm 50
• Rhoxal-Estradiol Derm 75
• Roxal-Estradiol Derm 100
• Vivelle 100 Mcg
• Vivelle 25 Mcg

Available Dosage Forms:

• Tablet
• Cream
• Patch, Extended Release
• Gel/Jelly
• Spray
• Emulsion
• Tablet, Enteric Coated
• Capsule

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Do not take Vivelle by mouth. Use on your skin only. Keep out of your mouth, nose, and eyes (may burn).
• Use this medicine at the same time of day.
• Do not use on skin that has any problems.
• Do not put on the face, breast, or vagina.
• Wash your hands before and after use.
• Put patch on clean, dry, healthy skin. Move the site with each new patch.
• Put patch on a site without hair.
• Do not place on breast. Place below waistline.
• Do not put the patch on the waistline.
• Do not use patches that are cut or do not look right.
• If the patch falls off, put a new one on.
• Wear only one patch at a time.

What do I do if I miss a dose?

• Put on a missed patch as soon as you think about it after taking off the old one.

• Store at room temperature.
• Store in a dry place. Do not store in a bathroom.
• After you take off a skin patch, be sure to fold the sticky sides of the patch to each other.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Vivelle, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Vivelle (estradiol transdermal biweekly patch). It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Vivelle.

Review Date: October 4, 2017

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.

      The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

      Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.

      Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

In a multiple-dose study consisting of three consecutive patch applications of the Vivelle system, which was conducted in 17 healthy, postmenopausal women, blood levels of estradiol and estrone were compared following application of these units to sites on the abdomen and buttocks in a crossover fashion. Patches that deliver nominal estradiol doses of approximately 0.0375 mg/day and 0.1 mg/day were applied to abdominal application sites while the 0.1 mg/day doses were also applied to sites on the buttocks. These systems increased estradiol levels above baseline within four hours and maintained respective mean levels of 25 and 79 pg/mL above baseline following application to the abdomen; slightly higher mean levels of 88 pg/mL above baseline were observed following application to the buttocks. At the same time, increases in estrone plasma concentrations averaged about 12 and 50 pg/mL, respectively, following application to the abdomen and 61 pg/mL for the buttocks. While plasma concentrations of estradiol and estrone remained slightly above baseline at 12 hours following removal of the patches in this study, results from another study show these levels to return to baseline values within 24 hours following removal of the patches.

      The figure (see Figure 1) illustrates the mean plasma concentrations of estradiol at steady state during application of these patches at four different dosages.

Figure 1
Steady-State Estradiol Plasma Concentrations
for Systems Applied to the Abdomen
Nonbaseline-Corrected Levels

      The corresponding pharmacokinetic parameters are summarized in Table 1 below.

Table 1
Steady-State Estradiol Pharmacokinetic Parameters
for Systems Applied to the Abdomen
(mean ± standard deviation)
Nonbaseline-Corrected Data*

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women, a significant proportion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Studies conducted with the Vivelle system show the drug has an apparent mean half-life of 4.4 ± 2.3 hours. After removal of the transdermal systems, serum concentrations of estradiol and estrone returned to baseline levels within 24 hours.

Vivelle was only investigated in postmenopausal women.

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, carbamazepine and rifampin 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 erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Data showing the number of systems in controlled studies that required replacement due to inadequate adhesion is not available.

In two controlled clinical trials of 356 subjects, the 0.075 and 0.1 mg doses were superior to placebo in relieving vasomotor symptoms at Week 4, and maintained efficacy through Weeks 8 and 12 of treatment. In this original study, the 0.0375 and 0.05 mg doses, however, did not differ from placebo until approximately Week 6; therefore, an additional 12-week placebo-controlled study in 255 patients was performed to establish the efficacy of the lowest dose of 0.0375 mg. The baseline mean daily number of hot flushes in these 255 patients was 11.5. Results at Weeks 4, 8, and 12 of treatment are shown in the figure below. (See Figure 2.)

Figure 2
Mean (SD) Change from Baseline in Mean Daily Number of Flushes
for Vivelle 0.0375 mg Versus Placebo in a 12-Week Trial

      The 0.0375-mg dose was superior to placebo in reducing both the frequency and severity of vasomotor symptoms at Week 4 and maintained efficacy through Weeks 8 and 12 of treatment. The following doses of Vivelle: 0.0375 mg, 0.05 mg, 0.075 mg, and 0.1 mg, are effective for the control of vasomotor symptoms.

      Efficacy and safety of the Vivelle system in the prevention of postmenopausal osteoporosis have been studied in a 2-year double-blind, randomized, placebo-controlled, parallel group study. A total of 261 hysterectomized (161) and non-hysterectomized (100), surgically or naturally menopausal women (within five years of menopause), with no evidence of osteoporosis (lumbar spine bone mineral density within two standard deviations of average peak bone mass, i.e., =0.827 g/cm2) were enrolled in this study; 194 patients were randomized to one of the four doses of Vivelle (0.1, 0.05, 0.0375, or 0.025 mg/day) and 67 patients to placebo. Over two years, study systems were applied to the buttock or the abdomen twice a week. Non-hysterectomized women received oral medroxyprogesterone acetate (2.5 mg/day) throughout the study.

      The study population comprised naturally (82%) or surgically (18%) menopausal, hysterectomized (61%) or non-hysterectomized (39%) women with a mean age of 52.0 years (range 27 to 62 years); the mean duration of menopause was 31.7 months (range 2 to 72 months). Two hundred thirty-two (89%) of randomized subjects (173 on active drug, 59 on placebo) contributed data to the analysis of percent change from baseline in bone mineral density (BMD) of the AP lumbar spine, the primary efficacy variable. Patients were given supplemental dietary calcium (1000 mg elemental calcium/day) but no supplemental vitamin D. There was an increase in BMD of the AP lumbar spine in all Vivelle dose groups; in contrast to this, a decrease in AP lumbar spine BMD was observed in placebo patients. All Vivelle doses were significantly superior to placebo (p<0.05) at all time points with the exception of Vivelle 0.05 mg/day at six months. The highest dose of Vivelle was superior to the three lower doses. There were no statistically significant differences in pairwise comparisons among the three lower doses. (See Figure 3.)

Figure 3
Bone Mineral Density - AP Lumbar Spine
Least Squares Means of Percentage Change from Baseline
All Randomized Patients with at Least One Post-Baseline Assessment Available with Last Post-Baseline Observation Carried Forward

      Analysis of percent change from baseline in femoral neck BMD, a secondary efficacy outcome variable, showed qualitatively similar results; all doses of Vivelle were significantly superior to placebo (p<0.05) at 24 months. The highest Vivelle dose was superior to placebo at all time points. A mixture of significant and non-significant results were obtained for the lower dose groups at earlier time points. The highest Vivelle dose was superior to the three lower doses, and there were no significant differences among the three lower doses at this skeletal site. (See Figure 4.)

Figure 4
Bone Mineral Density - Femoral Neck
Least Squares Means of Percentage Change from Baseline
All Randomized Patients with at Least One Post-Baseline Assessment Available with Last Post-Baseline Observation Carried Forward

      The mean serum osteocalcin (a marker of bone formation) and urinary excretion of cross-link N-telopeptides of type 1 collagen (a marker of bone resorption) decreased numerically in most of the active treatment groups relative to baseline. However, the decreases in both markers were inconsistent across treatment groups and the differences between active treatment groups and placebo were not statistically significant.

Women’s Health Initiative Studies

The Women’s Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms.

      The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79, 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 2 below.

Table 2
Relative and Absolute Risk Seen in the CE/MPA
Substudy of WHIa

      For those outcomes included in the “global index”, absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality. (See BOXED WARNINGS, WARNINGS, and PRECAUTIONS.)

Women’s Health Initiative Memory Study

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were aged 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of oral CE/MPA (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

      After an average follow-up of four years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia.)

Vivelle is indicated in the following:

1. Treatment of moderate to severe vasomotor symptoms associated with the menopause.
   
2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.
   
3. Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
   
4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risks of osteoporosis and non-estrogen medications should be carefully considered.

      The mainstays for decreasing the risk of postmenopausal osteoporosis are weight-bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacologic therapy. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation of 400-800 IU/day may also be required to ensure adequate daily intake in postmenopausal women.

Applies to estradiol: compounding powder, intramuscular solution, oral tablet, transdermal emulsion, transdermal film extended release, transdermal gel, transdermal spray, vaginal ring

Gastrointestinal

Cases of oral pigmentation and ischemic colitis have been reported rarely.[Ref]

Gastrointestinal side effects have included nausea, abdominal cramps, bloating and vomiting. Some studies have demonstrated a 2 to 4 fold increase in gallbladder disease in postmenopausal women taking estrogen therapy. Cholestatic jaundice, pancreatitis, and enlargement of hepatic hemangiomas have been reported. Postmarketing experience with the vaginal ring has included a few cases of bowel obstruction and vaginal ring use. Postmarketing side effects with Vivelle-Dot include nausea, vomiting, abdominal cramps, bloating, cholelithiasis and diarrhea.[Ref]

Oncologic

Oncologic side effects have included reports of an increased risk of endometrial carcinoma in patients with an intact uterus and less persuasively, with an increased risk of breast cancer.[Ref]

A number of studies have suggested that the risk of endometrial carcinoma is removed (or delayed) by the administration of progestins in combination with estrogen therapy.

The increased risk of breast cancer due to use of estrogens is controversial. Several studies have suggested that long-term estrogen therapy may be associated with a slightly increased risk of breast cancer. Meta analysis of 51 studies (epidemiological data) supports a modest risk increase associated with long-term hormone replacement therapy (HRT).

One study of Swedish women has reported that a 10% increase in the relative risk of breast cancer may occur and that the risk is related to increasing duration of estrogen therapy. In that study, women with more than nine years of estrogen use had a 70% greater relative risk of breast cancer than controls. That study, however, examined use of a variety of estrogen preparations of which estradiol was the most frequently prescribed. In addition, women who took progestins did not demonstrate a decreased risk of breast cancer and may even have been at higher risk.

The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens for more than 15 years was not ruled out.

The Case-Control Surveillance Study has reported that there is "no evidence that the use of unopposed conjugated estrogens increases the risk of breast cancer, even after long duration of use or long latent intervals, but the possibility of a modest increase (less than a doubling) could not be excluded."

Follow-up to the Nurses' Health Study of 1992 concluded, however, that there is an increased risk of breast cancer in women taking estrogen replacement therapy and that the risk is not reduced by concurrent use of progestins. (In that study, greater risk was associated with advanced age and prolonged duration of hormonal therapy.)

A study of middle-aged women in the Puget Sound area concluded that "on the whole, the use of estrogen with progestin HRT [hormone replacement therapy] does not appear to be associated with an increased risk of breast cancer in middle-aged women."

A prospective cohort study (11 years) of 37,105 women by Gapstur et al evaluated the histology of the breast cancer in women who ever used HRT. No association was found between duration of ever HRT use and the incidence of ductal carcinoma in situ or invasive ductal/lobular carcinoma. The duration of ever HRT use was associated with risk of invasive carcinoma with a favorable prognosis (relative risk (RR) = 1.81, 95% confidence interval (CI), 1.07 to 3.07 for HRT use less than or equal to 5 yrs and RR = 2.65, CI, 1.32 to 5.23 for HRT use > 5 yrs, p = 0.005). The relative risk of invasive carcinoma with a favorable prognosis for current users (adjusted for age and other risk factors) was 4.42, CI, 2.00 to 9.76 for less than or equal to 5 yrs and 2.63, CI, 1.18 to 5.89 for > 5 yrs). Risk of invasive ductal or lobular carcinoma for current users less than or equal to 5 yrs was RR = 1.38, CI, 1.03 to 1.85.[Ref]

Cardiovascular

The reported effects of estrogens on cardiovascular activity are variable. Alterations in lipid profiles in treated women are thought to be responsible for reducing cardiovascular risks. Data suggest estrogen use may increase blood pressure, particularly in patients receiving high doses, decrease blood pressure, or result in no change. In addition, noncontraceptive use of estrogens in young women (particularly smokers) may substantially increase the risk of nonfatal myocardial infarction. Other studies have concluded that no increased risk of myocardial infarction exists.[Ref]

Cardiovascular side effects have included studies suggesting that unopposed estrogen therapy decreased the risk of coronary heart disease by as much as 35%. Combination therapy with a progestin may have also decreased coronary risk. However, the extent of risk reduction with combination therapy has not been determined. Data are available that suggest combination therapy does not reduce the overall rate of coronary heart disease in postmenopausal women with established coronary disease. Postmarketing side effects with Vivelle-Dot include deep vein thrombosis, pulmonary embolism and thrombophlebitis.[Ref]

Metabolic

Metabolic side effects have included reports of generally favorable alterations in plasma lipid profiles. Specifically, increased HDL and decreased cholesterol and LDL levels have occurred. Estrogen therapy may have led to increased serum triglyceride levels resulting in pancreatitis in patients with familial lipoprotein metabolic defects.

Metabolic adverse effects such as hypercalcemia have occurred in patients with breast cancer and bone metastases.[Ref]

Endocrine

Endocrine side effects have included increased levels of thyroxin-binding globulin which led to increased total thyroid serum levels and a decreased in resin uptake of T3. Free thyroid hormone levels remained unchanged. Other endocrine effects have included decreased fasting plasma glucose.[Ref]

General

General side effects have included fluid retention and mastodynia. Alterations in libido have occurred. Postmarketing experience with the vaginal ring has included a few cases of toxic shock syndrome. Postmarketing side effects with Vivelle-Dot include decrease in weight, reduced carbohydrate tolerance and edema.[Ref]

Hepatic

Hepatic side effects have included reports of focal nodular hyperplasia, liver cell adenomas, hepatic hemangiomas, and well-differentiated hepatocellular carcinomas. Aggravation of porphyria has been reported. Postmarketing side effects with Vivelle-Dot include abnormal liver function tests.[Ref]

Many of the reports of hepatic tumors have occurred in women taking long-term oral contraceptives. However, some tumors have been reported in women taking isolated estrogen therapy.[Ref]

Hematologic

Hematologic side effects have included hypercoagulability and an increase in venous thromboembolism.[Ref]

The clinical significance of such hypercoagulability in postmenopausal women taking estrogens has not been determined.[Ref]

Ocular

Ocular side effects have included alterations in corneal curvature and contact lens discomfort. Retinal vascular thrombosis has been reported. Postmarketing side effects with Vivelle-Dot include intolerance to contact lenses.[Ref]

Hypersensitivity

Hypersensitivity side effects have included reports of reactions including anaphylaxis. Some reports have implicated the dyes contained in some conjugated estrogen formulations. Urticaria and angioedema have also been reported.[Ref]

Postmarketing reports concerning a transdermal product (Climara) have included a few cases in which there were a combination of the symptoms of generalized hives or rash with swelling of the throat or eyelid edema.[Ref]

Other

Other side effects have included reports of a possible increase in the risk of "fibrocystic breast disease" by as much as twofold. Postmarketing side effects with Vivelle-Dot include breast enlargement and pain, nipple discharge, fibrocystic breast changes and breast cancer.[Ref]

Psychiatric

Psychiatric side effects have included case reports of rapid mood cycling in patients with severe depression. Postmarketing side effects with Vivelle-Dot include nervousness, affect liability and irritability.[Ref]

Nervous system

Nervous system side effects have included dementia, dizziness, mental depression, headache, nervousness, irritability exacerbation of epilepsy and new onset or exacerbation of migraine headaches. A case of chorea has been reported in association with estrogen therapy.[Ref]

Dermatologic

Dermatologic side effects have included chloasma or melasma, which did not always resolve following discontinuation of estrogen therapy. Scalp hair loss, hirsutism, erythema nodosum, and hemorrhagic eruptions have occurred. Postmarketing side effects with Vivelle-Dot include erythema multiforme, pruritus, purpura and rash.[Ref]

Genitourinary

Genitourinary side effects have included abnormal uterine bleeding and dysmenorrhea. In some cases, this was bleeding related to endometrial carcinoma. In addition, estrogens have increased the size of preexisting uterine leiomyomata. Postmarketing experience with the vaginal ring has included a few cases of ring adherence to the vaginal wall, making removal difficult. Postmarketing side effects with Vivelle-Dot include vaginal hemorrhage, abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, uterine leiomyomata, vaginitis, vaginal discharge, ovarian cancer and endometrial hyperplasia.[Ref]

Musculoskeletal

Musculoskeletal side effects have included arthralgias. Postmarketing side effects with Vivelle-Dot include leg cramps.[Ref]

Some side effects of Vivelle may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.