Cenestin

synthetic conjugated estrogens

Dosage Form: tablet, film coated
Cenestin®

(synthetic conjugated estrogens, A) Tablets

Rx only

Rev. A 5/2011

 

 

799-33-100121 

ESTROGENS INCREASE THE 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. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)

CARDIOVASCULAR AND OTHER RISKS

Estrogens with and without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular disorders.)

The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated equine estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Cenestin Description

Synthetic conjugated estrogens, A tablets contain a blend of nine (9) synthetic estrogenic substances. The estrogenic substances are sodium estrone sulfate, sodium equilin sulfate, sodium 17α-dihydroequilin sulfate, sodium 17α-estradiol sulfate, sodium 17β-dihydroequilin sulfate, sodium 17α-dihydroequilenin sulfate, sodium 17β-dihydroequilenin sulfate, sodium equilenin sulfate and sodium 17β-estradiol sulfate.

The structural formulae for these estrogens are:

Sodium Estrone Sulfate

Sodium 17α-Dihydroequilin Sulfate

Sodium 17α-Estradiol Sulfate

Sodium Equilenin Sulfate

Sodium 17β-Dihydroequilenin Sulfate

Sodium Equilin Sulfate

Sodium 17β-Dihydroequilin Sulfate

Sodium 17β-Estradiol Sulfate

Sodium 17α-Dihydroequilenin Sulfate

Tablets for oral administration, are available in 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg and 1.25 mg strengths of synthetic conjugated estrogens, A. Tablets also contain the following inactive ingredients: ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80 (except 0.45 mg tablets), pregelatinized starch, titanium dioxide, and triethyl citrate.

-0.3 mg tablets also contain FD&C Blue No. 2 aluminum lake and D&C Yellow No. 10 aluminum lake.

-0.45 mg tablets also contain FD&C Yellow No. 6/Sunset Yellow FCF lake.

-0.625 mg tablets also contain FD&C Red No. 40 aluminum lake.

-0.9 mg tablets do not contain additional color additives.

-1.25 mg tablets also contain FD&C Blue No. 2 aluminum lake.

Cenestin - Clinical Pharmacology

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

Absorption

Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several hours. The effect of food on the bioavailability of synthetic conjugated estrogens, A from Cenestin has not been studied.

Table 1 PHARMACOKINETIC  PARAMETERS FOR UNCONJUGATED AND CONJUGATED ESTROGENS IN HEALTHY POSTMENOPAUSAL WOMEN UNDER FASTING CONDITIONS

Pharmacokinetic Parameters of Unconjugated Estrogens Following a Dose of 2 x 0.625 mg Cenestin
Drug	Cmax (pg/mL) CV%	Tmax (h) CV%	AUC0-72h (pg•hr/mL) CV%
Baseline-corrected estrone	84.5 (41.7)	8.25 (35.6)	1749 (43.8)
Equilin	45.6 (47.3)	7.78 (28.8)	723 (67.9)

Pharmacokinetic Parameters of Conjugated Estrogens Following a Dose of 2 x 0.625 mg Cenestin
Drug	Cmax (pg/mL) CV%	Tmax (h) CV%	t ½ (h) CV%	AUC0-72h (pg•hr/mL) CV%
Baseline-corrected estrone	4.43 (40.4)	7.7 (30.3)	10.6 (25.4)	69.89 (39.2)
Equilin	3.27 (43.5)	5.8 (31.1)	9.7 (23.0)	46.46 (47.5)

Distribution

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.

Metabolism

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 portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates.

Special Populations

Cenestin was investigated in postmenopausal women. No pharmacokinetic studies were conducted in special populations, including patients with renal or hepatic impairment.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers and 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.

Clinical Studies

Effects on vasomotor symptoms

A randomized, placebo-controlled multicenter clinical study was conducted evaluating the effectiveness of Cenestin for the treatment of moderate to severe vasomotor symptoms in 120 postmenopausal women between 38 and 66 years of age (68% were Caucasian). Patients were randomized to receive either placebo or 0.625 mg Cenestin daily for 12 weeks. Dose titration was allowed after one week of treatment. The starting dose was either doubled (2 x 0.625 mg Cenestin or placebo taken daily) or reduced (0.3 mg Cenestin or placebo taken daily), if necessary. Efficacy was assessed at 4 and 12 weeks of treatment. By week 12, 10% of the study participants remained on a single 0.625 mg Cenestin tablet daily while 77% required two (0.625 mg) tablets daily. The results in Table 2 indicate that compared to placebo, Cenestin produced a reduction in moderate to severe vasomotor symptoms at weeks 4 and 12.

A second randomized, placebo-controlled multicenter clinical study was conducted evaluating the effectiveness of 0.45 mg Cenestin tablets, for the treatment of moderate to severe vasomotor symptoms in 104 menopausal women between 52 and 74 years of age (76% were Caucasian). Patients were randomized to receive either placebo or 0.45 mg Cenestin daily for 12 weeks. Efficacy was assessed at 4 and 12 weeks of treatment. The mean change in the number of moderate to severe hot flushes per week shown in Table 3 indicate that compared to placebo, 0.45 mg Cenestin produced a reduction in moderate to severe vasomotor symptoms at weeks 4 and 12. A corresponding reduction in the severity of hot flushes was demonstrated at weeks 5 and 12.

Table 2 Clinical Response* Mean Change in the Number of Moderate to Severe Hot Flushes Per Week, 0.625 mg and 2 x 0.625 mg Cenestin, ITT Population

* Intent-to-treat population = 117 † Combined results for 0.625 mg and 0.625 mg Cenestin tablets.
	Cenestin† 0.625 mg and 2 x 0.625 mg (n=70)	Placebo (n=47)
Baseline
Mean # (SD)	96.8 (42.6)	94.1 (33.9)
Week 4
Mean # (SD)	28.7 (28.8)	45.7 (36.8)
Mean Change from Baseline (SD)	-68.1 (43.9)	-48.4 (46.2)
P-value vs. Placebo	p=.022
Week 12
Mean # (SD)	16.5 (25.7)	37.8 (38.7)
Mean Change from Baseline (SD)	-80.3 (50.3)	-56.3 (48.0)
P-value vs. Placebo	p=0.10
Mean = Arithmetic Mean, SD = Standard Deviation

Table 3 Clinical Response* Mean Change in the Number of Moderate to Severe Hot Flushes Per Week, 0.45 mg Cenestin, ITT Population

* Intent-to-treat population = 104
	Cenestin 0.45 mg (n=53)	Placebo (n=51)
Baseline
Mean # (SD)	95.9 (37.0)	95.9 (41.6)
Week 4
Mean # (SD)	45.7 (45.9)	59.4 (46.2)
Mean Change from Baseline (SD)	-50.3 (35.4)	-36.5 (42.9)
P-value vs. Placebo	p=0.14
Week 12
Mean # (SD)	26.1 (43.0)	50.5 (48.4)
Mean Change from Baseline (SD)	-69.9 (38.1)	-45.4 (44.7)
P-value vs. Placebo	p<.001
Mean = Arithmetic Mean, SD = Standard Deviation

Effects on vulvar and vaginal atrophy

The effects of 0.3 mg Cenestin on moderate to severe symptoms of vulvar and vaginal atrophy were confirmed in a 16-week, randomized, placebo-controlled, multicenter clinical study in 72 postmenopausal women between 30 and 77 years of age (53% were Caucasian). Patients were randomized to receive either placebo or 0.3 mg Cenestin daily for 16 weeks. Efficacy was assessed at weeks 12 and 16 for vaginal wall cytology and week 16 for vaginal pH. Results for percent of superficial cells from a maturation index of the vaginal mucosa are shown in Figure 2. Mean vaginal pH decreased from a baseline of 6.20 to 5.14 for Cenestin and increased to 6.15 from a baseline of 6.03 for placebo.

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 either the use of oral 0.625 mg conjugated equine 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 cause. 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 4 below:

Table 4 Relative and Absolute Risk Seen in the Estrogen/Progestin Substudy of the WHI*

* adapted from JAMA, 2002; 288:321-333. † a subset of the events was combined in a “global index,” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. ‡ nominal confidence intervals unadjusted for multiple looks and multiple comparisons. CE - conjugated estrogens § includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer. ¶ not included in Global Index.
Event†	Relative Risk Conjugated Equine Estrogens/Medroxyprogesterone Acetate vs Placebo at 5.2 years (95% CI‡)	Placebo n - 8102	CE/MPA n = 8506
		Absolute Risk per 10,000 Person-years
CHD events     Non-fatal MI     CHD death	1.29 (1.02-1.63) 1.32 (1.02-1.72) 1.18 (0.70-1.97)	30 23 6	37 30 7
Invasive breast cancer§	1.26 (1.00-1.59)	30	38
Stroke	1.41 (1.07-1.85)	21	29
Pulmonary embolism	2.13 (1.39-3.25)	8	16
Colorectal cancer	0.63 (0.43-0.92)	16	10
Endometrial cancer	0.83 (0.47-1.47)	6	5
Hip fracture	0.66 (0.45-0.98)	15	10
Death due to causes other    than the events above	0.92 (0.74-1.14)	40	37
Global index†	1.15 (1.03-1.28)	151	170
Deep vein thrombosis¶	2.07 (1.49-2.87)	13	26
Vertebral fractures¶	0.66 (0.44-0.98)	15	9
Other osteoporotic fractures¶	0.77 (0.69-0.86)	170	131

For those outcomes included in the “global index,” absolute excess risks per 10,000 person-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 sub-study of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo.

After an average follow-up of 4 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 this finding applies to younger postmenopausal women. (See BOXED WARNING and WARNINGS, Dementia.)

Indications and Usage for Cenestin

Cenestin therapy is indicated for the:

1. Treatment of moderate-to-severe vasomotor symptoms associated with the menopause.

• 0.45 mg Cenestin


• 0.625 mg Cenestin


• 0.9 mg Cenestin


• 1.25 mg Cenestin

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.

• 0.3 mg Cenestin

Contraindications

Cenestin should not be used in women with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.


2. Known, suspected, or history of cancer of the breast.


3. Known or suspected estrogen-dependent neoplasia.


4. Active deep vein thrombosis, pulmonary embolism or a history of these conditions.


5. Active or recent (e.g., within the past year) arterial thromboembolic disease (e.g., stroke, myocardial infarction).


6. Liver dysfunction or disease.


7. Cenestin therapy should not be used in patients with known hypersensitivity to its ingredients.


8. Known or suspected pregnancy. There is no indication for Cenestin in pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy. (See PRECAUTIONS.)

Warnings

See BOXED WARNINGS.

 1. Cardiovascular disorders.

Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

a. Coronary heart disease and stroke.

In the Women’s Health Initiative (WHI) study, an increase in the number of strokes has been observed in women receiving CE compared to placebo.

In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs. 30 per 10,000 women-years). The increase in risk was observed in year one and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs. 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted.

In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625mg/2.5mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.


Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

 b. Venous thromboembolism (VTE)

In the Women's Health Initiative (WHI) study, an increase in VTE has been observed in women receiving CE compared to placebo.

In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

2. Malignant neoplasms.

a. Endometrial cancer.

The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women taking estrogen/progestin combinations 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 of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

b. Breast cancer.

The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA (see CLINICAL PHARMACOLOGY, Clinical Studies). The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration.

The CE/MPA sub-study of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy.

In the CE/MPA sub-study, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same sub-study, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

3. Dementia

In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use.)

4. Gallbladder disease

A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

5. Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

6. Visual abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or renal vascular lesions, estrogens should be permanently discontinued.

Precautions

A. General

1. Addition of a progestin when a woman has not had a hysterectomy. Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
   
   There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include a possible increased risk of breast cancer.


2. Elevated blood pressure. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.


3. Hypertriglyceridemia. In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.


4. Impaired liver function and past history of cholestatic jaundice. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.


5. Hypothyroidism. Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.


6. Fluid retention. Because estrogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.


7. Hypocalcemia. Estrogens should be used with caution in individuals with severe hypocalcemia.


8. Ovarian cancer. The CE/MPA substudy of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations.


9. Exacerbation of endometriosis. Endometriosis may be exacerbated with administration of estrogens. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen alone therapy. For patients known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.


10. Exacerbation of other conditions. Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with patients for whom they prescribe Cenestin.

C. Laboratory Tests

Estrogen administration should be initiated at the lowest dose for the approved indication and then guided by clinical response, rather than by serum hormone levels (e.g., estradiol, FSH).

D. Drug/Laboratory Test Interactions

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.


2. Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Patients on thyroid replacement therapy may require higher doses of thyroid hormone.


3. Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG)) leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).


4.  Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentration, increased triglyceride levels.


5. Impaired glucose tolerance.


6. Reduced response to metyrapone test.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women, with and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and ovarian cancer. (See BOXED WARNINGS, WARNINGS and PRECAUTIONS.)

Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

F. Pregnancy

Cenestin should not be used during pregnancy. (See CONTRAINDICATIONS.)

G. Nursing Mothers

Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk. Detectable amounts of estrogens have been identified in the milk of

Profasi HP

Pronunciation: KORE-ee-ON-ik goe-NAD-oh-troe-pin
Generic Name: Chorionic Gonadotropin
Brand Name: Examples include Novarel and Pregnyl

Profasi HP is used for:

Treating fertility problems in certain women who have not gone through menopause. Treating certain testicular development problems and stimulating the development of secondary sexual characteristics in certain patients. It is also used to treat boys 4 to 9 years old who have testicles that have not moved into the scrotum.

Profasi HP is a hormone. Human chorionic gonadotropin (HCG) stimulates cells in the testicles to produce androgens and in the ovaries to produce progesterone. Androgens cause the development of male secondary sexual characteristics (eg, hair growth, deepening voice) and may cause the testicles to drop. HCG acts like luteinizing hormone (LH) by stimulating ovulation (release of an egg) in women.

Do NOT use Profasi HP if:

• you are allergic to any ingredient in Profasi HP


• you have androgen (male sex hormone)-dependent tumors, prostate cancer, an active blood clot, brain lesions, unexplained uterine or genital bleeding, an enlarged ovary or ovarian cysts, or an enlargement or tumor of the pituitary gland


• you are experiencing abnormally early puberty


• you are pregnant

Contact your doctor or health care provider right away if any of these apply to you.

Before using Profasi HP:

Some medical conditions may interact with Profasi HP. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have asthma, uterine fibroids, heart or kidney problems, migraine headaches, polycystic ovarian syndrome, or epilepsy

Some MEDICINES MAY INTERACT with Profasi HP. However, no specific interactions with Profasi HP are known at this time.

Ask your health care provider if Profasi HP may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Profasi HP:

Use Profasi HP as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Profasi HP is usually administered as an injection at your doctor's office, hospital, or clinic. If you are using Profasi HP at home, carefully follow the injection procedures taught to you by your health care provider.


• If Profasi HP contains particles or is discolored, or if the vial is cracked or damaged in any way, do not use it.


• Using the technique described to you by your doctor, add the diluent to the vial that contains the medicine. Mix the solution by gently rotating the vial. DO NOT SHAKE. The solution should be clear and free of particles.


• Wipe the rubber stopper of the vial with an alcohol swab. Insert the needle straight through the center circle of the rubber stopper. Draw up the solution for injection. After drawing up the solution, switch needles. Be sure all air bubbles are tapped out of the syringe.


• Wipe the appropriate injection site (usually the upper thigh or buttocks) with an alcohol swab, then insert the syringe. To be sure that the needle is not in a vein, pull back on the plunger of the syringe while holding the syringe in place. If the syringe begins to fill with blood, the needle is in a vein. If this happens, remove the needle from the skin, throw the syringe away, and start the procedure again using new materials (drugs, syringes, etc.).


• After giving the injection, cover the injection site with a small bandage if necessary.


• Keep this product, as well as syringes and needles, out of the reach of children. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.


• If you miss a dose of Profasi HP, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Profasi HP.

Important safety information:

• Women need to have a thorough gynecological exam before beginning treatment with Profasi HP.


• Men need to have a complete medical and hormone evaluation before starting therapy with Profasi HP.


• Profasi HP may increase your chance of multiple births (eg, twins). Talk with your doctor to discuss your chances of multiple births.


• Use of Profasi HP can increase your risk of serious blood clots and ruptured ovarian cysts. Discuss the risk of these effects with your doctor.


• Ovarian hyperstimulation syndrome (OHSS) is a severe side effect that may occur in some women who use Profasi HP. Contact your doctor right away if you develop severe stomach pain or bloating; nausea, vomiting, or diarrhea; sudden unexplained weight gain; shortness of breath; or decreased urination.


• Profasi HP may interfere with certain lab tests. Be sure your doctor and lab personnel know you are using Profasi HP.


• Lab tests, including hormone levels, may be performed to monitor your progress or to check for side effects. Be sure to keep all doctor and lab appointments.


• Profasi HP is not recommended for use in CHILDREN younger than 4 years; safety and effectiveness in these children have not been confirmed.


• Profasi HP may have benzyl alcohol in it. Do not use it in NEWBORNS or INFANTS. It may cause serious and sometimes fatal nervous system problems and other side effects.


• PREGNANCY and BREAST-FEEDING: Do not use Profasi HP if you are pregnant. It may cause harm to the fetus. If you think you may be pregnant, contact your doctor right away. It is not known if Profasi HP is found in breast milk. If you are or will be breast-feeding while you are using Profasi HP, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Profasi HP:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Fatigue; headache; irritability; nausea; pain, swelling, bruising, or redness at the injection site; restlessness; tiredness.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); abnormal breast development; bloating or swelling in the stomach or pelvic area; breast tenderness; depression; infrequent urination; persistent or severe nausea, vomiting, or diarrhea; stomach or pelvic pain; sudden shortness of breath; swelling of the hands, feet, or legs; symptoms of a serious blood clot (eg, calf or leg pain, swelling, redness, or tenderness; chest, jaw, or left arm pain; confusion; fainting; numbness of an arm or leg; one-sided weakness; slurred speech; sudden, severe headache; vision changes); unusual early onset of puberty; weight gain.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Profasi HP side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Profasi HP:

Before mixing, store Profasi HP at room temperature between 68 and 77 degrees F (20 and 25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Different products have different storage instructions after mixing. Check with your doctor or pharmacist about how to store Profasi HP and how long it is good for after mixing. Keep Profasi HP out of the reach of children and away from pets.

General information:

• If you have any questions about Profasi HP, please talk with your doctor, pharmacist, or other health care provider.


• Profasi HP is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Profasi HP. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Profasi HP resources

• Profasi HP Side Effects (in more detail)
• Profasi HP Use in Pregnancy & Breastfeeding
• Profasi HP Drug Interactions
• Profasi HP Support Group
• 0 Reviews for Profasi HP - Add your own review/rating

Compare Profasi HP with other medications

• Female Infertility
• Hypogonadism, Male
• Ovulation Induction
• Prepubertal Cryptorchidism

Dioralyte Relief Raspberry and Blackcurrant

1. Name Of The Medicinal Product

Dioralyte Relief Raspberry

Dioralyte Relief Blackcurrant

2. Qualitative And Quantitative Composition

Active ingredients per sachet:

Pre-cooked Rice Powder	6g
Sodium Citrate PhEur	580mg
Sodium Chloride PhEur	350mg
Potassium Chloride PhEur	300mg

3. Pharmaceutical Form

Sachet containing powder for mixing with water prior to administration.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of fluid and electrolyte loss associated with acute diarrhoea.

4.2 Posology And Method Of Administration

Posology

Adults and children:

One sachet after every loose motion up to a maximum of 5 sachets per day for 3-4 days.

Infants from 3 months to one year under medical advice:

In the event of diarrhoea and depending on the extent of dehydration (loss of weight assessed at less than 10%) 150 to 200 ml/kg/24 hours of preparation may be given.

•   half the volume is to be given during the first 8 hours, and the other half during the next 16 hours.

•   in the event of vomiting accompanying the diarrhoea, the amount administered can be divided up (5 to 10 ml every 5 minutes) and this may be gradually increased until the infant can drink normally.

Method of Administration

Pour the contents of one sachet into a large glass. Add 200ml of drinking water. Mix well until the liquid has a milky appearance and drink the whole glassful Ensure that no solid is remaining at the bottom of the glass and do not use extra water to rinse out the glass. For infants and where drinking water is not available, the water should be freshly boiled and cooled. The solution should be made up immediately before use.

4.3 Contraindications

Dioralyte Relief should not be used in patients with phenylketonuria. However, there may be a number of conditions where treatment with Dioralyte Relief may be inappropriate, e.g. intestinal obstruction requiring surgical intervention, cases of severe renal or hepatic impairment.

4.4 Special Warnings And Precautions For Use

For oral administration only. Dioralyte Relief should not be reconstituted in diluents other than water.

Each sachet should always be dissolved in 200ml water.

Dioralyte Relief should not be administered to infants under 3 months and for those aged 3 months to 1 year, administered under medical advice.

Infants under the age of 2 with diarrhoea should be seen by the physician as soon as possible.

If diarrhoea persists unremittingly for longer than 36 hours the patient should be reassessed by the physician.

No specific precautions are necessary in the elderly. However, care should be taken when administering Dioralyte Relief solution in cases of severe renal or hepatic impairment or other conditions where normal electrolyte balance may be disturbed. Dioralyte Rlief should not be used for self-treatment by patients on low potassium or sodium diets. The use of Dioralyte Relief in patients with these conditions should be supervised by a physician.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Dioralyte Relief is not contraindicated in pregnancy or lactation but should be used on medical advice.

4.7 Effects On Ability To Drive And Use Machines

Dioralyte Relief could not be expected to affect the ability to drive or use machines.

4.8 Undesirable Effects

None known.

4.9 Overdose

In the event of significant overdose, serum electrolytes should be evaluated as soon as possible, appropriate steps taken to correct any abnormalities and levels monitored until return to normal levels is established. This is particularly important in the very young.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Dioralyte Relief contains a balanced amount of electrolytes, starch and proteins in water. Oral rehydration therapy with Dioralyte Relief enables a dehydrated subject to be rehydrated rapidly. The presence of pre-cooked rice in the formulation enables watery stools to return to normal more rapidly.

The advantages of Dioralyte Relief are bound with its composition.

•Water: the appropriate amount is essential to correct dehydration.

•Starch: low osmotic capacity (unlike pure glucose) thus preventing any additional loss of fluid through the stools. Rice starch contains 20% amylose and 80% amylopectin.

•Proteins: specific nutritional properties.

•Electrolytes: essential for restoring the ionic equilibrium. The role of citrate is to correct the acidosis that occurs as a result of diarrhoea. Citrate also enhances the absorption of Na⁺ and is more stable than bicarbonate.

5.2 Pharmacokinetic Properties

Content of electrolytes in the reconstituted preparation:

Na+	60 mmol/l
Cl-	50 mmol/l
K+	20 mmol/l
Citrate	10 mmol/l (or 30 meq/l)
Osmolarity	140 mosm/l

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Dioralyte Relief Raspberry: Raspberry Flavour Givaudan 611417E, hypromellose, aspartame, ethanol 96%, purified water

Dioralyte Relief Blackcurrant: Blackcurrant Flavour Firmenich 501017, hypromellose, aspartame, ethanol 96%, purified water

6.2 Incompatibilities

None known.

6.3 Shelf Life

A shelf life of 36 months is given for unopened sachets of the product when stored under the conditions given in section 6.4. Once reconstituted, any solution should be used within one hour, or within 24 hours if stored in a refrigerator.

6.4 Special Precautions For Storage

Store in a dry place under 25^oC.

6.5 Nature And Contents Of Container

Carton containing paper/PVDC sachets of Dioralyte Relief Raspberry or Blackcurrant powder. Dioralyte Relief Raspberry or Blackcurrant is available in packs of 6 sachets.

6.6 Special Precautions For Disposal And Other Handling

See section 4.2 for instructions on reconstitution.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

Dioralyte Relief Raspberry: PL 04425/0280

Dioralyte Relief Blackcurant: PL 04425/0273

9. Date Of First Authorisation/Renewal Of The Authorisation

Dioralyte Relief Raspberry: 19 March 2009

Dioralyte Relief Blackcurant: 9 February 2009

10. Date Of Revision Of The Text

19 March 2009

11 LEGAL CLASSIFICATION

GSL

Difflam Spray

1. Name Of The Medicinal Product

Difflam Spray

2. Qualitative And Quantitative Composition

Each metered dose pump spray delivers Benzydamine hydrochloride 0.15% w/v, approximately 175 microlitres per puff.

3. Pharmaceutical Form

Difflam Spray is a metered dose pump throat spray.

4. Clinical Particulars

4.1 Therapeutic Indications

Difflam Spray is a locally acting analgesic and anti-inflammatory treatment for the throat and mouth.

It is especially useful for the relief of pain in traumatic conditions such as following tonsillectomy or the use of a naso-gastric tube; dental surgery.

4.2 Posology And Method Of Administration

For oral administration.

Adults, adolescents and elderly: 4 to 8 puffs every 1½-3 hourly.

Children(6-12): 4 puffs every 1½-3 hourly.

Children under 6: One puff to be administered per 4 kg body weight, up to a maximum of 4 puffs, 1½-3 hourly.

Because of the small amount of drug applied, elderly patients can receive the same dose as adults.

4.3 Contraindications

Difflam Spray is contra-indicated in patients with known hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

Avoid contact with the eyes.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Difflam should not be used in pregnancy or lactation unless considered essential by the physician. There is no evidence of a teratogenic effect in animal studies.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

Side-effects are minor. Occasionally, oral tissue numbness or 'stinging' sensations may occur. The stinging has been reported to disappear upon continuation of the treatment, however if it persists it is recommended that treatment be discontinued. Hypersensitivity reactions occur very rarely but may be associated with pruritus rash, urticaria, photodermatitis and occasionally laryngospasm or bronchospasm.

4.9 Overdose

Difflam is unlikely to cause adverse systemic effects, even if accidental ingestion should occur. No special measures are required.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Benzydamine exerts an anti-inflammatory and analgesic action by stabilising the cellular membrane and inhibiting prostaglandin synthesis.

5.2 Pharmacokinetic Properties

Following oral administration, Benzydamine is rapidly absorbed from the gastrointestinal tract and maximum plasma levels reached after 2-4 hours. The most important aspect of the tissue distribution of Benzydamine is its tendency to concentrate at the site of inflammation.

About half of the Benzydamine is excreted unchanged via the kidney at a rate of 10% of the dose within the first 24 hours. The remainder is metabolised, mostly to N-Oxide.

5.3 Preclinical Safety Data

Non-Clinical Data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated toxicity, genotoxicity, cardiogenic potential, and toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glycerol Ph. Eur.

Saccharin FU

Sodium Bicarbonate Ph. Eur.

Ethanol FU

Methylhydroxybenzoate Ph. Eur.

Mouthwash Flavour

Polysorbate 20 Ph. Eur.

Purified Water Ph. Eur.

6.2 Incompatibilities

None.

6.3 Shelf Life

The shelf life expiry date for this product shall not exceed 3 years from the date of its manufacture.

6.4 Special Precautions For Storage

Do not store above 30°C, do not refrigerate or freeze. Keep out of the reach of children.

6.5 Nature And Contents Of Container

Difflam Spray is presented in a 30 ml HDPE bottle with 170 μl valve pump spray.

6.6 Special Precautions For Disposal And Other Handling

The patient should read the instruction leaflet before use.

7. Marketing Authorisation Holder

Meda Pharmaceuticals Ltd

249 West George Street

Glasgow

G2 4RB

Trading as:

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

8. Marketing Authorisation Number(S)

PL 15142/0046

9. Date Of First Authorisation/Renewal Of The Authorisation

30^th November 1984 / 05^th March 2004

10. Date Of Revision Of The Text

17^th June 2011

Enalaprilat

Pronunciation: en-AL-a-pril-AT
Generic Name: Enalaprilat
Brand Name: Generic only. No brands available.

Enalaprilat may cause injury or death to the fetus if used after the third month of pregnancy. If you think you may be pregnant, contact your doctor right away.

Enalaprilat is used for:

Treating high blood pressure in patients unable to take Enalaprilat by mouth. It may be used alone or with other medicines. It may also be used for other conditions as determined by your doctor.

Enalaprilat is an angiotensin-converting enzyme (ACE) inhibitor. It works by helping to relax blood vessels. This helps to lower blood pressure.

Do NOT use Enalaprilat if:

• you are allergic to any ingredient in Enalaprilat or similar medicines (eg, captopril, lisinopril)


• you are pregnant


• you have a history of sudden or severe swelling (angioedema) of the throat, airway, face, lips, hands, or feet following the use of Enalaprilat, similar medicines, or for any other reasons


• you are taking dextran sulfate

Contact your doctor or health care provider right away if any of these apply to you.

Before using Enalaprilat:

Some medical conditions may interact with Enalaprilat. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have a history of liver or kidney problems or kidney transplant, or if you are receiving dialysis


• if you have a history of bone marrow problems, low blood counts, low blood sodium, high blood potassium, the blood disease porphyria, lupus, scleroderma, collagen vascular disease, narrowing or hardening of the arteries of the brain or heart, or chest pain


• if you have diabetes, especially if you are also taking aliskiren

Some MEDICINES MAY INTERACT with Enalaprilat. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Diuretics (eg, furosemide, hydrochlorothiazide) because excessive decreases in blood pressure may occur, which may cause dizziness, especially upon standing, or fainting


• Dextran sulfate because it may increase the risk of allergic reaction (eg, rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue) and lightheadedness upon standing


• Nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, aspirin, indomethacin) because they may decrease Enalaprilat's effectiveness and the risk of kidney damage may be increased


• Certain gold-containing medicines (eg, sodium aurothiomalate) because flushing, nausea, vomiting, and low blood pressure may occur


• Lithium or thiopurines (eg, azathioprine) because the risk of serious side effects may be increased by Enalaprilat


• Oral diabetes medicine (eg, glyburide) because side effects, including a low blood sugar level (eg, dizziness, headache, hunger, shakiness or weakness, sweating), may be increased by Enalaprilat


• Angiotensin receptor blockers (eg, losartan) because the risk of serious kidney problems and high blood potassium levels may be increased


• Aldosterone blockers (eg, eplerenone), aliskiren, potassium-sparing diuretics (eg, amiloride), or potassium supplements because the risk of high blood potassium levels may be increased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Enalaprilat may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Enalaprilat:

Use Enalaprilat as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Enalaprilat is usually given as an injection at your doctor's office, hospital, or clinic. If you will be using Enalaprilat at home, a health care provider will teach you how to use it. Be sure you understand how to use Enalaprilat. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have any questions.


• Do not use Enalaprilat if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• If you miss a dose of Enalaprilat, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Enalaprilat.

Important safety information:

• Enalaprilat may cause dizziness or lightheadedness. These effects may be worse if you take it with alcohol or certain medicines. Use Enalaprilat with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Check with your doctor before you use a salt substitute or a product that has potassium in it.


• If vomiting or diarrhea occurs, you will need to take care not to become dehydrated. Contact your doctor for instructions.


• Patients who take medicine for high blood pressure often feel tired or run down for a few weeks after starting treatment. Be sure to take your medicine even if you may not feel "normal." Tell your doctor if you develop any new symptoms.


• Enalaprilat may not work as well in black patients. They may also be at greater risk of side effects. Contact your doctor if your symptoms do not improve or if they become worse.


• Enalaprilat may cause you to become sunburned more easily. Avoid the sun, sunlamps, or tanning booths until you know how you react to Enalaprilat. Use a sunscreen or wear protective clothing if you must be outside for more than a short time.


• Tell your doctor or dentist that you take Enalaprilat before you receive any medical or dental care, emergency care, or surgery.


• Lab tests, including liver function, kidney function, and complete blood cell counts, may be performed while you use Enalaprilat. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.


• Enalaprilat should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.


• PREGNANCY and BREAST-FEEDING: Enalaprilat may cause birth defects or fetal death if you use it while you are pregnant. If you think you may be pregnant, contact your doctor right away. Enalaprilat is found in breast milk. If you are or will be breast-feeding while you use Enalaprilat, check with your doctor. Discuss any possible risks to your baby.

Possible side effects of Enalaprilat:

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Diarrhea; dizziness or lightheadedness when sitting up or standing; headache; nausea; persistent, dry cough; tiredness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; hoarseness; infection (eg, fever, sore throat); irregular or slow heartbeat; unusual stomach pain; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Enalaprilat side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include dizziness; lightheadedness, especially upon standing; weakness.

Proper storage of Enalaprilat:

Store Enalaprilat at room temperature below 86 degrees (30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Enalaprilat out of the reach of children and away from pets.

General information:

• If you have any questions about Enalaprilat, please talk with your doctor, pharmacist, or other health care provider.


• Enalaprilat is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Enalaprilat. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Enalaprilat resources

• Enalaprilat Side Effects (in more detail)
• Enalaprilat Support Group
• 0 Reviews · Be the first to review/rate this drug

• enalapril Advanced Consumer (Micromedex) - Includes Dosage Information


• Enalaprilat/Enalapril Maleate Monograph (AHFS DI)


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Norinyl 1+35

Generic Name: ethinyl estradiol and norethindrone (ETH in il ess tra DYE ole and nor ETH in drone)

Brand Names: Aranelle, Balziva, Brevicon, Briellyn, Cyclafem 1/35, Cyclafem 7/7/7, Estrostep Fe, Femcon FE, Generess Fe, Gildess FE 1.5/0.03, Gildess FE 1/0.2, Junel 1.5/30, Junel 1/20, Junel Fe 1.5/30, Junel Fe 1/20, Leena, Lo Loestrin Fe, Loestrin 21 1.5/30, Loestrin 21 1/20, Loestrin 24 Fe, Loestrin Fe 1.5/30, Loestrin Fe 1/20, Microgestin 1.5/30, Microgestin 1/20, Microgestin FE 1.5/30, Microgestin FE 1/20, Modicon, Necon 0.5/35, Necon 1/35, Necon 10/11, Necon 7/7/7, Norinyl 1+35, Nortrel 0.5/35, Nortrel 1/35, Nortrel 7/7/7, Ortho-Novum 1/35, Ortho-Novum 7/7/7, Ovcon 35, Ovcon 35 Fe, Ovcon 50, Tilia Fe, Tri-Legest Fe, Tri-Norinyl, Zenchent Fe, Zeosa

What is Norinyl 1+35 (ethinyl estradiol and norethindrone)?

Ethinyl estradiol and norethindrone contains a combination of female hormones that prevent ovulation (the release of an egg from an ovary). This medication also causes changes in your cervical mucus and uterine lining, making it harder for sperm to reach the uterus and harder for a fertilized egg to attach to the uterus.

Ethinyl estradiol and norethindrone are used as contraception to prevent pregnancy. It is also used to treat severe acne.

Ethinyl estradiol and norethindrone may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Norinyl 1+35 (ethinyl estradiol and norethindrone)?

Do not use birth control pills if you are pregnant or if you have recently had a baby. Do not use this medication if you have any of the following conditions: a history of stroke or blood clot, circulation problems, a hormone-related cancer such as breast or uterine cancer, abnormal vaginal bleeding, liver disease or liver cancer, or a history of jaundice caused by birth control pills.

You may need to use back-up birth control, such as condoms or a spermicide, when you first start using this medication. Follow your doctor's instructions.

Taking hormones can increase your risk of blood clots, stroke, or heart attack, especially if you smoke and are older than 35.

Some drugs can make birth control pills less effective, which may result in pregnancy. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

What should I discuss with my healthcare provider before taking Norinyl 1+35 (ethinyl estradiol and norethindrone)?

This medication can cause birth defects. Do not use if you are pregnant. Tell your doctor right away if you become pregnant, or if you miss two menstrual periods in a row. If you have recently had a baby, wait at least 4 weeks before taking birth control pills (6 weeks if you are breast-feeding). You should not take birth control pills if you have:

• 
  

  coronary artery disease, a severe or uncontrolled heart valve disorder, untreated or uncontrolled high blood pressure;

  
  


• 
  

  a history of a stroke, blood clot, or circulation problems;

  
  


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  a hormone-related cancer such as breast or uterine cancer;

  
  


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  unusual vaginal bleeding that has not been checked by a doctor;

  
  


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  liver disease or liver cancer;

  
  


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  severe migraine headaches; or

  
  


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  a history of jaundice caused by pregnancy or birth control pills.

  
  

To make sure you can safely take this medication, tell your doctor if you have any of these other conditions:

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  high blood pressure or a history of heart disease;

  
  


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  high cholesterol, gallbladder disease, or diabetes;

  
  


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  migraine headaches or a history of depression; or

  
  


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  a history of breast cancer or an abnormal mammogram.

  
  

The hormones in birth control pills can pass into breast milk and may harm a nursing baby. This medication may also slow breast milk production. Do not use if you are breast-feeding a baby.

How should I take Norinyl 1+35 (ethinyl estradiol and norethindrone)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Take your first pill on the first day of your period or on the first Sunday after your period begins (follow your doctor's instructions).

You may need to use back-up birth control, such as condoms or a spermicide, when you first start using this medication. Follow your doctor's instructions.

The 28-day birth control pack contains seven "reminder" pills to keep you on your regular cycle. Your period will usually begin while you are using these reminder pills.

You may have breakthrough bleeding, especially during the first 3 months. Tell your doctor if this bleeding continues or is very heavy.

Take one pill every day, no more than 24 hours apart. When the pills run out, start a new pack the following day. You may get pregnant if you do not use this medication regularly. Get your prescription refilled before you run out of pills completely.

The chewable tablet may be chewed or swallowed whole. If chewed, drink a full glass of water just after you swallow the pill.

If you need surgery or medical tests or if you will be on bed rest, you may need to stop using this medication for a short time. Any doctor or surgeon who treats you should know that you are using birth control pills.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Missing a pill increases your risk of becoming pregnant. If you miss one "active" pill, take two pills on the day that you remember. Then take one pill per day for the rest of the pack.

If you miss two "active" pills in a row in week one or two, take two pills per day for two days in a row. Then take one pill per day for the rest of the pack. Use back-up birth control for at least 7 days following the missed pills.

If you miss two "active" pills in a row in week three, or if you miss three pills in a row during any of the first 3 weeks, throw out the rest of the pack and start a new one the same day if you are a Day 1 starter. If you are a Sunday starter, keep taking a pill every day until Sunday. On Sunday, throw out the rest of the pack and start a new one that day.

If you miss two or more pills, you may not have a period during the month. If you miss a period for two months in a row, call your doctor because you might be pregnant.

If you miss any reminder pills, throw them away and keep taking one pill per day until the pack is empty. You do not need back-up birth control if you miss a reminder pill.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Overdose symptoms may include nausea, vomiting, and vaginal bleeding.

What should I avoid while taking Norinyl 1+35 (ethinyl estradiol and norethindrone)?

Do not smoke while using birth control pills, especially if you are older than 35. Smoking can increase your risk of blood clots, stroke, or heart attack caused by birth control pills.

Birth control pills will not protect you from sexually transmitted diseases--including HIV and AIDS. Using a condom is the only way to protect yourself from these diseases.

Norinyl 1+35 (ethinyl estradiol and norethindrone) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have any of these serious side effects:

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  sudden numbness or weakness, especially on one side of the body;

  
  


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  sudden severe headache, confusion, problems with vision, speech, or balance;

  
  


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  sudden cough, wheezing, rapid breathing, coughing up blood;

  
  


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  pain, swelling, warmth, or redness in one or both legs;

  
  


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  chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling;

  
  


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  a change in the pattern or severity of migraine headaches;

  
  


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  pain in your upper stomach, jaundice (yellowing of the skin or eyes);

  
  


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  a lump in your breast;

  
  


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  swelling in your hands, ankles, or feet; or

  
  


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  symptoms of depression (sleep problems, weakness, mood changes).

  
  

Less serious side effects may include:

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  mild nausea or vomiting, appetite or weight changes;

  
  


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  breast swelling or tenderness;

  
  


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  headache, nervousness, dizziness;

  
  


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  problems with contact lenses;

  
  


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  freckles or darkening of facial skin, loss of scalp hair; or

  
  


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  vaginal itching or discharge.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Norinyl 1+35 (ethinyl estradiol and norethindrone)?

Some drugs can make ethinyl estradiol and norethindrone less effective, which may result in pregnancy. Before using ethinyl estradiol and norethindrone, tell your doctor if you are using any of the following drugs:

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  acetaminophen (Tylenol) or ascorbic acid (vitamin C);

  
  


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  bosentan (Tracleer);

  
  


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  prednisolone (Orapred);

  
  


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  St. John's wort;

  
  


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  theophylline (Elixophyllin, Theo-24, Uniphyl);

  
  


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  an antibiotic;

  
  


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  HIV or AIDS medications;

  
  


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  phenobarbital (Solfoton) and other barbiturates; or

  
  


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  seizure medication.

  
  

This list is not complete and other drugs may interact with birth control pills. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Norinyl 1+35 resources

• Norinyl 1+35 Side Effects (in more detail)
• Norinyl 1+35 Use in Pregnancy & Breastfeeding
• Drug Images
• Norinyl 1+35 Drug Interactions
• 1 Review for Norinyl+35 - Add your own review/rating

Compare Norinyl 1+35 with other medications

• Abnormal Uterine Bleeding
• Acne
• Birth Control
• Endometriosis
• Gonadotropin Inhibition
• Menstrual Disorders
• Polycystic Ovary Syndrome
• Postmenopausal Symptoms
• Prevention of Osteoporosis

Where can I get more information?

• Your pharmacist can provide more information about ethinyl estradiol and norethindrone.

See also: Norinyl+35 side effects (in more detail)