Teslac

testolactone

Dosage Form: Tablets, USP

CIII

Teslac Description

Teslac® (testolactone tablets, USP) is available for oral administration as tablets providing 50 mg testolactone per tablet. Testolactone is a synthetic antineoplastic agent that is structurally distinct from the androgen steroid nucleus in possessing a six-membered lactone ring in place of the usual five-membered carbocyclic D-ring. Testolactone is chemically designated as 13-hydroxy-3-oxo-13,17-secoandrosta-1,4-dien-17-oic acid δ-lactone. Graphic formula:

Inactive ingredients: calcium stearate, cornstarch, gelatin, and lactose.

Testolactone is a white, odorless, crystalline solid, soluble in ethanol and slightly soluble in water.

Teslac - Clinical Pharmacology

Although the precise mechanism by which testolactone produces its clinical antineoplastic effects has not been established, its principal action is reported to be inhibition of steroid aromatase activity and consequent reduction in estrone synthesis from adrenal androstenedione, the major source of estrogen in postmenopausal women. Based on in vitro studies, the aromatase inhibition may be noncompetitive and irreversible. This phenomenon may account for the persistence of testolactone’s effect on estrogen synthesis after drug withdrawal.

Despite some similarity to testosterone, testolactone has no in vivo androgenic effect. No other hormonal effects have been reported in clinical studies in patients receiving testolactone. In one study, testolactone administered orally (1000 mg/day) was reported to increase renal tubular reabsorption of calcium but to have no effect on serum calcium concentration. The mechanism of the hypocalciuric effect is unknown. No clinical effects in humans of testolactone on adrenal function have been reported; however, one study noted an increase in urinary excretion of 17-ketosteroids in most of the patients treated with 150 mg/day orally.

Testolactone is well absorbed from the gastrointestinal tract. It is metabolized to several derivatives in the liver, all of which preserve the lactone D-ring. These metabolites, as well as some unmetabolized drug, are excreted in the urine. Additional pharmacokinetic data in humans are unavailable.

For information concerning carcinogenesis, mutagenesis, pregnancy, and lactation, see the corresponding PRECAUTIONS sections.

In animals, parenteral but not oral testolactone reduced cortisone acetate induced hepatic glycogen deposits. In animal tests conducted to detect any hormonal activity for testolactone, some evidence of antiandrogenic and antiglucocorticoid activity was seen; increased growth rate in the newborn was suggested. However there was no clear manifestation of androgenic, estrogenic or antiestrogenic, progestational or antiprogestational, gonadotropin-like or antigonadotropic effects. Testolactone did not demonstrate anti-inflammatory, mineralocorticoid-like, or glucocorticoid-like properties.

Indications and Usage for Teslac

Teslac (testolactone tablets, USP) is recommended as adjunctive therapy in the palliative treatment of advanced or disseminated breast cancer in postmenopausal women when hormonal therapy is indicated. It may also be used in women who were diagnosed as having had disseminated breast carcinoma when premenopausal, in whom ovarian function has been subsequently terminated.

Teslac (testolactone tablets, USP) was found to be effective in approximately 15 percent of patients with advanced or disseminated mammary cancer evaluated according to the following criteria: 1) those with a measurable decrease in size of all demonstrable tumor masses; 2) those in whom more than 50 percent of non-osseous lesions decreased in size although all bone lesions remained static; and 3) those in whom more than 50 percent of total lesions improved while the remainder were static.

Contraindications

Testolactone is contraindicated in the treatment of breast cancer in men and in patients with a history of hypersensitivity to the drug.

Precautions

Information for Patients

The physician should be consulted regarding missed doses. Notify the physician if adverse reactions occur or become more pronounced.

Laboratory Tests

Plasma calcium levels should be routinely determined in any patient receiving therapy for mammary cancer, particularly during periods of active remission of bony metastases. If hypercalcemia occurs, appropriate measures should be instituted.

Drug Interactions

When administered concurrently, testolactone may increase the effects of oral anticoagulants; monitor and adjust anticoagulant dosage accordingly.

Drug/Laboratory Test Interactions

Physiologic effects of testolactone may result in decreased estradiol concentrations with radioimmunoassays for estradiol, increased plasma calcium concentrations (see PRECAUTIONS, Laboratory Tests), and increased 24-hour urinary excretion of creatine and 17-ketosteroids.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to evaluate carcinogenic potential or mutagenesis. Testolactone did not affect fertility in male or female rats.

Pregnancy

Teratogenic Effects, Category C

In rats, testolactone has been shown to produce increased fetal mortality, increased abnormal fetal development, and increased mortality in growing pups when given at doses 5 to 15 times the recommended human dose. In rabbits, no teratologic effects were observed at doses 2.5 to 7.5 times the recommended human dose. There are no adequate and well controlled studies in pregnant women. Testolactone is intended for use only in postmenopausal women and should not be used during pregnancy.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether or not to discontinue nursing.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Insufficient data from clinical studies of Teslac are available for patients 65 years of age and older to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, caution should be exercised when prescribing to elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Testolactone and its metabolites appear to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

Certain signs and symptoms have been reported in association with the use of this drug but, in these instances, it is often impossible to determine the relationship of the underlying disease and drug administration to the reported reaction. Such reactions include maculopapular erythema, increase in blood pressure, paresthesia, malaise, aches and edema of the extremities, glossitis, anorexia and nausea and vomiting. Alopecia alone and with associated nail growth disturbance have been reported rarely; these side effects subsided without interruption of treatment.

Drug Abuse and Dependence

Teslac is classified as a controlled substance under the Anabolic Steroids Control Act of 1990 and has been assigned to Schedule III.

Overdosage

There have been no reports of acute overdosage with testolactone tablets.

Teslac Dosage and Administration

The recommended oral dose is 250 mg qid.

In order to evaluate the response, therapy with testolactone should be continued for a minimum of three months unless there is active progression of the disease.

How is Teslac Supplied

Teslac® (testolactone tablets, USP), 50 mg/tablet: bottles of 100 (NDC 0003-0690-50). Each round, white, biconvex tablet is imprinted with the identification number 690.

Storage

Store at controlled room temperature 25° C (77° F).

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

Made in Australia

J4666B

YT001

Teslac  testolactone  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0003-0690 Route of Administration ORAL DEA Schedule CIII

INGREDIENTS Name (Active Moiety) Type Strength testolactone (testolactone) Active 50 MILLIGRAM  In 1 TABLET calcium stearate Inactive   cornstarch Inactive   gelatin Inactive   lactose Inactive

Product Characteristics Color WHITE (WHITE) Score no score Shape ROUND (ROUND) Size 10MM Flavor Imprint Code SQUIBB;690 Contains          Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0003-0690-50 100 TABLET In 1 BOTTLE None

Revised: 07/2006Bristol-Myers Squibb Company

More Teslac resources

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

• Teslac Concise Consumer Information (Cerner Multum)


• Teslac Advanced Consumer (Micromedex) - Includes Dosage Information


• Teslac MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Teslac with other medications

• Breast Cancer, Palliative

CombiPatch

estradiol and norethindrone acetate

Dosage Form: patch, extended release
CombiPatch

T2005-16/T2006-59

101932-6

      CombiPatch®

      (estradiol/norethindrone acetate transdermal system)

      Rx only

      Prescribing Information

WARNING

Estrogens and progestins should not be used for the prevention of cardiovascular disease or dementia. (See WARNINGS, Cardiovascular Disorders and Dementia.)

      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 five years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo (see CLINICAL PHARMACOLOGY, Clinical Studies and WARNINGS, Cardiovascular Disorders and Malignant Neoplasms, Breast Cancer).

      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 four 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, WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

      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.

DESCRIPTION

CombiPatch® (estradiol/norethindrone acetate transdermal system) is an adhesive-based matrix transdermal patch designed to release both estradiol and norethindrone acetate (NETA), a progestational agent, continuously upon application to intact skin.

      Two systems are available, providing the following delivery rates of estradiol and norethindrone acetate.

System Size	Estradiol (mg)	NETA1 (mg)	Nominal Delivery Rate2 (mg per day) Estradiol/NETA
9 sq cm round	0.62	2.7	0.05/0.14
16 sq cm round	0.51	4.8	0.05/0.25

1       NETA = norethindrone acetate.

2       Based on in vivo/in vitro flux data, delivery of both components per day via skin of average permeability (interindividual variation in skin permeability is approximately 20%).

      Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17β-diol. The molecular weight of estradiol is 272.39 and the molecular formula is C18H24O2.

      Norethindrone acetate USP is a white to creamy white, odorless, crystalline powder, chemically described as 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular weight of norethindrone acetate is 340.47 and the molecular formula is C22H28O3.

      The structural formulas for estradiol and norethindrone acetate are

     

      CombiPatch transdermal systems are comprised of three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyolefin film backing, (2) an adhesive layer containing estradiol, norethindrone acetate, acrylic adhesive, silicone adhesive, oleyl alcohol, oleic acid NF, povidone USP and dipropylene glycol, and (3) a polyester release protective liner, which is attached to the adhesive surface and must be removed before the system can be used.

     

      The active components of the system are estradiol USP and norethindrone acetate USP. The remaining components of the system are pharmacologically inactive.

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

Estradiol: Estrogens used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Administration of CombiPatch every three to four days in postmenopausal women produces average steady-state estradiol serum concentrations of 45 to 50 pg/mL, which are equivalent to the normal ranges observed at the early follicular phase in premenopausal women. These concentrations are achieved within 12 to 24 hours following CombiPatch application. Minimal fluctuations in serum estradiol concentrations are observed following CombiPatch application, indicating consistent hormone delivery over the application interval.

      In one study, serum concentrations of estradiol were measured in 40 healthy, postmenopausal women throughout three consecutive CombiPatch applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table I below.

Table I. Mean (SD) Serum Estradiol and Estrone Concentrations (pg/mL) at Steady-State (Uncorrected for Baseline Levels)

Estradiol
System Size	Dose Estradiol/NETA (mg per day)	Cmax	Cmin	Cavg
9 sq cm	0.05/0.14	71 (32)	27 (17)	45 (21)
16 sq cm	0.05/0.25	71 (30)	37 (17)	50 (21)
Estrone
9 sq cm	0.05/0.14	72 (23)	49 (19)	54 (19)
16 sq cm	0.05/0.25	78 (22)	58 (22)	60 (18)

Norethindrone: Progestins used in hormone therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. Norethindrone steady-state concentrations are attained within 24 hours of application of the CombiPatch transdermal delivery systems. Minimal fluctuations in serum norethindrone concentrations are observed following CombiPatch treatment, indicating consistent hormone delivery over the application interval. Serum concentrations of norethindrone increase linearly with increasing doses of norethindrone acetate.

      In one study, serum concentrations of norethindrone were measured in 40 healthy, postmenopausal women throughout three consecutive CombiPatch applications to the abdomen (each dose was applied for three 3.5-day periods). The corresponding pharmacokinetic parameters are summarized in Table II below.

Table II. Mean (SD) Serum Norethindrone Concentrations (pg/mL) at Steady-State

System Size	Dose Estradiol/NETA (mg per day)	Cmax	Cmin	Cavg
9 sq cm	0.05/0.14	617 (341)	386 (137)	489 (244)
16 sq cm	0.05/0.25	1,060 (543)	686 (306)	840 (414)

Distribution

Estradiol: 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.

Norethindrone: In plasma, norethindrone is bound approximately 90% to SHBG and albumin.

Metabolism

Estradiol: 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. Transdermally delivered estradiol is metabolized only to a small extent by the skin and bypasses the first-pass effect seen with orally administered estrogen products. Therapeutic estradiol serum levels with lower circulating levels of estrone and estrone conjugates are achieved with smaller transdermal doses (daily and total) as compared to oral therapy.

Norethindrone: Norethindrone acetate is hydrolyzed to the active moiety, norethindrone, in most tissues including skin and blood. Norethindrone is primarily metabolized in the liver; however, transdermal administration significantly decreases metabolism because hepatic first-pass effect is avoided.

Excretion

Estradiol: Estradiol, estrone and estriol are excreted in the urine along with glucuronide and sulfate conjugates. Estradiol has a short elimination half-life of approximately two to three hours; therefore, a rapid decline in serum levels is observed after the CombiPatch estradiol/norethindrone acetate transdermal system is removed. Within four to eight hours serum estradiol concentrations return to untreated, postmenopausal levels (<20 pg/mL).

      Concentration data from Phase II and III studies indicate that the pharmacokinetics of estradiol did not change over time, suggesting no evidence of the accumulation of estradiol following extended patch wear periods (up to one year).

Norethindrone: The elimination half-life of norethindrone is reported to be six to eight hours. Norethindrone serum concentrations diminish rapidly and are less than 50 pg/mL within 48 hours after removal of the CombiPatch transdermal delivery system.

      Concentration data from Phase II and III studies indicate that the pharmacokinetics of norethindrone did not change over time, suggesting no evidence of the accumulation of norethindrone following extended patch wear periods (up to one year).

Special Populations

CombiPatch has been studied only in postmenopausal women.

Drug Interactions

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.

Adhesion

Averaging across six clinical trials lasting three months to one year, of 1,287 patients treated, CombiPatch transdermal systems completely adhered to the skin nearly 90% of the time over the 3- to 4-day wear period. Less than 2% of the patients required reapplication or replacement of systems due to lifting or detachment. Only two patients (0.2%) discontinued therapy during clinical trials due to adhesion failure.

Clinical Studies

Effects on Vasomotor Symptoms

In two clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in postmenopausal women (n=332), CombiPatch was administered for three 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, CombiPatch was applied throughout the three cycles, replacing the system twice weekly. In the Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle® 0.05 mg) was applied twice weekly during the first 14 days of a 28-day cycle; CombiPatch was applied for the remaining 14 days of the cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from baseline to endpoint with either the Continuous Combined or Continuous Sequential administration of CombiPatch at all doses as compared to placebo (intent-to-treat population). (See tables below.)

Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch® Continuous Combined Transdermal Therapy

	CombiPatch® Continuous Combined		Placebo
Adjusted Mean Change from Baseline1	0.05/0.14 mg per day2 n=57	0.05/0.25 mg per day2 n=52	n=51
Number of Hot Flushes3	-9.35	-8.95	-6.2
Daily Intensity of Hot Flushes3,4	-4.65,6	-5.05	-2.87

1. Means were adjusted for imbalance among treatment groups and investigators (least squares mean from ANOVA).
   


2. Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
   


3. Population represents those patients who had baseline and endpoint observations.
   


4. The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 4-6, severe = 7-9).
   


5. P value versus placebo = <0.001.
   


6. Total number of patients with available data is 56.
   


7. Total number of patients with available data is 50.

Adjusted Mean Change in the Number of Hot Flushes and Daily Intensity of Hot Flushes per Day in CombiPatch® Continuous Sequential Transdermal Therapy

	CombiPatch® Continuous Sequential		Placebo
Adjusted Mean Change from Baseline1	0.05/0.14 mg per day2 n=54	0.05/0.25 mg per day2 n=59	n=53
Number of Hot Flushes3	-9.35	-9.55	-5.5
Daily Intensity of Hot Flushes3,4	-4.45	-4.55	-2.1

1. Means were adjusted for imbalance among treatment groups and investigators (least squares 
   
   mean from ANOVA).
   


2. Represents the milligrams of estradiol/norethindrone acetate delivered daily by each system.
   


3. Population represents those patients who had baseline and endpoint observations.
   


4. The intensity of hot flushes was evaluated on a scale of 0 to 9 (none = 0, mild = 1-3, moderate = 
   
   4-6, severe = 7-9).
   


5. P value versus placebo = <0.001.

Effects on the Edometrium

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

      Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the efficacy of estrogen therapy for its approved indications.

      CombiPatch was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after one year of therapy in two Phase II clinical trials. Nine hundred fifty-five (955) postmenopausal women (with intact uteri) were treated with (i) a continuous regimen of CombiPatch alone (Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch transdermal system (Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was significantly less after one year of therapy with either CombiPatch regimen than with the estradiol-only transdermal system. The tables below summarize these results (intent-to-treat populations).

Incidence of Endometrial Hyperplasia in a Continuous Combined CombiPatch® Regimen

	CombiPatch® Continuous Combined		Vivelle® Continuous
	0.05/0.14 mg per day1	0.05/0.25 mg per day1	0.05 mg per day
No. of Patients       with Biopsies2	123	98	103
No. (%) of Patients       with Hyperplasia	1 (<1%)3	1 (1%)3,4	39 (38%)5

1. Represents milligrams of estradiol/NETA delivered daily by each system.
   


2. Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
   


3. Comparison of continuous combined regimen versus estradiol-only patch was significant (p value <0.001).
   


4. This patient had hyperplasia at baseline.
   


5. One of 39 patients had hyperplasia in an endometrial polyp.

Incidence of Endometrial Hyperplasia in a Continuous Sequential CombiPatch® Regimen

	CombiPatch® Continuous Sequential		Vivelle® Continuous
	0.05/0.14 mg per day1	0.05/0.25 mg per day1	0.05 mg per day
No. of Patients       with Biopsies2	117	114	115
No. (%) of Patients       with Hyperplasia	1 (<1%)3,4	1 (<1%)3,5	23 (20%)

1. Represents milligrams of estradiol/NETA delivered daily by each system.
   


2. Biopsy after 12 cycles of treatment or hyperplasia before cycle 12.
   


3. Comparison of continuous sequential regimen versus estradiol-only patch was significant (p value <0.001).
   


4. This patient had hyperplasia at baseline.
   


5. This patient had hyperplasia in an endometrial polyp.

Effects on Uterine Bleeding or Spotting

With the Continuous Combined regimen, of the women treated with CombiPatch and who completed the one-year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 through 12 was 53% and 39% for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. Women who experienced bleeding, usually characterized it as light (intensity of 1.3 on a scale of 1 to 4) with a duration of four and six days for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively.

Incidence of Cumulative Amenorrhea* in CombiPatch® Continuous Combined Transdermal Therapy by Cycle over a One-Year Period (Intent-to-Treat Population)

*Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sustained to the end of the study.

Information Regarding Lipid Effects

In the CE/MPA substudy of the WHI (n=16,608 predominantly healthy postmenopausal women) hormone therapy lowered the level of low-density lipoprotein (LDL) cholesterol and increased the level of high-density lipoprotein (HDL), yet an increased risk of coronary heart disease events was observed. Therefore, estrogens and progestins should not be used for the prevention of cardiovascular disease. (See BOXED WARNING and CLINICAL PHARMACOLOGY, Clinical Studies.)

      The results of clinical trials conducted in a 90% Caucasian population at low risk for cardiovascular disease showed that compared to Vivelle (an estrogen-alone treatment), CombiPatch demonstrated significantly greater reductions in total cholesterol (TC) concentrations. Mean high density lipoprotein-cholesterol (HDL-C) values, however, decreased after one year of CombiPatch therapy whereas they were noted to increase in Vivelle users. Shifts in mean TC/HDL-C were minimal after one year of therapy in both Vivelle and CombiPatch treatment groups. Decreases in triglycerides were observed in both CombiPatch regimens.

      The following tables summarize lipid parameters from these two clinical trials in 955 postmenopausal women (with intact uteri) after one year of therapy. Subjects were treated with (i) a continuous regimen of CombiPatch alone (Continuous Combined regimen), (ii) a sequential CombiPatch regimen consisting of an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch transdermal system (Continuous Sequential regimen), or (iii) a continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The values below represent mean percent change from baseline in patients with data at baseline and one year.

Lipid Profile Values, Adjusted Mean Percent Change from Baseline After One Year of Continuous Combined CombiPatch® Transdermal Therapy

	CombiPatch® Continuous Combined		Vivelle® Continuous
Lipid Parameter (%)	0.05/0.14 mg per day1 n=122	0.05/0.25 mg per day1 n=99	0.05 mg per day n=79
Total Cholesterol	-5.4%2	-8.6%3	-2.0%
HDL-C	-3.1%3	-9.1%3	+7.3%
LDL-C	-4.6%4	-7.6%5	-3.4%
Triglycerides	-4.6%	-9.5%	-6.7%

1. Represents milligrams of estradiol/NETA delivered daily by each system.
   


2. Comparison with estradiol-only patch was significant (p <0.05).
   


3. Comparison with estradiol-only patch was significant (p <0.001).
   


4. Total number of patients with available data is 121.
   


5. Total number of patients with available data is 97.

Lipid Profile Values, Adjusted Mean Percent Change from Baseline After One Year of Continuous Sequential CombiPatch® Transdermal Therapy

	CombiPatch® Continuous Sequential		Vivelle® Continuous
Lipid Parameter (%)	0.05/0.14 mg per day1 n=117	0.05/0.25 mg per day1 n=115	0.05 mg per day n=105
Total Cholesterol	-4.1%2	-9.0%3	-1.0%
HDL-C	-4.7%3	-8.9%3	+0.9%
LDL-C	-1.2%4	-6.8%2,5	-2.0%6
Triglycerides	-8.2%3	-14.1%3	+13.2%

1. Represents milligrams of estradiol/NETA delivered daily by each system.
   


2. Comparison with estradiol-only patch was significant (p <0.05).
   


3. Comparison with estradiol-only patch was significant (p <0.001).
   


4. Total number of patients with available data is 116.
   


5. Total number of patients with available data is 114.
   


6. Total number of patients with available data is 103.

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 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 III below.

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

Eventc	Relative Risk CE/MPA vs. Placebo at 5.2 Years (95% CI*)	Placebo n=8,102	CE/MPA n=8,506
		Absolute Risk per 10,000 Women-Years
CHD Events	1.29 (1.02-1.63)	30	37
Nonfatal MI	1.32 (1.02-1.72)	23	30
CHD Death	1.18 (0.70-1.97)	6	7
Invasive Breast Cancerb	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 Indexc	1.15 (1.03-1.28)	151	170
Deep Vein Thrombosisd	2.07 (1.49-2.87)	13	26
Vertebral Fracturesd	0.66 (0.44-0.98)	15	9
Other Osteoporotic Fracturesd	0.77 (0.69-0.86)	170	131

aAdapted from JAMA, 2002: 288: 321-333.

b Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.

c 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.

d Not included in global index.

* Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

      For those outcomes included in the “global index”, absolute excess risks per 10,000 women-years in the group treated with CE/MPA were seven more CHD events, eight more strokes, eight more PEs, and eight more invasive breast cancers, while absolute risk reductions per 10,000 women-years were six fewer colorectal cancers and five 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 WARNING, 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 WARNING and WARNINGS, Dementia.)

INDICATIONS AND USAGE

In women with an intact uterus, CombiPatch is indicated for the following:

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


• 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.

• Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

CONTRAINDICATIONS

CombiPatch should not be used in women under any of the following conditions: 

• Undiagnosed abnormal genital bleeding.
  


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


• Known or suspected estrogen-dependent neoplasia.
  


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


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


• Liver dysfunction or disease.
  


• CombiPatch should not be used in patients with known hypersensitivity to its ingredients.
  


• Known or suspected pregnancy. There is no indication for CombiPatch 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 WARNING.

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/progestins 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.

Coronary Heart Disease and Stroke

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

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

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

      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-0.625 mg/2.5 mg 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 one, 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 in 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.

Venous Thromboembolism (VTE)

In the Women’s Health Initiative (WHI) study, an increase in VTE was 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 four to six weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Malignant Neoplasms

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 substudy 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 substudy, 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 versus 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 versus 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 versus 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, 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 health care provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

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 users of unopposed estrogen is about 2- to 12-fold or greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than on

Efcortelan Ointment

1308714

0603

Efcortelan ointment

hydrocortisone

It is important to read this carefully before starting treatment

Following this advice gives the ointment a chance to work safely and effectively.

What you should know about Efcortelan ointment

Efcortelan ointment is one of a group of medicines called topical steroids.

“Topical” means they are put on the skin. Topical steroids reduce the redness and itchiness of certain skin problems. (They should not be confused with “anabolic” steroids misused by some body builders and athletes and taken as tablets or injections).

What is in your ointment

The ointment contains:

The active ingredient - hydrocortisone 0·5% w/w, 1% w/w or 2·5% w/w (see label) in a base containing white soft paraffin and liquid paraffin

The ointment is packed in 30 g tubes.

Product licence holder and manufacturer

Product Licence held by

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex

UB11 1BT

Manufactured by

Glaxo Wellcome Operations

Greenford

Middlesex

UB6 0NN

What your ointment does

Efcortelan ointment is a mild treatment for inflamed skin conditions such as eczema and dermatitis, insect bite reactions and inflammation of the external ear. Efcortelan ointment is a mild topical steroid and is often used to manage skin problems between short courses of stronger preparations.

Before you use your ointment

This ointment has been prescribed to treat the skin problem that you showed to your doctor.

Do not put it on any other skin problems as it could make them worse, especially:

• skin infections such as cold sores, herpes, chicken pox, impetigo, ringworm, athletes foot and thrush

Tell your doctor before you start using the ointment:

• If you have ever had an allergy to any creams or ointments in the past


• If you think you may be pregnant

Even so, your doctor may still want you to use the ointment.

Face -

You should not normally use on the face for many weeks or months.

Children -

Do not use under the nappy, or airtight dressing of an infant for more than a week. (These make it easier for the active ingredient to pass through the skin).

How to use your ointment

If your doctor has told you in detail how much to use and how often then keep to this advice.

If you are not sure then follow the advice on the back of this leaflet.

Unless told by your doctor:

• 
  You should not use more than this


• 
  You should not use on large areas of the body for a long time (such as nearly every day for many weeks or months)

Although Efcortelan ointment is generally regarded as safe even when used like this for many months it may be possible to produce side effects if overused.

This ointment is for use on the skin only, but if accidentally swallowed small amounts are not harmful.

It is important to follow the instructions on this leaflet. If, on a few occasions by mistake you apply more than the recommended amount do not worry.

If you forget to apply your ointment, apply the correct dose when you remember or if it is close to your next application then wait until this time.

You will find out more about your ointment on the back of this leaflet

Guidance on how much ointment to use

If your doctor has told you in detail how to use the ointment keep to that advice otherwise:-

Two or three times a day, after washing your hands, gently rub the correct amount of ointment into the skin until it has all disappeared. Unless used for treating the hands wash them again after using the ointment. Anyone who helps to rub in the ointment should also do the same or wear disposable plastic gloves.

For an adult:

You should find that:

• two fingertips of ointment will treat both hands or one foot


• three fingertips of ointment will treat one arm


• six fingertips of ointment will treat one leg


• fourteen fingertips of ointment will treat the front and back of one trunk

Do not worry if you find you need a little more or a little less than this - it is only a rough guide.

For a child:

The smaller the child the less you use.

A child of 6 months to 1 year needs about a quarter of the adult amount and a child of 4 years about one third.

Efcortelan Ointment Side Effects

Most people find using this ointment causes no problems when used in the right amount for the correct length of time. (See above).

If you find your condition gets worse during treatment you may be allergic to the ointment or have a skin infection.

Stop using the ointment and tell your doctor as soon as possible

Using more than the correct amount may:

• thin the skin so that it damages easily


• allow the active ingredient to pass through the skin and affect other parts of the body, especially in infants and children, during pregnancy, and if used under a nappy or air-tight dressing

Repeated courses of topical steroids over a long time may sometimes cause changes in hair growth and skin colour. Striae (stretch marks) and surface veins may become noticeable.

If you feel unwell or have any unusual discomfort you do not understand, tell your doctor as soon as possible.

Where to keep your ointment

As with all medicines keep this ointment safely away from children.

Store below 25°C.

What to do with any unused ointment

If your doctor stops your treatment, return any unused ointment to a pharmacist. Only keep it if your doctor tells you to.

Do not use the ointment after the expiry date on the tube end or carton.

Remember

This ointment was prescribed for you so never give it to someone else to try - even if they seem to have the same problem. There may be reasons why it could harm that person.

Further information

This leaflet does not contain all the information about your medicine. If you have any questions or are not sure about anything, ask your doctor or pharmacist who has the information you need and will advise you.

A source of information is:

National Eczema Society

163 Eversholt Street

London

NW1 1BU

You may also be able to find out more from books in public libraries.

You may want to read this leaflet again. Please do not throw it away until you have finished your treatment

The information provided applies only to Efcortelan ointment

Efcortelan is a registered trademark of the GlaxoSmithKline group of companies

© 2002 GlaxoSmithKline group of companies

Leaflet written October 2002

Avage

Generic Name: tazarotene topical (ta ZAR oh teen)

Brand Names: Avage, Tazorac

What is Avage (tazarotene topical)?

Tazarotene is a compound similar to vitamin A. It helps the skin to renew itself more quickly and may improve the appearance and texture of skin.

The Tazorac brand of tazarotene topical gel and cream are used to treat plaque psoriasis (psoriasis with scaly patches) and to treat facial acne. The Avage brand of tazarotene cream is used to reduce the appearance of fine wrinkles on the face, mottled light and dark skin patches on the face, and benign facial lentigines (noncancerous freckles).

Tazarotene topical may also be used for purposes other than those listed in this medication guide.

What is the most important information I should know about Avage (tazarotene topical)?

Do not use tazarotene topical if you are pregnant or if you could become pregnant. Tazarotene topical is in the FDA pregnancy category X. This means that tazarotene topical is known to cause birth defects in an unborn baby. You must take a pregnancy test and have negative results within two weeks before starting treatment with tazarotene topical and treatment should be started during a menstrual period. Brith control must be used during treatment. If you become pregnant, stop using birth control, or miss your menstrual period, immediately stop using tazarotene topical and notify your doctor. Avoid exposure to sunlight or artificial UV rays (e.g., sunlamps). Use a sunscreen (minimum SPF 15) and wear protective clothing during the day when being treated with tazarotene topical. Do not use tazarotene topical on skin that is sunburned, windburned, dry, chapped, or irritated. Also avoid using this medication in wounds or on areas of eczema. Wait until these conditions have fully healed before using tazarotene topical.

Avoid as much as possible other topical products with a strong drying effect, products with high concentrations of alcohol, astringents, spices, peel of lime, medicated soaps or shampoos, permanent wave solutions, electrolysis, chemical hair removers or waxes, or other products that might dry or irritate the skin unless instructed otherwise by your doctor.

What should I discuss with my healthcare provider before using Avage (tazarotene topical)?

Do not use tazarotene topical without first talking to your doctor if you

• 
  

  are especially sensitive to sunlight;

  
  


• 
  

  spend a considerable amount of time in the sun;

  
  


• 
  

  have eczema, sunburn, or another skin condition;

  
  


• 
  

  are taking vitamin A;

  
  


• 
  

  lentigo maligna (a type of skin cancer);

  
  


• 
  

  are using other prescription or over-the-counter medicines on your skin; or

  
  


• 
  

  are taking any other prescription or over-the-counter medicines, including vitamins and herbal supplements.

  
  

You may not be able to use tazarotene topical, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Do not use tazarotene topical if you are pregnant or if you could become pregnant. Tazarotene topical is in the FDA pregnancy category X. This means that tazarotene topical is known to cause birth defects in an unborn baby. You must take a pregnancy test and have negative results within two weeks before starting treatment with tazarotene topical and treatment should be started during a menstrual period. Brith control must be used during treatment. If you become pregnant, stop using birth control, or miss your menstrual period, immediately stop using tazarotene topical and notify your doctor. It is not known whether tazarotene topical passes into breast milk. Do not use tazarotene topical without first talking to your doctor if you are breast-feeding a baby.

How should I use Avage (tazarotene topical)?

Use tazarotene topical exactly as directed by your doctor. If you do not understand these instructions, ask your pharmacist, nurse, or doctor to explain them to you.

Wash your hands before and after applying this medication (unless affected areas are on the hands).

Tazarotene topical is usually applied once daily at bedtime. Follow your doctor's instructions.

Cleanse the skin with a gentle cleanser and allow it to dry completely (20 to 30 minutes). If a bath or shower is taken prior to application of tazarotene topical, the skin should be dry before applying the gel or cream. Apply a thin film of tazarotene topical to the affected skin. Avoid applying the medication to unaffected areas. If medication accidentally gets on areas that do not need treatment, wash it off.

If a cream or lotion is used to soften or lubricate the skin, it can be applied either before or after application of tazarotene topical. Allow the first cream or lotion applied to be absorbed into the skin and dry completely before application of the second product.

Do not apply tazarotene topical to the eyes, ears, nostrils, mouth, angles of the nose, mucous membranes, open sores, or irritated skin. If you get medication in any of these areas, rinse it off with water. Do not use tazarotene topical on skin that is sunburned, windburned, dry, chapped, or irritated. Also avoid using this medication in wounds or on areas of eczema. Wait until these conditions have fully healed before using tazarotene topical. Do not cover treated areas with dressings or bandages. Do not apply tazarotene topical more often than is directed. Using too much of this medication may cause marked skin redness, peeling, or discomfort and will not lead to more rapid or better results.

Application of this medication may cause a passing feeling of burning or stinging. If irritation is excessive, stop using tazarotene topical and contact your doctor.

Your skin may be more sensitive to weather extremes such as cold and wind during treatment with tazarotene topical. Protect your skin with clothing and use a moisturizing cream or lotion as needed.

Apply a sunscreen, SPF 15 or greater, to the skin daily.

Do not use tazarotene topical beyond the date printed on the bottom seal of the tube. Store tazarotene topical at room temperature away from moisture and heat.

What happens if I miss a dose?

If you forget or miss a dose, do not try to make it up. Return to your normal application schedule as soon as you can. Do not apply a double dose of tazarotene topical.

What happens if I overdose?

An overdose of this medication is unlikely to occur. If you do suspect an overdose, or if tazarotene topical has been ingested, call an emergency room or poison control center for advice.

Symptoms of excessive topical use of tazarotene topical include marked redness, peeling or discomfort.

What should I avoid while using Avage (tazarotene topical)?

Avoid exposure to sunlight or artificial UV rays (e.g., sunlamps). Use a sunscreen (minimum SPF 15) and wear protective clothing during the day when being treated with tazarotene topical.

Your skin may be more sensitive to weather extremes such as cold and wind during treatment with tazarotene topical. Protect your skin with clothing and use a moisturizing cream or lotion as needed.

Do not use tazarotene topical on skin that is sunburned, windburned, dry, chapped, or irritated. Also avoid using this medication in wounds or on areas of eczema. Wait until these conditions have fully healed before using tazarotene topical.

Avoid as much as possible other topical products with a strong drying effect, products with high concentrations of alcohol, astringents, spices, peel of lime, medicated soaps or shampoos, permanent wave solutions, electrolysis, chemical hair removers or waxes, or other products that might dry or irritate the skin unless instructed otherwise by your doctor.

Avage (tazarotene topical) side effects

Serious side effects are not likely to occur. Stop using tazarotene topical and seek emergency medical attention if you experience an allergic reaction (shortness of breath; closing of the throat; swelling of the lips, face, or tongue; or hives).

You may experience some skin burning, warmth, stinging, tingling, itching, redness, swelling, dryness, peeling, or irritation while using tazarotene topical. If these side effects are excessive, talk to your doctor. You may need a lower dose or less frequent applications of tazarotene topical.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Avage (tazarotene topical)?

Do not use tazarotene topical without first talking to your doctor if you are taking any of the following medicines:

• 
  

  a thiazide diuretic such as hydrochlorothiazide (HCTZ, HydroDiuril, Esidrix, Microzide, Oretic), chlorothiazide (Diuril), chlorthalidone (Hygroton, Thalitone), indapamide (Lozol), metolazone (Mykrox, Zaroxolyn), and others;

  
  


• 
  

  a tetracycline antibiotic such as tetracycline (Sumycin, Panmycin, Robitet, others), minocycline (Dynacin, Minocin, Vectrin), doxycycline (Doryx, Monodox, Vibramycin, Vibra-Tabs), demeclocycline (Declomycin), and others;

  
  


• 
  

  a fluoroquinolone antibiotic such as lomefloxacin (Maxaquin), sparfloxacin (Zagam), ciprofloxacin (Cipro), ofloxacin (Floxin), and others;

  
  


• 
  

  a sulfonamide antibiotic such as sulfamethoxazole (Gantanol), sulfisoxazole (Gantrisin), sulfamethoxazole-trimethoprim (Bactrim, Septra, Cotrim), and others; or

  
  


• 
  

  a phenothiazine such as chlorpromazine (Thorazine), prochlorperazine (Compazine), fluphenazine (Permitil, Prolixin), promethazine (Phenergan, Promethegan), perphenazine (Trilafon), and others.

  
  

The medications listed above may increase the sensitivity of the skin to UV rays from sunlight or artificial light (e.g., sunlamps). Generally, tazarotene topical should not be used during treatment with any of the medicines listed above.

Avoid as much as possible other topical products with a strong drying effect, products with high concentrations of alcohol, astringents, spices, peel of lime, medicated soaps or shampoos, permanent wave solutions, electrolysis, chemical hair removers or waxes, or other products that might dry or irritate the skin unless instructed otherwise by your doctor.

Drugs other than those listed here may also interact with tazarotene topical. Talk to your doctor and pharmacist before taking or using any prescription or over-the-counter medicines, including vitamins and herbal products.

More Avage resources

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

• Avage Prescribing Information (FDA)


• Avage Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Avage Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Tazorac Prescribing Information (FDA)


• Tazorac Cream MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Avage with other medications

• Facial Wrinkles

Where can I get more information?

• Your pharmacist has additional information about tazarotene topical written for health professionals that you may read.

See also: Avage side effects (in more detail)

Ny-Tannic

Pronunciation: klor-fen-IHR-ah-meen/fen-il-EF-rin
Generic Name: Chlorpheniramine/Phenylephrine
Brand Name: Examples include Ny-Tannic and Rynatan

Ny-Tannic is used for:

Relieving symptoms of sinus congestion, sinus pressure, runny nose, and sneezing due to colds, upper respiratory infections, and allergies. It may also be used for other conditions as determined by your doctor.

Ny-Tannic is an antihistamine and decongestant combination. The antihistamine works by blocking the action of histamine, which helps reduce symptoms such as watery eyes and sneezing. The decongestant promotes sinus and nasal drainage, relieving congestion and pressure.

Do NOT use Ny-Tannic if:

• you are allergic to any ingredient in Ny-Tannic


• you have severe high blood pressure, severe heart blood vessel disease, rapid heartbeat, or severe heart problems


• you are taking sodium oxybate (GHB), or you have taken furazolidone or a monoamine oxidase (MAO) inhibitor (eg, phenelzine) within the last 14 days

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

Before using Ny-Tannic:

Some medical conditions may interact with Ny-Tannic. 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 fast, slow, or irregular heartbeat


• if you have a history of asthma, lung problems (eg, emphysema), adrenal gland problems (eg, adrenal gland tumor), heart problems, high blood pressure, diabetes, heart blood vessel problems, stroke, glaucoma, a blockage of your stomach or intestines, ulcers, a blockage of your bladder, trouble urinating, an enlarged prostate, seizures, or an overactive thyroid

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

• Beta-blockers (eg, propranolol), catechol-O-methyltransferase (COMT) inhibitors (eg, tolcapone), furazolidone, indomethacin, MAO inhibitors (eg, phenelzine), sodium oxybate (GHB), or tricyclic antidepressants (eg, amitriptyline) because they may increase the risk of Ny-Tannic's side effects


• Digoxin or droxidopa because the risk of irregular heartbeat or heart attack may be increased


• Bromocriptine or hydantoins (eg, phenytoin) because the risk of their side effects may be increased by Ny-Tannic


• Guanethidine, guanadrel, mecamylamine, methyldopa, or reserpine because their effectiveness may be decreased by Ny-Tannic

This may not be a complete list of all interactions that may occur. Ask your health care provider if Ny-Tannic 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 Ny-Tannic:

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

• Ny-Tannic may be taken with or without food.


• If you miss a dose of Ny-Tannic, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Ny-Tannic.

Important safety information:

• Ny-Tannic may cause dizziness, drowsiness, or blurred vision. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Ny-Tannic. Using Ny-Tannic alone, with certain other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Do not take nonprescription medicines that contain stimulants, such as products used for dieting (appetite suppressants) without checking with you doctor.


• Do NOT exceed the recommended dose or take Ny-Tannic for longer than prescribed without checking with your doctor.


• If your symptoms do not improve within 5 to 7 days or if they become worse, consult your doctor.


• Ny-Tannic may cause increased sensitivity to the sun. Avoid exposure to the sun, sunlamps, or tanning booths until you know how you react to Ny-Tannic. Use a sunscreen or wear protective clothing if you must be outside for a prolonged period.


• If you are scheduled for allergy skin testing, do not take Ny-Tannic for several days before the test because it may decrease your response to the skin tests.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Ny-Tannic.


• Use Ny-Tannic with caution in the ELDERLY because they may be more sensitive to its effects.


• Use Ny-Tannic with caution in CHILDREN because they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Ny-Tannic, discuss with your doctor the benefits and risks of using Ny-Tannic during pregnancy. It is unknown if Ny-Tannic is excreted in breast milk. Do not breast-feed while taking Ny-Tannic.

Possible side effects of Ny-Tannic:

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:

Constipation; diarrhea; dizziness; drowsiness; excitability; headache; loss of appetite; nausea; nervousness or anxiety; trouble sleeping; upset stomach; vomiting; weakness.

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

Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); difficulty urinating or inability to urinate; fast or irregular heartbeat; hallucinations; seizures; severe dizziness, lightheadedness, or headache; tremor; vision changes.

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: Ny-Tannic 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 blurred vision; confusion; hallucinations; seizures; severe dizziness, lightheadedness, or headache; severe drowsiness; unusually fast, slow, or irregular heartbeat; vomiting.

Proper storage of Ny-Tannic:

Store Ny-Tannic at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Ny-Tannic out of the reach of children and away from pets.

General information:

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


• Ny-Tannic 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 Ny-Tannic. 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 Ny-Tannic resources

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

• Ny-Tannic Concise Consumer Information (Cerner Multum)


• Histatab Plus Concise Consumer Information (Cerner Multum)


• Rynatan Prescribing Information (FDA)


• Sonahist Prescribing Information (FDA)

Compare Ny-Tannic with other medications

• Cold Symptoms
• Hay Fever