ESTRACOMB

Main information

  • Trade name:
  • ESTRACOMB PATCH
  • Dosage:
  • 30MG; 4MG; 10MG
  • Pharmaceutical form:
  • PATCH
  • Composition:
  • NORETHINDRONE ACETATE 30MG; ESTRADIOL 4MG; ESTRADIOL 10MG
  • Administration route:
  • TRANSDERMAL
  • Units in package:
  • 8
  • Prescription type:
  • Prescription
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESTRACOMB PATCH
    Canada
  • Language:
  • English

Therapeutic information

  • Therapeutic area:
  • ESTROGENS
  • Product summary:
  • Active ingredient group (AIG) number: 0336586001; AHFS: 68:16.04

Other information

Status

  • Source:
  • Health Canada
  • Authorization status:
  • APPROVED
  • Authorization number:
  • 02108186
  • Authorization date:
  • 27-06-1997
  • Last update:
  • 25-11-2018

Summary of Product characteristics: dosage,interactions,side effects

ESTRACOMB*

Page 1 of 47

PRODUCT MONOGRAPH

ESTRACOMB*

ESTRADERM* +

ESTRAGEST*

(Estradiol-17ß + Norethindrone Acetate and Estradiol-17ß)

Transdermal Therapeutic System

Progestin-Estrogen

Novartis Pharmaceuticals Canada Inc.

Dorval, Québec, H9S 1A9

Submission Control Number 120563

Date of Revision:

February 05, 2009

* registered trademark

ESTRACOMB*

Page 2 of 47

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION.........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3

INDICATIONS AND CLINICAL USE..............................................................................3

WARNINGS AND PRECAUTIONS..................................................................................5

ADVERSE REACTIONS..................................................................................................12

DRUG INTERACTIONS ..................................................................................................16

DOSAGE AND ADMINISTRATION..............................................................................18

OVERDOSAGE ................................................................................................................21

ACTION AND CLINICAL PHARMACOLOGY ............................................................22

SPECIAL HANDLING INSTRUCTIONS .......................................................................27

STORAGE AND STABILITY..........................................................................................27

PART II: SCIENTIFIC INFORMATION ...............................................................................30

PHARMACEUTICAL INFORMATION..........................................................................30

CLINICAL TRIALS..........................................................................................................31

DETAILED PHARMACOLOGY.....................................................................................32

REFERENCES ..................................................................................................................33

PART III: CONSUMER INFORMATION..............................................................................38

ESTRACOMB*

Page 3 of 47

Pr

ESTRACOMB*

ESTRADERM* +

ESTRAGEST*

(Estradiol-17ß + Norethindrone Acetate and Estradiol-17ß)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Clinically Relevant Nonmedicinal Ingredients

Transdermal

Patches of

ESTRADERM*50µg

Patches of

ESTRAGEST*250/50

Cellulose compounds, ethanol, ethylene-vinyl

acetate copolymer, light mineral oil, polyester

and polyisobutylene.

INDICATIONS AND CLINICAL USE

ESTRACOMB* (estradiol-17ß and NETA/estradiol-17ß) is indicated for:

the relief of menopausal and postmenopausal symptoms occurring in naturally or

surgically induced estrogen deficiency states.

the prevention of osteoporosis in naturally occurring or surgically induced estrogen-

deficiency states in addition to other important therapeutic measures such as adequate

diet, calcium and vitamin D intake, cessation of smoking and regular weight-bearing

exercise. ESTRACOMB* is to be considered in light of other available therapies for

osteoporosis prevention and therapy should only be continued as long as the benefits

outweigh the risks for the individual. (see Boxed Warning)

ESTRACOMB* is recommended for the above indications only in women with intact uteri since

the regimen includes a progestin whose role is to prevent endometrial hyperplasia/carcinoma.

Geriatrics (> 65 years of age):

No clinical studies were conducted to evaluate the effect of ESTRACOMB* on women more

than 65 years old.

Pediatrics:

ESTRACOMB* should not be used in children

ESTRACOMB*

Page 4 of 47

CONTRAINDICATIONS

Known or suspected hypersensitivity to this drug or to any ingredient in the formulation or to

any component of the patch. For a complete listing, see Dosage Forms, Composition and

Packaging section.

Liver dysfunction or disease as long as liver function tests have failed to return to normal.

Known or suspected estrogen-dependent or progestin-dependent malignant neoplasia such as

endometrial cancer.

Endometrial hyperplasia

Known, suspected or past history of breast cancer

Undiagnosed abnormal genital bleeding

Known or suspected pregnancy

Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction,

coronary heart disease)

Active or past history of confirmed venous thromboembolism (such as deep venous

thrombosis or pulmonary embolism) or active thrombophlebitis

Partial or complete loss of vision from ophthalmic vascular disease

Known thrombophilic disorders

Porphyria

Classical Migraine

Breast feeding

ESTRACOMB*

Page 5 of 47

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

The Women’s Health Initiative (WHI) trial examined the health benefits and risks of oral

combined

estrogen

plus

progestin

therapy

(n=16,608)

oral

estrogen-alone

therapy

(n=10,739) in postmenopausal women aged 50 to 79 years.

57, 8, 52

estrogen plus progestin

arm of the WHI trial (mean age 63.3 years) indicated an increased

risk of

myocardial infarction

(MI),

stroke, invasive breast cancer, pulmonary emboli

deep

vein

thrombosis

in postmenopausal women receiving treatment with combined conjugated

equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5 mg/day) for

5.2 years compared to those receiving placebo.

estrogen-alone

arm of the WHI trial (mean age 63.6 years) indicated an increased risk of

stroke

deep vein thrombosis

in hysterectomized women treated with CEE-alone (0.625

mg/day) for 6.8 years compared to those receiving placebo.

Therefore, the following should be given serious consideration at the time of prescribing:

Estrogens with or without progestins

should not

be prescribed for primary or secondary

prevention of cardiovascular diseases.

Estrogens with or without progestins should be prescribed at

the lowest effective dose

the approved indication.

For the prevention of osteoporosis, ESTRACOMB* should be considered in light of other

available therapies.

Estrogens with or without progestins should be prescribed for

the shortest period

possible

for the approved indication.

Carcinogenesis and Mutagenesis

Breast Cancer

Available epidemiological data indicate that the use of combined

estrogen plus progestin

postmenopausal women is associated with an increased risk of invasive breast cancer.

In the

estrogen plus progestin

arm of the WHI trial, among 10,000 women over a one-year

period, there were:

8 more cases of invasive breast cancer (38 on combined HRT versus 30 on placebo).

The WHI study also reported that the invasive breast cancers diagnosed in the

estrogen plus

progestin

group were similar in histology but were larger (mean (SD), 1.7 cm (1.1) vs. 1.5 cm

(0.9), respectively; P=0.04) and were at a more advanced stage compared with those diagnosed

in the placebo group. The percentage of women with abnormal mammograms (recommendations

for short-interval follow-up, a suspicious abnormality, or highly suggestive of malignancy) was

ESTRACOMB*

Page 6 of 47

significantly

higher

estrogen

plus

progestin

group

versus

placebo

group.

This

difference appeared at year one and persisted in each year thereafter.

In the

estrogen-alone

arm of the WHI trial, there was no statistically significant difference in the

rate

invasive

breast

cancer

hysterectomized

women

treated

with

conjugated

equine

estrogens versus women treated with placebo.

It is recommended that estrogens with or without progestins not be given to women with existing

breast cancer or those with a previous history of the disease. (see CONTRAINDICATIONS)

There is a need for caution in prescribing estrogens with or without progestins for women with

known risk factors associated with the development of breast cancer, such as strong family

history of breast cancer (first degree relative) or who present a breast condition with an increased

risk (breast nodules, fibrocystic disease of the breast, abnormal mammograms and/or atypical

hyperplasia at breast biopsy).

Other known risk factors for the development of breast cancer such as nulliparity, obesity, early

menarche, late age at first full term pregnancy and at menopause should also be evaluated.

It is recommended that women undergo mammography prior to the start of HRT treatment and at

regular intervals during treatment, as deemed appropriate by the treating physician and according

to the perceived risks for each patient.

overall

benefits

possible

risks

hormone

replacement

therapy

should

fully

considered and discussed with patients. It is important that the modest increased risk of being

diagnosed with breast cancer after 4 years of treatment with combined estrogen plus progestin

HRT (as reported in the results of WHI-trial) be discussed with the patient and weighed against

its known benefits.

Instructions for regular self-examination of the breasts should be included in this counselling

.

Endometrial Hyperplasia & Endometrial Carcinoma

Estrogen should be prescribed with an appropriate dosage of a progestin for women with intact

uteri in order to prevent endometrial hyperplasia/carcinoma.

The risk of endometrial hyperplasia/carcinoma in users of unopposed estrogens who have intact

uteri is greater than in non-users and appears to depend on the duration of treatment and the

estrogen dose. The greatest risk appears to be associated with prolonged use. It has been shown

that adequate concomitant progestogen therapy lowers the incidence of endometrial hyperplasia

and therefore the potential risk of endometrial carcinoma associated with prolonged use of

estrogen therapy (see DOSAGE AND ADMINSITRATION-Coadministration Of Progestins).

Ovarian Cancer

Some recent epidemiologic studies have found that the use of hormone replacement therapy

(estrogen-alone and estrogen plus progestin therapies), in particular for five or more years, has

been associated with an increased risk of ovarian cancer.

ESTRACOMB*

Page 7 of 47

Hepatocellular Carcinomas

Hepatocellular carcinoma has also been reported in women taking estrogen-containing oral

contraceptives. The causal relationship of this malignancy to these drugs is not known.

Cardiovascular

The results of the Heart and Estrogen/progestin Replacement Studies (HERS and HERS II) and

the Women’s Health Initiative (WHI) trial indicate that the use of

estrogen plus progestin

associated with an increased risk of coronary heart disease (CHD) in postmenopausal women.

25, 23

The results of the WHI trial indicate that the use of

estrogen-alone

estrogen plus

progestin

is associated with an increased risk of stroke in postmenopausal women.

57, 52

WHI trial findings

In the combined

estrogen plus progestin

arm of the WHI trial, among 10,000 women over a one-

year period, there were:

8 more cases of stroke (29 on combined HRT versus 21 on placebo)

7 more cases of CHD ( 37 on combined HRT versus 30 on placebo).

In the

estrogen-alone

arm of the WHI trial of women with prior hysterectomy, among 10,000

women over a one-year period, there were/was:

12 more cases of stroke (44 on

estrogen-alone

therapy versus 32 on placebo)

no statistically significant difference in the rate of CHD.

HERS and HERS II findings

In the Heart and Estrogen/progestin Replacement Study (HERS) of postmenopausal women with

documented heart disease (n=2763, average age 66.7 years), a randomized placebo-controlled

clinical trial of secondary prevention of coronary heart disease (CHD), treatment with 0.625

mg/day oral conjugated equine estrogen (CEE) plus 2.5 mg medroxyprogesterone acetate (MPA)

demonstrated no cardiovascular benefit. Specifically, during an average follow-up of 4.1 years,

treatment with CEE plus 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 hormone-

treated group than in the placebo group in year 1, but not during the subsequent years.

From the original HERS trial, 2321 women consented to participate in an open label extension of

HERS, known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a

total of 6.8 years overall. After 6.8 years, hormone therapy did not reduce the risk of

cardiovascular events in women with CHD.

Blood pressure

Women using hormone replacement therapy sometimes experience increased blood pressure.

Blood pressure should be monitored with HRT use. Elevation of blood pressure in previously

normotensive

hypertensive

patients

should

investigated

have

discontinued.

ESTRACOMB*

Page 8 of 47

Ear/Nose/Throat

Otosclerosis

Estrogens should be used with caution in patients with otosclerosis.

Endocrine and Metabolism

Glucose and lipid metabolism

A worsening of glucose tolerance and lipid metabolism have been observed in a significant

percentage of peri- and post-menopausal patients. Therefore, diabetic patients or those with a

predisposition to diabetes should be observed closely to detect any alterations in carbohydrate or

lipid metabolism, especially in triglyceride blood levels.

Women with familial hypertriglyceridemia need special surveillance. Lipid-lowering measures

are recommended additionally, before treatment is started.

Calcium and phosphorus metabolism

Because the prolonged use of estrogens with or without progestins, influences the metabolism of

calcium and phosphorus, estrogens with or without progestins should be used with caution in

patients with metabolic and malignant bone diseases associated with hypercalcemia, and in

patients with renal insufficiency.

Hypothyroidism

Patients who require thyroid hormone replacement therapy and who are also taking estrogen

should have their thyroid function monitored regularly to assure that thyroid hormone levels

remain in an acceptable range. (see

Drug-Laboratory Test

Interactions

Genitourinary

Vaginal bleeding

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, occurring during

therapy should prompt appropriate diagnostic measures to rule out the possibility of uterine

malignancy and the treatment should be re-evaluated.

Uterine leiomyomata

Pre-existing uterine leiomyomata may increase in size during estrogen use. Growth, pain or

tenderness

uterine

leiomyomata

requires

discontinuation

medication

appropriate

investigation.

Endometriosis

Symptoms and physical findings associated with a previous diagnosis of endometriosis may

reappear or become aggravated with estrogen use.

ESTRACOMB*

Page 9 of 47

Hematologic

Venous Thromboembolism

Available epidemiological data indicate that the use of estrogen with or without progestin by

postmenopausal

women

associated

with

increased

risk

developing

venous

thromboembolism (VTE).

In the estrogen plus progestin arm of the WHI trial, among 10,000 women on combined HRT

over a one-year period, there were 18 more cases of venous thromboembolism, including 8 more

cases of pulmonary embolism.

In the

estrogen-alone

arm of the WHI trial, among 10,000 women on estrogen therapy over a

one-year period, there were 7 more cases of venous thromboembolism, although there was no

statistically significant difference in the rate of pulmonary embolism.

Generally recognized risk factors for VTE include a personal history, a family history (the

occurrence

direct

relative

relatively

early

indicate

genetic

predisposition) severe obesity (body mass index > 30 kg/m

) and systemic lupus erythematosus.

The risk of VTE also increases with age and smoking.

A history of recurrent spontaneous abortions should be investigated to exclude thrombophilic

predisposition. In patients in whom thrombophilia is confirmed, the use of ESTRACOMB* is

viewed as contraindicated.

The risk of VTE may be temporarily increased with prolonged immobilization, major surgery, or

trauma. In women on HRT, attention should be given to prophylactic measures to prevent VTE

following surgery. Also, patients with varicose veins should be closely supervised. The physician

should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal

thrombosis, cerebral embolism and pulmonary embolism). If these occur or are suspected,

hormone therapy should be discontinued immediately given the risks of long-term disability or

fatality.

If feasible, estrogens with or without progestins should be discontinued at least 4 weeks before

major surgery which may be associated with an increased risk of thromboembolism, or during

periods of prolonged immobilization. The treatment should not be restarted until the woman is

completely mobile.

Hepatic/ Biliary/ Pancreatic

Benign Hepatic Adenomas

Benign hepatic adenomas have been associated with the use of combined estrogen and progestin

oral contraceptives. Although benign and rare, these tumours may rupture and cause death from

intra-abdominal hemorrhage. Such lesions have not yet been reported in association with other

estrogen or progestin preparations, but they should be

considered

if abdominal pain and

tenderness, abdominal mass, or hypovolemic shock occurs in patients receiving estrogen.

ESTRACOMB*

Page 10 of 47

Gallbladder Diseases

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving

postmenopausal estrogens has been reported.

Hepatic hemangiomas

Particular caution is indicated in women with hepatic hemangiomas, as estrogen may cause an

exacerbation of this condition.

Jaundice

Caution is advised in patients with a history of liver and/or biliary disorders. If cholestatic

jaundice develops during treatment, the treatment should be discontinued and appropriate

investigations carried out.

Liver function tests

Liver function tests should be done periodically in subjects who are suspected of having hepatic

disease. For information on endocrine and liver function tests, see the section under

Monitoring

and Laboratory Tests

Immune

Angioedema

Estrogens may induce or exacerbate symptoms of angioedema, in particular in women with

hereditary angioedema.

Systemic lupus erythematosus

Particular caution is indicated in women with systemic lupus erythematosus.

Neurologic

Cerebrovascular insufficiency

Patients who develop visual disturbances, classical migraine, transient aphasia, paralysis or loss

of consciousness should discontinue medication.

Dementia

Available epidemiological data indicate that the use of combined

estrogen plus progestin

women age 65 and over may increase the risk of developing probable

dementia.

The Women’s Health Initiative Memory Study (WHIMS), a clinical substudy of the WHI, was

designed to assess whether postmenopausal hormone replacement therapy (oral

estrogen plus

progestin

or oral

estrogen-alone

) reduces the risk of dementia in women aged 65 and over (age

range 65-79 years) and free of dementia at baseline.

44, 45

In the

estrogen plus progestin

arm of the WHIMS (n=4532), women with intact uteri were

treated

with

daily

0.625

conjugated

equine

estrogens

(CEE)

plus

ESTRACOMB*

Page 11 of 47

medroxyprogesterone acetate (MPA) or placebo for an average of 4.05 years. The results, when

extrapolated to 10,000 women treated over a one-year period showed:

23 more cases of probable dementia (45 on combined HRT versus 22 on placebo).

In the

estrogen-alone

arm of the WHIMS (n=2947), women with prior hysterectomy were

treated with daily 0.625 mg CEE or placebo for an average of 5.21 years. The results, when

extrapolated to 10,000 women treated over a one-year period showed:

12 more cases of probable dementia (37 on

estrogen-alone

versus 25 on placebo),

although this difference did not reach statistical significance.

When data from the

estrogen plus progestin

arm of the WHIMS and the

estrogen alone

arm of

the WHIMS were combined, as per the original WHIMS protocol, in 10,000 women over a one-

year period, there were:

18 more cases of probable dementia (41 on

estrogen plus progestin

estrogen-alone

versus 23 on placebo).

For transdermal estrogen-only or estrogen-progestogen combined products, no large randomized

clinical trials have assessed the HRT-associated risk of probable dementia to date. Therefore

there are no data to support the conclusion that the frequency of probable dementia is different

with ESTRACOMB*.

Epilepsy

Particular caution is indicated in women with epilepsy, as estrogen, with or without progestins,

may cause an exacerbation of this condition.

Renal

Fluid retention

Estrogens with or without progestins may cause fluid retention. Therefore, particular caution is

indicated in cardiac or renal dysfunction or asthma. If, in any of the above-mentioned conditions,

a worsening of the underlying disease is diagnosed or suspected during treatment, the benefits

and risks of treatment should be reassessed based on the individual case.

Skin

Contact Sensitization

Contact sensitization is known to occur with topical applications. Although it is extremely rare,

patients who develop contact sensitization to any component of the patch should be warned that

a severe hypersensitivity reaction may occur with continuing exposure to the causative agent.

Special Populations

Pregnant women:

ESTRACOMB* must not be used during pregnancy. Both estrogens and

progestogens may cause foetal harm when administered to a pregnant woman.

ESTRACOMB*

Page 12 of 47

Nursing women:

ESTRACOMB*

must not be used while breastfeeding.

Pediatrics:

ESTRACOMB* should not be used in children.

Geriatrics (> 65 years of age):

No clinical studies were conducted to evaluate the effect of

estradiol on women more than 65 years old.

Monitoring and Laboratory Tests

Before ESTRACOMB* (estradiol-17ß and NETA/estradiol-17β) is administered, the patient

should have a complete physical examination including a blood pressure determination. Breasts

and pelvic organs should be appropriately examined and a Papanicolaou smear should be

performed. Endometrial biopsy should be done only when indicated. Baseline tests should

include mammography, measurements of blood glucose, calcium, triglycerides and cholesterol,

and liver function tests.

The first follow-up examination should be done within 3-6 months after initiation of treatment to

assess response to treatment. Thereafter, examinations should be made at intervals at least once a

year. Appropriate investigations should be arranged at regular intervals as determined by the

physician.

The importance of regular self-examination of the breasts should be discussed with the patient.

Women should be advised that changes in their breasts should be reported to their doctor or

nurse.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

See WARNINGS AND PRECAUTIONS regarding potential induction of malignant neoplasms

and adverse effects similar to those of oral contraceptives.

The following adverse reactions have been reported with estrogen/progestin combinations in

general.

Blood and lymphatic system disorders

Altered coagulation tests (see WARNINGS AND PRECAUTIONS

- Drug-Laboratory Tests

Interactions

Cardiac disorders

Palpitations; increase in blood pressure (see WARNINGS AND PRECAUTIONS); coronary

thrombosis.

ESTRACOMB*

Page 13 of 47

Endocrine disorders

Increased blood sugar levels; decreased glucose tolerance.

Eye disorders

Neuro-ocular lesions (e.g., retinal thrombosis, optic neuritis), visual disturbances; steepening of

the corneal curvature; intolerance to contact lenses.

Gastrointestinal disorders

Nausea; vomiting; abdominal discomfort (cramps, pressure, pain); bloating.

General disorders and administration site conditions

Fatigue; changes in appetite; changes in body weight; change in libido.

Hepatobiliary disorders

Gallbladder disorder; asymptomatic impaired liver function; cholestatic jaundice.

Musculoskeletal and connective tissue disorders

Musculoskeletal pain including leg pain not related to thromboembolic disease (usually transient,

lasting 3-6 weeks) may occur.

Nervous system disorders

Aggravation of migraine episodes; headaches;

dizziness; neuritis.

Psychiatric disorders

Mental depression; nervousness; irritability.

Renal and urinary disorders

Cystitis; dysuria; sodium retention; edema.

Reproductive system and breast disorders

Breakthrough

bleeding;

spotting;

change

menstrual

flow;

dysmenorrhea;

vaginal

itching/discharge;

dyspareunia

endometrial

hyperplasia;

pre-menstrual-like

syndrome;

reactivation of endometriosis; changes in cervical erosion and amount of cervical secretion;

breast swelling and tenderness.

Skin and subcutaneous tissue disorders

Loss of scalp hair; chloasma or melasma, which may persist when drug is discontinued;

erythema nodosum; erythema multiforme; hemorrhagic skin eruptions; hirsutism, acne.

Vascular disorders

Isolated cases of thrombophlebitis; thromboembolic disorders.

Overview of Adverse Drug Reactions with ESTRACOMB*

This section summarizes adverse drug reaction data pooled from clinical trials, published

ESTRACOMB*

Page 14 of 47

investigations and post-marketing experience.

The data on adverse events from 5 pooled clinical trials are included. 3 clinical trials had a 2

years duration and 2 had a 1 year duration. A total safety population of 941 patients on HRT and

207 patients on placebo was identified.

most

commonly

reported

adverse

reaction

ESTRACOMB*

(estradiol-17ß

NETA/estradiol-17 β) in clinical trials was redness and irritation at the application site. This

occurred in about 17% of the women treated and caused approximately 2% to discontinue

therapy.

Frequency estimate :very common ≥10%, common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%;

rare ≥ 0.01% to < 0.1%; very rare < 0.01%; with unknown frequency.

Table 1

Most Common Adverse Drug Reactions (≥1%)

Nervous system disorders

Common:

Headache

Gastrointestinal disorders

Common:

Nausea, Abdominal pain, Abdominal distension

Reproductive system and breast disorders

Very common:

Breast tenderness , menstrual disorder

Common:

Endometrial hyperplasia, premenstrual syndrome, dysmenorrhoea

General disorders and administration site conditions

Very common:

Application site reaction

Less Common Adverse Drug Reactions (<1%)

Cardiovascular system disorders:

Very rare: Blood pressure increased

General disorders and administration site conditions:

Rare: Oedema, weight fluctuation, pain in extremity

Hepatobiliary system disorders:

Very rare: Jaundice cholestatic, liver function test abnormal

Immune system disorders:

Very rare: Anaphylactoid reactions

Nervous system disorders:

Rare: Dizziness

Reproductive system and breast disorders:

Uncommon: Breast cancer

Skin and subcutaneous tissue disorders:

Very rare: Pruritus, rash, pigmentation disorders

Vascular disorders:

Very rare: Embolism, varicose veins

ESTRACOMB*

Page 15 of 47

Adverse Drug Reactions with unknown frequency

Immune system disorders:

Not Known: Hypersensitivity

Skin and subcutaneous tissue disorders:

Not Known: Erythema nodosum, Erythema multiforme

Not Known: Hypersensitivity, including allergic contact dermatitis and isolated cases of

anaphylactoid reactions (some of the patients had a history of previous allergy or allergic

disorders)

Not Known: Reversible post-inflammatory pigmentation and precipitation or aggravation

of porphyria cutanea tarda in predisposed individuals

Abnormal Hematologic and Clinical Chemistry Findings

Table-2-Abnormal hematologic and clinical chemistry

Laboratory parameters

Effect

Antithrombin III

Coagulation factors VII, VIII, IX, X

Corticosteroid

binding

globulin

(CBG)

CBG ↑ in serum

increased circulating corticosteroids.

free or biologically active hormone concentrations are

unchanged

Fibrinogen and fibrinogen activity

↑ levels

Folate

↓ serum concentration

↓ Resin uptake , reflecting the elevated TBG

Free T

concentration unaltered

Glucose

impaired glucose tolerance

METOPIRONE test

Reduced response

Norepinephrine-induced

platelet

aggregability

Prothrombin

time

partial

tromboplastin time

Sex-hormone binding globulin

(SHBG)

SHBG↑ in serum

increased circulating corticosteroids.

free or biologically active hormone concentrations are

unchanged

Sulfobromophthalein

↑ retention

Triglyceride and Phospholipid

↑ serum concentration

Thyroxin-binding globulin (TBG)

increased circulating total thyroid hormone (T

) as

measured by column or radioimmunoassay

If adverse symptoms persist, the prescription of HRT should be re-considered.

ESTRACOMB*

Page 16 of 47

DRUG INTERACTIONS

Overview

Estrogens

diminish

effectiveness

anticoagulant,

antidiabetic

antihypertensive agents.

Preparations

inducing

liver

enzymes

(e.g.

barbiturates,

hydantoins,

carbamazepine,

meprobamates, phenylbutazone or rifampicin) may interfere with the activity of orally

administered estrogens.

Drug-Drug Interactions

The following section contains information on drug interactions with ethinyl estradiol-containing

products (specifically, oral contraceptives) that have been reported in the public literature. It is

unknown whether such interactions occur with drug products containing other types of estrogens.

Table 3- Established or Potential Drug-Drug Interactions

Drug

Ref

Effect

Clinical

Comment

Anticonvulsants

(phenobarbital, phenytoin,

carbamazepin)

↑ metabolism of

ethinyl estradiol

↓ plasma

concentration of

estradiol

Acetaminophen

↑ AUC and/or plasma

concentration of

ethinyl estradiol

↓ plasma

concentration of

acetaminophen

Therapeutic

monitoring is

recommended

Acid ascorbic

↑ AUC and/or plasma

concentration of

ethinyl estradiol

Therapeutic

monitoring is

recommended

Aminoglutethimide with

medroxyprogesterone

acetate (MPA)

↓ bioavailability of

Therapeutic

monitoring is

recommended

Atorvastatin

↑ AUC values for

ethinyl estradiol by 20

Therapeutic

monitoring is

recommended

Clofibric acid

↑ clearance of

clofibric acid

Therapeutic

monitoring is

recommended

ESTRACOMB*

Page 17 of 47

Cyclosporin

↑ plasma

concentration of

cyclosporine.

Therapeutic

monitoring is

recommended

Morphine

↑ clearance of

morphine

Therapeutic

monitoring is

recommended

Prednisolone

↑ plasma

concentration of

prednisolone

Therapeutic

monitoring is

recommended

Rifampicinª

↑ metabolism of

ethinyl estradiol

↓ plasma

concentration of

estradiol

Salicylic acid

↑ clearance of

salicylic acid

Therapeutic

monitoring is

recommended

Temazepam

↑ clearance of

temazepam

Therapeutic

monitoring is

recommended

Theophylline

↑ plasma

concentration of

theophylline

Therapeutic

monitoring is

recommended

Troglitazone

↓ plasma

concentrations of

ethinyl estradiol by 30

Therapeutic

monitoring is

recommended

Temazepam

↑ clearance of

temazepam

Therapeutic

monitoring is

recommended

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

ª Clinical pharmacokinetics studies have not demonstrated any consistent effect of antibiotics

(other than rifampicin) on plasma concentrations of synthetic steroids.

Drug-Food Interactions

The interaction of ESTRACOMB* with food has not been studied.

Drug-Herb Interactions

It was found that some herbal products (e.g., St. John’s wort) which are available as over-the-

counter (OTC) products might interfere with steroid metabolism, and therefore, alter the efficacy

and safety of estrogen/progestin products.

ESTRACOMB*

Page 18 of 47

Physicians and other health care providers should be made aware of other non-prescription

products concomitantly used by the patient, including herbal and natural products obtained from

the widely spread health stores.

Drug-Laboratory Test Interactions

The results of certain endocrine and liver function tests may be affected by estrogen-containing

products:

increased

prothrombin

time

partial

thromboplastin

time;

increased

levels

fibrinogen

fibrinogen

activity;

increased

coagulation

factors

VII,

VIII,

increased norepinephrine-induced platelet aggregability; decreased antithrombin III;

increased thyroxine-binding globulin (TBG), leading to increased circulating total thyroid

hormone (T

) as measured by column or radioimmunoassay; T

resin uptake is decreased,

reflecting the elevated TBG; free T

concentration is unaltered;

other binding proteins may be elevated in serum i.e., corticosteroid binding globulin

(CBG),

sex-hormone

binding

globulin

(SHBG),

leading

increased

circulating

corticosteroids

steroids

respectively;

free

biologically

active

hormone

concentrations are unchanged;

impaired glucose tolerance;

increased serum triglyceride and phospholipid concentration.

(See also

table in Abnormal Hematological Clinical Chemistry Findings

section)

In clinical trials with ESTRACOMB*, no effect on fibrinogen, antithrombin III, TBG, CBG or

SHBG was seen.

The results of the above laboratory tests should not be considered reliable unless therapy has

been discontinued for two to four weeks. The pathologist should be informed that the patient is

receiving hormone replacement therapy (HRT) when relevant specimens are submitted.

Drug-Lifestyle Interactions:

Specific drug-lifestyle interaction studies have not been conducted with ESTRACOMB*

Acute alcohol ingestion during HRT may lead to elevations in circulating estradiol levels

DOSAGE AND ADMINISTRATION

Dosing Considerations

In women who are not currently taking oral estrogens, treatment with ESTRACOMB*

(estradiol-17ß and NETA/estradiol-17ß) can be initiated at once. In women who are

currently taking oral estrogen, treatment with ESTRACOMB* can be initiated on

reappearance of menopausal symptoms, following discontinuation of oral therapy.

One 28-day treatment cycle with ESTRACOMB* consists of 8 patches; 4 patches of

ESTRADERM* 50 and 4 patches of ESTRAGEST* 250/50. Therapy is started with

ESTRADERM* 50. For 2 weeks, one ESTRADERM* 50 patch is applied twice weekly,

ESTRACOMB*

Page 19 of 47

i.e., the patch should be changed every 3-4 days. For the following 2 weeks, one

ESTRAGEST* 250/50 patch is applied twice weekly, i.e., the patch should be changed

every 3-4 days. Once the 8 patches of ESTRACOMB* have been used in the

recommended sequence over a 28-day period, the subsequent treatment cycle is again

started with ESTRADERM* 50 IMMEDIATELY after removal of the last ESTRAGEST*

250/50 patch. See Figure 1.

Figure 1:

ESTRACOMB* (estradiol-17ß followed by NETA/estradiol-17ß) provides, therefore, 14

days of progestin per cycle. The addition of sufficient NETA to induce secretory

transformation of the endometrium during estrogen replacement therapy is mandatory.

As observed in the normal menstrual cycle, cyclical administration of NETA from

ESTRAGEST* 250/50 should induce REGULAR CYCLICAL bleeding with mean onset

towards the end of the ESTRAGEST* 250/50 application phase. The normal duration of

vaginal bleeding associated with ESTRACOMB* is around 6 days. This cyclical

bleeding is expected to be of light intensity or spotting for 60-70% of this time. There are

individual variations in these parameters. Once all 8 patches of ESTRACOMB* have

been used as recommended, the first ESTRADERM* 50 patch of the new cycle is applied

even if some vaginal bleeding still persists. Vaginal bleeding should stop early in the

new cycle.

Abnormal vaginal bleeding, due to its prolongation, irregularity or heaviness, in any

patient receiving hormone replacement therapy requires institution of prompt diagnostic

measures like endometrial biopsy or curettage to rule out the possibility of uterine

malignancy.

The short-term effects of NETA co-administration may include vaginal bleeding during

or after NETA treatment, breast tenderness, and mood and weight changes. The long-

term effects generally depend on the dosage and type of progestin used. The lowest

effective dose of estrogen and progestin should be prescribed (see

Coadministration of

Progestins

ESTRACOMB*

Page 20 of 47

WARNINGS AND PRECAUTIONS section on the examination of the patient before

ESTRACOMB* administration.

Recommended Dose

and Dosage Adjustment

1.

Menopausal symptoms

Treatment

menopausal

symptoms

usually

initiated

with

patch

that

releases

50μg

estradiol-17ß per day. Therefore, therapy can be initiated with ESTRACOMB* in women with

an intact uterus. Thereafter the dosage should be adapted to the needs of the individual.

Breast discomfort, breakthrough or heavy vaginal bleeding, water retention, bloating or nausea

(if persisting for more than six weeks), are generally signs that the estrogen dose is too high and

needs to be lowered. If on the other hand, the selected dose fails to eliminate the signs and

symptoms of estrogen deficiency, a higher dose of estrogen may be considered.

Women

with

intact

uterus

whose

menopausal

symptoms

require

ESTRADERM*

ESTRADERM* 100 should receive appropriate treatment with oral progestins in order to

prevent endometrial hyperplasia (see

Coadministration of Progestins-

Details provided in the

ESTRADERM* Product Monograph).

For maintenance therapy one should always use the lowest dose that still proves effective. The

requirement for hormone replacement therapy for menopausal symptoms should be reassessed

periodically. Attempts to taper or discontinue the medication should be made at 3- to 6-month

intervals.

2.

Prevention of Oteoporosis

For optimal prevention of postmenopausal bone loss in women for whom the drug is indicated,

therapy should be initiated as soon as possible after diagnosis of menopause. The dosage of

estradiol-17ß may require adjustment according to the patient's clinical status, the plasma

estradiol-17ß levels and the results of bone mineral density studies.

Women with an intact uterus whose condition requires ESTRADERM* 25 or ESTRADERM*

100 should receive appropriate treatment with oral progestins in order to prevent endometrial

hyperplasia

(see

Coadministration

of

Progestins-

Details

provided

ESTRADERM*

Product Monograph).

Discontinuation of hormone replacement therapy may reestablish the natural rate of bone loss.

Missed Dose

Patients who miss applying a patch of ESTRACOMB*, should apply a new patch as soon as

possible. The subsequent patch should be applied according to the original treatment schedule.

The interruption of treatment might increase the likelihood of recurrence of symptoms.

Administration

Patch Application

ESTRACOMB*

Page 21 of 47

The physician should discuss the most appropriate placement of the patch with the patient.

Immediately after removal of a patch from the pouch and removal of the protective liner, the

adhesive side of the ESTRADERM* 50 or ESTRAGEST* 250/50 patch should be placed on a

clean, dry area of intact skin. The area selected should not be oily, damaged or irritated, and not

exposed to the sun. The site selected should also be one at which little wrinkling of the skin

occurs during movement of the body, preferably the buttocks, lower abdomen or hip. The patch

may also be placed on the side or lower back. Experience to date has shown that less irritation of

the skin occurs on the buttocks than on other sites of application. Therefore, it is advisable to

apply ESTRADERM* 50 or ESTRAGEST* 250/50 to the buttocks. The waistline should be

avoided, since tight clothing may dislodge the patch. The patch should be pressed firmly in

place with the palm of the hand, making sure there is good contact, especially around the edges.

In the event that a patch should fall off, it can be reapplied. If it fails to adhere then a new patch

may be applied. In either case, the original treatment schedule should be continued. Patches

should not be applied to the same skin site twice in succession. After use, ESTRACOMB*

patches should be folded (adhesive surfaces pressed together) and discarded out of the reach of

children.

ESTRADERM* 50 and ESTRAGEST* 250/50 must not be applied to the breasts to avoid

potentially harmful effects on the breast tissue.

Coadministration of Progestins

Estrogen replacement therapy should be supplemented by sequential progestin therapy only in

women with intact uteri.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Center.

Symptoms of overdose

Numerous reports of ingestion of large doses of estrogen products and estrogen-containing oral

contraceptives by young children have not revealed acute serious ill effects. Overdosage with

estrogen may cause nausea, breast discomfort, fluid retention, bloating or vaginal bleeding in

women.

Progestin(norethindrone

acetate)

overdosage

been

characterized

depressed

mood,

tiredness, acne and hirsutism.

Treatment of overdose

Owing to the mode of administration (transdermal), plasma levels of estradiol-17ß can be rapidly

reduced by removal of the patch. Symptomatic treatment should be given.

ESTRACOMB*

Page 22 of 47

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ESTRACOMB* (estradiol-17ß and norethindrone acetate (NETA)/estradiol-17 ß) is designed to

provide continuous estrogen and sequential progestin therapy, in a 28-day treatment cycle, for

women with intact uteri.

ESTRACOMB*

contains

types

transdermal

therapeutic

systems,

ESTRADERM* 50 (10 cm

) and ESTRAGEST* 250/50 (20 cm

). ESTRADERM* 50 contains

estradiol-17ß

ESTRAGEST*

250/50

contains

norethindrone

acetate

(NETA)

estradiol-17ß, respectively.

Both transdermal therapeutic systems included in ESTRACOMB* are designed to deliver daily

about 50µg estradiol-17ß, a physiologic hormone, transdermally into the systemic circulation.

Due to the transdermal route of administration, the estradiol-17ß does not undergo first-pass liver

metabolism. Resultant estradiol-17ß plasma levels, which are between 110-147 pM/L (30-40

pg/mL) above baseline (typically 37 pM/L (10 pg/mL)), are comparable to those seen in

premenopausal women in the early follicular phase of the menstrual cycle. Estradiol-17ß

stimulates target tissues such as the uterus, breast and vagina.

NETA is administered only when the transdermal therapeutic system ESTRAGEST* 250/50 is

correctly used. NETA, after hydrolysis to the active form, NET (norethindrone), shares some of

the biological effects of the endogenously produced progestin, progesterone. Like progesterone,

NET induces protein synthesis thereby limiting excessive growth stimulation of the endometrium

by estrogen. NET induces the enzyme 17ß-hydroxysteroid-dehydroxygenase, which locally

oxidizes estradiol to estrone. After application of an ESTRAGEST* 250/50 patch, plasma NET

levels range between 0.5 and 1.0 ng/mL (1675 to 3351 pM/L).

The tissue effects of NET are dependent on prior estrogen stimulation. One of the major target

organs for NET is the uterus, where it acts by inducing secretory transformation of the estrogen-

primed endometrium. Once transformation of the endometrium is completed, the estrogen-

primed endometrium is shed resulting in a regular cyclical bleeding. However, amenorrhea has

also been reported to occur during treatment with ESTRACOMB*.

Estrogen replacement therapy decreases the rate of bone loss in menopausal women; evidence of

estrogen receptors on bone cells suggests there is a direct effect of estrogen on bone.

Pharmacodynamics

Hormone Replacement Therapy

ESTRACOMB*

(estradiol-17ß

NETA/estradiol-17ß)

provides

continuous,

controlled

transdermal delivery of estradiol-17ß such that estradiol-17ß levels as well as the E2/E1 ratio in

postmenopausal

women

restored

those

seen

early

follicular

phase

premenopausal range (see

Pharmacokinetics

). ESTRACOMB* thus alleviates the symptoms of

estradiol-17ß deficiency in postmenopausal women.

ESTRACOMB*

Page 23 of 47

Placebo-controlled clinical studies have demonstrated that treatment with ESTRADERM* 50 or

ESTRADERM* 100 (50 µg and 100 µg per day respectively) prevents bone loss in

postmenopausal women. Treatment with ESTRADERM* 50 showed maintenance of bone

density. In addition, urinary excretion of both calcium and hydroxyproline are reduced during

ESTRADERM* 50, ESTRADERM* 100 and ESTRACOMB* treatment.

Coadministration Of Progestins

Estrogen replacement therapy should be supplemented by sequential progestin therapy only in

women with intact uteri.

It is not possible to give accurate values for the relative clinical effectiveness of different

progestins because careful comparisons are limited in number, and different responses have been

used in the published studies. In various tests in women, the relative potencies of the progestins

are not the same. Furthermore, some progestins possess more or less estrogenic and androgenic

activities than do others.

In general, progestins have been administered sequentially for 10 to 14 days during each

estrogen cycle. Published data suggest that 12 to 14 days of sequential progestin treatment during

estrogen replacement therapy virtually eliminates the occurrence of endometrial hyperplasia, and

thereby irregular bleeding and endometrial carcinoma, compared to estrogen treatment alone.

There are possible additional risks that may be associated with the inclusion of a progestin in

estrogen replacement regimens. The potential risks include adverse effects on carbohydrate and

lipid metabolism, mood changes and edema. The choice and dose of progestin may be important

in minimizing these adverse effects and may differ among women.

It is not possible to give accurate values for the relative clinical effectiveness of different

progestins because careful comparisons are limited in number, and different responses have been

used in the published studies. In various tests in women, the relative potencies of the progestins

are not the same. Furthermore, some progestins possess more or less estrogenic and androgenic

activities than do others.

In general, progestins have been administered sequentially for 10 to 14 days during each

estrogen cycle. Published data suggest that 12 to 14 days of sequential progestin treatment

during

estrogen

replacement

therapy

virtually

eliminates

occurrence

endometrial

hyperplasia, and thereby irregular bleeding and endometrial carcinoma, compared to estrogen

treatment alone.

As shown by endometrial biopsies, the administration of ESTRADERM* 50 for 2 weeks in

sequence with ESTRAGEST* 250/50 for 2 weeks, resulted in the transformation of the estrogen-

primed endometrium to a secretory state, and was effective in protecting against endometrial

hyperplasia. In addition, control of menopausal symptoms and of cyclic bleeding was achieved.

NETA administered by the transdermal route was effective at doses lower than those used orally,

owing to the absence of first-pass metabolism.

ESTRACOMB*

Page 24 of 47

There are possible additional risks that may be associated with the inclusion of a progestin in

estrogen replacement regimens. The potential risks include adverse effects on carbohydrate and

lipid metabolism, mood changes and edema. The choice and dose of progestin may be important

in minimizing these adverse effects and may differ among women.

Treatment with ESTRACOMB* for up to 1 year decreased plasma total and LDL cholesterol as

compared

with

pretreatment

levels.

cholesterol

decreased

slightly

during

ESTRAGEST* 250/50 phase of treatment only. The effect on triglyceride levels was varied. In

trial

triglyceride

levels

were

decreased

during

both

ESTRADERM* 50

ESTRAGEST* 250/50 phases of treatment. In two other trials treatment with ESTRACOMB*

had no significant effect on triglyceride levels.

Pharmacokinetics

ESTRADERM* 50 And Estradiol-17ß

Absorption:

Studies in postmenopausal women using ESTRADERM* 50, which provides 50 μg

of exogenous estradiol-17ß per day, showed increased blood levels within 4 hours. Mean serum

estradiol-17ß levels ranged from 110-147 pM/L (30 to 40 pg/mL) above baseline values, which

are around 37 pM/L (10 pg/mL). Estradiol-17ß to estrone ratios were approximately 1. Serum

concentrations of estradiol-17ß and estrone returned to pre-application levels within 24 hours

after removal of the patch. The daily urinary output of estradiol-17ß conjugates increased 3 to

10 times the baseline values and returned to near baseline values within 2 days after removal of

the patch.

Distribution:

Estradiol-17ß delivered by the transdermal route results in an E

ratio of

approximately 1. By comparison, typical E

ratios following oral estrogen therapy are 0.1 to

0.3 because estrone levels increase to a greater extent than estradiol-17ß levels. The extensive

first-pass liver metabolism leads to supraphysiological plasma concentrations of estrone and, in

patients on prolonged treatment, to accumulation of estrone and estrone sulphate.

Metabolism:

Metabolism and plasma levels of estradiol-17ß delivered transdermally are similar

to those in premenopausal women.

Estradiol-17ß

rapidly

metabolized,

primarily

liver

gut.

most

important

metabolites are estriol and estrone and their conjugates (glucuronides, sulphates); these are far

less

active

than

estradiol-17ß.

bulk

metabolites

excreted

urine

glucuronides and sulphates. Estrogen metabolites are also subject to enterohepatic circulation.

The skin metabolizes estradiol-17ß only to a small extent.

Excretion:

The plasma elimination half-life of estradiol-17ß is approximately 1 hour. Mean

plasma clearance rates of estradiol-17ß and estrone in women have been estimated to be 735

L/(daym

) and 1213 L/(daym

), respectively. Because of its short half-life and rapid clearance,

estradiol-17ß permits a rapid cessation of estrogen therapy when cycling is desirable.

ESTRACOMB*

Page 25 of 47

ESTRAGEST* 250/50 And Norethindrone Acetate

Absorption:

The skin is the rate limiting barrier for the uptake of NETA and NET, since the flux

of NETA from the transdermal therapeutic system

in vitro

is several times higher than that of

NETA/NET through the epidermis. The inter-individual variability of NETA/NET uptake is

nevertheless low. After the first application of a patch, plasma NET levels rise within 2 days to

steady-state levels ranging between 1675 to 3351 pM/L (0.5 and 1.0 ng/mL) (means 2346 to

2681 pM/L (0.7 to 0.8 ng/mL)) with repeated application. Two days after removal of the

ESTRAGEST*

250/50

system,

concentrations

again

close

pre-treatment

measurement of 503 pM/L (0.15 ng/mL).

Throughout the application period of ESTRAGEST* 250/50 there is no accumulation of either

NET or estradiol-17ß in plasma. Mean excretion of conjugates of NET and estradiol-17ß in

urine corresponds to the respective concentration profile in plasma. With repeated application of

ESTRAGEST* 250/50, NET plasma levels were in the same range as those found after single

administration, demonstrating the absence of a skin depot.

For both NET and estradiol-17ß, the individual and mean AUC in plasma approximately doubles

when two ESTRAGEST* 250/50 systems are applied simultaneously.

Distribution:

ESTRAGEST*

250/50

delivers

same

amount

estradiol-17ß

ESTRADERM* 50. The concentration profile of estradiol-17ß is similar to that produced by

ESTRADERM* 50. Sequential application of ESTRADERM* 50 and ESTRAGEST* 250/50

resulted in estradiol-17ß plasma concentrations raised to levels similar to those in the early to

mid-follicular phase of the menstrual cycle 110-147 pM/L (30-40 pg/mL) above baseline, which

is typically 37 pM/L (10 pg/mL)). The E

ratio was observed to undergo a corresponding

shift

from

between

approximately

ESTRAGEST*

250/50

provides

pharmacologic replacement of estrogen in the same way as ESTRADERM* 50.

Metabolism:

Norethindrone acetate (NETA) released by the ESTRAGEST* 250/50 patch is

extensively hydrolysed by esterases during diffusion through the skin. Hydrolysis also occurs in

whole blood and most other organs. The product of cleavage, norethindrone (NET), is the active

hormone circulating in the body.

NET is primarily metabolized in the liver by reduction of the α,β-unsaturated ketone structure in

ring

molecule.

Among

four

possible

stereoisomeric

tetrahydrosteroids,

5β,3-hydroxy-derivative is the main metabolite in plasma. These compounds are predominantly

excreted in urine or feces as sulphate and glucuronide conjugates.

Excretion:

NET is eliminated from plasma with a mean half-life of 6 to 8 hours. The total

plasma clearance of NET averages 340 L/(daym

) after oral administration of NETA. The

pharmacokinetics of NET are not altered during long-term administration.

ESTRACOMB*

Page 26 of 47

Special Populations and Conditions

Pediatrics:

ESTRACOMB* should not be used in children

Geriatrics (> 65 years of age):

No clinical studies were conducted to evaluate the effect of

estradiol on women more than 65 years old.

Gender:

ESTRACOMB* should be used in women only.

Estrogen pharmacology

Estradiol-17ß is the major estrogenic hormone secreted by the human ovary. Among numerous

effects, estradiol-17ß is largely responsible for the development and maintenance of the female

reproductive

system

secondary

sexual

characteristics.

promotes

growth

development of the vagina, uterus, fallopian tubes, and breasts. Estradiol-17ß contributes to the

shaping of the skeleton, to the maintenance of tone and elasticity of urogenital structures, to

changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its

termination, to the growth of axillary and pubic hair, and to the pigmentation of the nipples and

genitals. Estradiol-17ß also affects the release of pituitary gonadotropins.

After menopause, when the ovaries have ceased to function, only small amounts of estradiol-17ß

are still produced, i.e., from the aromatization of androstenedione to estrone and to a lesser

extent, testosterone to estradiol-17ß. Estrone is transformed to estradiol-17ß by the enzyme

17ß-hydroxysteroid-dehydrogenase. Both enzymes prevail in fat, liver and muscle tissue.

In premenopausal women, the ratio of estradiol-17ß (E

) to estrone (E

) (i.e., E

ratio) in the

plasma is in the range of 0.5 to 2, depending on the phase of the menstrual cycle. The E

ratio

for untreated postmenopausal women is below 0.5.

Loss of the ovarian estradiol-17ß production after menopause can result in the following:

instability

thermoregulation

causing

flushes

associated

with

sleep

disturbance

excessive sweating; accelerated loss of bone matrix and mineral, resulting in osteoporosis;

alterations

lipid

metabolism;

urogenital

atrophy,

causing

dyspareunia

urinary

incontinence.

The protection against endometrial hyperplasia in women with intact uteri is necessary during

long-term therapy.

Published data suggest that 12 to 14 days of sequential progestin treatment during estrogen

replacement therapy reduces the occurrence of endometrial hyperplasia, and thereby irregular

bleeding and endometrial carcinoma, compared to estrogen treatment alone.

Progestin pharmacology

Norethindrone acetate (NETA) is a potent progestin that essentially mimics the biological effects

of progesterone. Tissue effects of NETA are dependent on prior estrogen stimulation, and

ESTRACOMB*

Page 27 of 47

NETA receptors have been identified in all tissues containing estrogen receptors

(see Estradiol-

17ß above)

NETA

induces

protein

synthesis

also

reduces

number

estrogen

progestin

receptors, thereby limiting excessive growth stimulation of target tissues by estrogen. 17-

hydroxysteroid-dehydrogenase, which locally oxidizes estradiol-17ß to its weaker estrogenic

metabolite estrone, is also induced by NETA.

One of the major targets of NETA is the uterus, where it induces secretory transformation of the

estrogen-primed endometrium. Once transformation of the endometrium is completed, the

estrogen-primed endometrium is shed resulting in a regular cyclical bleeding.

Progestin is combined with estrogen for protection against endometrial hyperplasia during long-

term therapy of women with intact uteri.

STORAGE AND STABILITY

Store patches in a cool dry place (not below 25°C) . Do not freeze.

Store in the original package

Each patch is individually sealed in a separate pouch. Do not store out of the pouch. Apply

immediately upon removal from the protective pouch. Patches should be applied in whole

Keep ESTRADERM* 50 and ESTRAGEST* 250/50 patches out of the reach and sight of

children and pets both before use and when disposing of used patches.

Use ESTRACOMB* within 6 months of purchase or before the expiry date shown on the pack,

whichever comes first.

Do not use any ESTRACOMB* pack that is damaged or shows signs of tampering.

SPECIAL HANDLING INSTRUCTIONS

See DOSAGE AND ADMINISTRATION- Patch Application section.

DOSAGE FORMS, COMPOSITION AND PACKAGING

The first type of transdermal system to be applied on the skin to initiate a 28-day treatment cycle

is ESTRADERM* 50. ESTRADERM* 50 is a thin, round, multilayer, transparent transdermal

therapeutic

system,

i.e.,

adhesive

patch,

containing

estradiol-17ß

that

designed

application to an area of intact skin.

ESTRACOMB*

Page 28 of 47

The ESTRADERM* 50 patch comprises five layers. Proceeding from the visible surface toward

the surface attached to the skin, these layers are:

a transparent polyester

backing film

a drug

reservoir

of estradiol-17ß and ethanol gelled with hydroxypropyl cellulose

an ethylene vinyl acetate copolymer

release-controlling membrane

adhesive

formulation of light mineral oil and polyisobutylene

protective liner

of siliconized polyethylene terephthalate film that is attached to

the adhesive surface and must be removed before the patch can be used.

The active component of the patch is estradiol-17ß. The nonmedicinal ingredients of the patches

are: cellulose compounds, ethanol, ethylene-vinyl acetate copolymer, light mineral oil, polyester

and polyisobutylene.

The drug reservoir provides a source for continuous delivery of drug for up to 4 days.

Shape

Cross section

ESTRADERM* 50 (the round patch)

The second type of transdermal therapeutic system to be applied on the skin during the last

14 days of a 28-day treatment cycle is ESTRAGEST* 250/50. ESTRAGEST* 250/50 is a thin,

twin-shaped, multilayer, transparent patch, with two separate drug reservoir chambers and an

adhesive surface for application to an area of intact skin. ESTRAGEST* 250/50 is comprised of

the same 5 layers as ESTRADERM* 50. The active substances are released from the drug

reservoirs, penetrate the skin and pass directly into the bloodstream (see PHARMACEUTICAL

INFORMATION).

ESTRAGEST* 250/50 contains a fixed combination of norethindrone acetate (NETA) and

estradiol-17ß. ESTRAGEST* 250/50 releases controlled amounts of NETA and estradiol-17ß

simultaneously through the skin for up to 4 days.

ESTRAGEST* 250/50 (the twin-shaped patch)

Shape

Cross section

ESTRACOMB*

Page 29 of 47

The ESTRACOMB* (estradiol-17β and NETA/estradiol-17β) package consists of the following

systems and releases estradiol and NETA at the following rate over a period of 4 days:

ESTRADERM

ESTRAGEST

250/50

Estradiol-17ß Dosage

Nominal

in vivo

delivery

50 µg/day

50 µg/day

NETA Dosage

Nominal

in vivo

delivery

250 µg/day

Total Estradiol-17ß Content

4 mg

10 mg

Total NETA Content

30 mg

Drug-Releasing Area

10 cm

20 cm

Shape of patch

Round

Twin

Printed (backing side)

CG FNF

In order to achieve the same delivery rate of estradiol-17ß for the ESTRAGEST* 250/50 patch

as the ESTRADERM* 50 patch, the content of estradiol-17ß had to be increased.

One ESTRACOMB* package contains four ESTRADERM* 50 patches (two patches per week)

and four ESTRAGEST* 250/50 patches (two patches per week) for a 28-day treatment cycle.

ESTRACOMB*

Page 30 of 47

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

ESTRADERM* 50

Proper name

Estradiol-17β (i.e., E

Chemical name

estra-1,3,5 (10)-triene-3,17ß-diol

Molecular formula

Molecular mass

272.39

Structural formula

Physicochemical properties

Estradiol is a white crystalline powder.

ESTRAGEST* 250/50

Proper name

Norethindrone acetate (i.e.,

NETA)

Estradiol-17β (i.e., E

Chemical name

17-hydroxy-19-nor-17

"

pregn-

4-en-20-yn-3-one-acetate

estra-1,3,5

(10)-triene-3,17ß-diol

Molecular formula

Molecular mass

340.46

272.39

Structural formula

ESTRACOMB*

Page 31 of 47

Physicochemical properties

White to yellowish white

crystalline powder.

Estradiol is a white crystalline

powder.

CLINICAL TRIALS

Efficacy and Tolerability studies

Three pivotal studies (SP/NE 1, SP/NE 2, SP/NE 4) were conducted with ESTRACOMB* for 12

or 13 cycles (1 year) to assess endometrial response by biopsy. The overall incidence of

endometrial hyperplasia after 1 year was below 2% (3 of the 296 patients). It was comparable to

the pre-trial incidence, and much lower than the published incidence of about 40% endometrial

hyperplasia with unopposed estrogen treatment for the same period of treatment.

Table 4:

Summary of patient demographics for clinical trials

Study #

Trial design

Dosage, route of

administration and

duration

Study subjects (N=

population treated)

Mean age

SP/NE 1

Open, non-comparative

within patient

comparison of

tolerability and efficacy

72 patients evaluated

for efficacy

94 patients evaluated

for tolerability

54.0

54.1

SP/NE 2

Open, non-comparative

367 patients evaluated

for efficacy and for

tolerability

52.1

SP/NE 4

Open, non-comparative,

multi-center

ESTRADERM* 50 twice

weekly, week 1 and 2 ;

NETA/E2-TTS twice

weekly, week 3 and 4

Duration: 12 to 13 cycles

of 4 weeks

136 patients evaluated

for efficacy

139 patients evaluated

for tolerability

53.0

SP/NE 3

Open comparative,

parallel randomized

-ESTRADERM* 50 twice

weekly, week 1 and 2 ;

NETA/E2-TTS twice

weekly, week 3 and 4

-conjugated estrogens

0.625 mg o.d. and

norgestrel 0.15 mg o.d. 12

days/cycle

Duration: 6 cycles of 4

weeks

61 patients evaluated

for efficacy

60 patients evaluated

for tolerability

Bleeding patterns were studied in 4 pivotal trials (SP/NE 1, SP/NE 2, SP/NE 3, SP/NE 4)

with

ESTRACOMB* (over 5300 treatment cycles).

Bleeding was generally well controlled. It occurred in 89.9% of all cycles for patients who

completed the studies. Irregular bleeding occurred in 6.9 % of all cycles. The mean onset of

ESTRACOMB*

Page 32 of 47

bleeding (including irregular bleeding) was between 12.1 and 12.4 days of the combined

treatment and lasted for 5.9 to 6.5 days.

Although it was not the primary objective, every pivotal clinical trial with ESTRACOMB*

showed that the efficacy of ESTRADERM*, in the relief of menopausal and postmenopausal

symptoms

prevention

osteoporosis,

maintained

when

administered

combination with ESTRAGEST*.

As shown by endometrial biopsies, the administration of ESTRADERM* 50 for 2 weeks in

sequence with ESTRAGEST* 250/50 for 2 weeks, resulted in the transformation of the estrogen-

primed endometrium to a secretory state, and was effective in protecting against endometrial

hyperplasia. In addition, control of menopausal symptoms and of cyclic bleeding was achieved.

NETA administered by the transdermal route was effective at doses lower than those used orally,

owing to the absence of first-pass metabolism.

DETAILED PHARMACOLOGY

See Action and Clinical Pharmacology (Part I)

TOXICOLOGY

Preclinical safety data

The toxicity profile of estradiol has been well established in the literature. Long-term continuous

administration

natural

synthetic

estrogens

certain

animal

species

increases

frequency of carcinomas of the breast, uterus, cervix, vagina, testis and liver.

Norethindrone acetate was not mutagenic in a battery of

in vitro

in vivo

genetic toxicity

assays.

ESTRACOMB*

Page 33 of 47

REFERENCES

Adami S, Suppi R, Bertoldo F, Rossini M, Residori M, Maresca V, et al. Transdermal

estradiol in the treatment of postmenopausal bone loss. Bone and Mineral, Elsevier

1989;7:79-86.

Armstrong BK. Oestrogen therapy after menopause-boon or bane? Med J 1988

Aug;148:213-4.

Beral V. Million W, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement

therapy in the Million Women Study. Lancet 2007; 69 (9574):1703-10.

Bergkvist L,

Adami HO, Persson I, Hoover R, Schairer C. The risk of breast cancer after

estrogen and estrogen-progestin replacement. N Engl J Med 1989;321(5):293-7.

Brinton LA, Hoover RN, Fraument JF Jr. Menopausal estrogens and breast cancer risk:

an expanded case-control study. Br J Cancer 1986;54:825-32.

CGS 15885 ESTRADERM TTS Single case file of spontaneous reports on adverse

reactions. Ciba-Geigy Ltd., Basel, (data available on request).

Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu JK, Eggena P, et al. Biologic

effects of transdermal estradiol. N Engl J Med 1986;314(25):1615-20.

Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D,

et al. The

Women's Health Initiative randomized trial. Influence of estrogen plus progestin on

breast cancer and mammography in healthy postmenopausal women. JAMA

2003;289(24):3243-53.

Clisham P, et al. Bleeding patterns and endometrial histology (EH) with long-term

transdermal estrogen therapy (TE). Fertil and Steril 1988;Suppl.:24f.

Colditz GA, Stampfer MJ, Willett WC, Hennekens CH, Rosner B, Speizer FE.

Prospective study of estrogen replacement therapy and risk of breast cancer in

postmenopausal women. JAMA 1990;264(20):2648-53.

Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE, Stampfer MJ

et al. The

use of estrogens and progestins and the risk of breast cancer in postmenopausal women.

N Engl J Med 1995;332(24):1589-93.

Colditz GA, Egan KM, Stampfer MJ. Hormone replacement therapy and risk of breast

cancer: Results from epidemiologic studies. Am J Obstet Gynecol 1993;168:1473-80.

COLLABORATIVE GROUP on hormonal factors in breast cancer. Breast Cancer and

Hormone Replacement Therapy. The Lancet 1997;350:1047-59.

ESTRACOMB*

Page 34 of 47

Crook D, Cust MP, Gangar KF, Worthington M, Hillard TC, Stevenson JC,

et al.

Comparison of transdermal and oral estrogen-progestin therapy: Effects of serum lipids

and lipoproteins. Am J Obstet Gynecol 1992;116:950-5.

Daly E, Vessey MP, et al. Risk of Venous thromboembolism in users of hormone

replacement therapy. Lancet 1996;348:977-80.

Daly E, Vessey MP, Painter R. Case-control study of venous thromboembolism risk in

users of hormone replacement therapy. Lancet 1996:348:1027-30.

Davis GF, and Winter L. Cumulative irritation study of placebo transdermal estrogen

patches. Curr Ther Res 1987;42: 719-21.

Dupont WD, Page DL. Menopausal estrogen replacement therapy and breast cancer. Arch

Intern Med 1991;151:67-72.

Editorial Transdermal estrogen. Med Lett Drugs Ther 1985;27(699):119-20.

Grambrell RD. Update on hormone replacement therapy. Am Fam Phys 1992;46:87-96S.

Gambrell RD. Evidence supports estrogen-progestogen replacement therapy. Postgrad

Med 1985;78(1):35-8.

Gambrell RD. Hormones in the etiology and prevention of breast and endometrial cancer.

South Med J 1984;77(12):1509-15.

Grady S, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M,

et al for the

HERS Research Group. Cardiovascular disease outcomes during 6.8 years of hormone

therapy. Heart and Estrogen/progestin replacement study follow-up (HERS II). JAMA

2002;288(1):49-57.

Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE

et al.

Prospective study of exogenous hormones and risk of pulmonary embolism in women.

Lancet 1996;348:983-7.

Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B,

et al for the Heart and

Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of

estrogen plus progestin for secondary prevention of coronary heart disease in

postmenopausal women. JAMA 1998;280(7):605-13.

Hunt K, Vessey M, McPherson K. Long term surveillance of mortality and cancer

incidence in women receiving hormone replacement therapy. Obstet Gynaecol

1987;94:620-35.

ESTRACOMB*

Page 35 of 47

Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for

idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet

1996;348:981-3.

Kaufman DW, Miller DR, Rosenberg G L, Helmrich SP, Stolley P, Schottenfeld D

et al.

Non-contraceptive estrogen use and the risk of breast cancer. JAMA 1984;252:63-7.

La Vecchia C, Decarli A, Parazzini F, Gentile A, Liberati C, Franceschi S. Non-

contraceptive oestrogens and the risks of breast cancer in women. Int J Cancer

1986;38:853-8.

Laufer LR, DeFazio JL, Lu JK, Meldrum DR, Eggena P, Sambhi MP, et al. Estrogen

replacement therapy by transdermal estradiol administration. Am J Obstet Gynecol

1983;146(5):533-40.

Lacey JV Jr, Brinton LA, Leitzmann MF, Mouw T, Hollenbeck A, Schatzkin A, et al.

Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-

AARP Diet and Health Study Cohort. J Natl Cancer Inst. 2006;98(19):1397-405.

Martindale: Drugdex evaluations. Estrogens, Mechanism of Action/Pharmacology. On

line, June 22, 2006.

Naessén T, Persson I, Adami HO, Bergström R, Bergkvist L. Hormone replacement

therapy and the risk for first hip fracture. Ann Int Med 1990;113(2):95-103.

Padwick ML, Endacott J, Whitehead MI . Efficacy, acceptability, and metabolic effects of

transdermal estradiol in the management of postmenopausal women. Am J Obstet

Gynecol 1985;152(8):1085-91.

Padwick ML, Pryse-Davies J, Whitehead MI. A simple method for determining the

optimal dosage of progestogen in postmenopausal women receiving estrogens. N Engl J

Med 1986;315(15):930-4.

Paganini-Hill A, Ross RK, Gerkins VR, Henderson BE, Arthur M, Mack TM.

Menopausal oestrogen therapy and hip fractures. Ann Int Med 1981;95(1):28-31.

Palmer JR, RosenbergG L, Clarke EA, Miller DR, Shapiro S. Breast cancer risk after

estrogen replacement therapy: Results from the Toronto breast cancer study. Am J

Epidemiol 1991;134:1386-95.

Pérez Gutthann S, Garcia Rodrigues LA, Castellsague J, Duque Oliart A. Hormone

replacement therapy and risk of venous thromboembolism: population based case-control

study. Br Med J 1997;314:796-800.

ESTRACOMB*

Page 36 of 47

Place VA, Powers M, Darley PE, Schenkel L, Good WR. A double-blind comparative

study of Estraderm and Premarin in the amelioration of postmenopausal symptoms. Am J

Obstet Gynecol 1985;152(8):1092-9.

Powers MS, Schenkel L, Darley PE, Good WR, Balestra JC, Place VA. Pharmacokinetics

and pharmacodynamics of transdermal dosage forms of 17ß-estradiol: Comparison with

conventional oral estrogens used for hormone replacement. Am J Obstet Gynecol

1985;152(8):1099-106.

Ribot C, Tremollieres F, Pouilles JM, Louvet JP, Peyron R. Preventive effects of

transdermal administration of 17ß-estradiol on postmenopausal bone loss: A 2-year

prospective study. Gynecol Endocrinol 1989;3:259-67.

Selby PL, Peacock M. Dose dependent response of symptoms, pituitary, and bone to

transdermal oestrogen in post menopausal women. Br Med J 1986;293:1337-9.

Selby PL, and Peacock M. The effect of transdermal oestrogen on bone, calcium -

regulating hormones and liver in postmenopausal women. Clin Endocrinol

1986;25(5):543-7.

Shumaker SA, Legault, C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. The

Women's Health Initiative Memory Study : A randomized controlled trial. Estrogen plus

progestin and the incidence of dementia and mild cognitive impairment in postmenopausal

women. JAMA 2003; 289(20):2651-62.

Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. Conjugated Equine

Estrogens

Incidence

Probable

Dementia

Mild

Cognitive

Impairment

Postmenopausal

Women.

Women’s

Health

Initiative

Memory

Study.

JAMA

2004;

291(24):2947-58.

Sillero-Arenas M, Delgado-Rodriguez M. Rodrigues-Canteras R, Bueno-Cavanillas A,

Galvez-Vargas R. Menopausal hormone replacement therapy and breast cancer: A meta-

analysis. Obstet Gynecol 1992;79:286-94.

Stanford JL, Weiss NS, Voigt LF, Daling JR, Habel LA, Rossing MA. Combined

estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in

middle-aged women. JAMA 1995;274(2):137-42.

Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM, Flanders WD, et al. A meta-

analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA

1991;265(15):1985-90.

Steingold KA, Laufer L, Chetkowski RJ, DeFazio JD, Matt DW, Meldrum DR, et al.

Treatment of hot flashes with transdermal estradiol administration. J Clin Endocrinol

Metab 1985;61(4):627-32.

ESTRACOMB*

Page 37 of 47

Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of

transdermal versus oral hormone replacement therapy on bone density in spine and

proximal femur in postmenopausal women. Lancet 1990;336:265-9.

Sureau C, Ribot C., Limouzin-Lamothe M. A., Jamin C.. Objectif, qualité de vie! Les

estrogènes: Une approche globale du traitement de la ménopause. Sem Hop Paris

1989;65(36-37):2225-32.

The Women’s Health Initiative Steering Committee. Effects of conjugated equine

estrogen in postmenopausal women with hysterectomy. The Women’s Health Initiative

randomized controlled trial. JAMA 2004;291(14):1701 –12.

Utian WH. Biosynthesis and physiologic effects of estrogen and pathophysiologic effects

of estrogen deficiency: A review. Am J Obstet Gynecol 1989;161:1828-31.

Vandenbroucke JP, Helmerhorst FM. Risk of venous thrombosis with hormone-

replacement therapy Lancet 1996;348:972.

Whitehead MI, Padwick ML, Endacott J, Pryse-Davies J. Endometrial responses to

transdermal estradiol in postmenopausal women. Am J Obstet Gynecol 1985;152(8):1079-

Winter MI, and Fraser D. Controversies concerning the safety of estrogen replacement

therapy. Am J Obstet Gynecol 1987;56:1313-22.

Writing Group for the Women's Health Initiative Investigators. Risks and benefits of

estrogen plus progestin in healthy postmenopausal women. Principal results from the

Women's Health Initiative Randomized Controlled Trial. JAMA 2002;288(3):321-33.

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 38 of 47

PART III: CONSUMER INFORMATION

ESTRACOMB * contains two types of

transdermal therapeutic systems (patches):

ESTRADERM* 50 ( estradiol-17β)

ESTRAGEST *250/50 (estradiol-17β +

Norethindrone Acetate)

This leaflet is part III of a three-part «Product

Monograph" published when ESTRACOMB*

was

approved

for

sale

in

Canada

and

is

designed

specifically

for

Consumers.

This

leaflet

is

a

summary

and

will

not

tell

you

everything

about

ESTRACOMB*.

Contact

your

doctor

or

pharmacist

if

you

have

any

questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

ESTRACOMB* should only be used if you have a

uterus (it has not been surgically removed)

reduce

moderate

severe

menopausal symptoms.

To prevent osteoporosis

Some

women

more

likely

develop

osteoporosis after menopause than others. If you

have been prescribed ESTRACOMB* only for the

prevention

osteoporosis

should

discuss

other alternative therapies with your doctor. . In

addition,

should

discuss

adequate

diet,

calcium

vitamin

intake,

cessation

smoking

regular

physical

weight-bearing

exercise with your doctor or pharmacist.

ESTRACOMB* should be used only under the

supervision of a doctor, with regular follow-up at

least once a year to identify side effects associated

with its use. Your first follow-up visit should be

within 3 to 6 months of starting treatment. Your

visit may include a blood pressure check, a breast

exam, a Pap smear and pelvic exam. You should

have a mammogram before starting treatment and

regular

intervals

recommended

your

doctor. Your doctor may recommend some blood

tests.

You should carefully discuss the risks and benefits

of hormone replacement therapy (HRT) with your

doctor. You should regularly talk with your doctor

about whether you still need treatment with HRT.

What it does:

Uses of Estrogens

The main estrogen produced by your ovaries prior

to menopause is estradiol, and this is the same

estrogen

that

ESTRADERM*

ESTRAGEST*. When applied to the skin, the

ESTRADERM*

ESTRAGEST*

patches

continually release small, controlled quantities of

estradiol, which pass through your skin and into

your

bloodstream.

amount

estrogen

prescribed depends on your body's needs.

Treatment with ESTRACOMB* offers relief from

menopausal symptoms for women with uteri. With

ESTRACOMB*, you receive estradiol throughout

the entire 28-day cycle, and norethindrone acetate

(NETA), a progestin, during the last 2 weeks of

28-day

cycle.

progestin

provides

important protection for your uterus

(See Uses Of

Progestins)

Your

body

normally

makes

estrogens

progestins

(female

hormones)

mainly

ovaries. Between ages 45 and 55, the ovaries

gradually stop making estrogens. This leads to a

decrease in body estrogen levels and a natural

menopause

(the

monthly

menstrual

periods). If both ovaries are removed during an

operation before natural menopause takes place,

sudden

decrease

estrogen

levels

causes

"surgical menopause".

Menopause is not a disease - it is a natural life

event and different women experience menopause

symptoms

differently.

all women

suffer obvious symptoms of estrogen deficiency.

When the estrogen levels begin decreasing, some

women

develop

very

uncomfortable

symptoms,

such as feelings of warmth in the face, neck, and

chest,

sudden

intense

episodes

heat

sweating ("hot flashes" or " hot flushes"). Using

estrogen drugs can help the body adjust to lower

estrogen levels and reduce these symptoms.

Osteoporosis is a thinning of the bones that makes

them

weaker

allows

them

break

more

easily. In osteoporosis, the bones of the spine,

wrists and hips break most often. The bones of

both men and women start to thin after about age

40, but women lose bone faster after menopause.

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 39 of 47

Using estrogens after menopause slows down bone

thinning and may prevent bones from breaking.

Uses Of Progestins

Progestins used in hormone replacement therapy

have similar effects to the female sex hormone

progesterone.

During

child

bearing

years,

progesterone is responsible for regulation of the

menstrual

cycle.

estradiol

delivered

ESTRACOMB*

only

relieves

your

menopausal

symptoms,

but,

like

estrogens

produced by your body, may also stimulate growth

of the inner lining of the uterus, the endometrium.

In menopausal and postmenopausal women with

intact

uteri,

stimulation

growth

endometrium may result in irregular bleeding. In

some cases this may progress into a disorder of the

uterus

known

endometrial

hyperplasia

(overgrowth of the lining of the uterus), which

increases the risk of endometrial cancer (cancer of

the lining of the uterus). The development of

estrogen-mediated disorders of the uterus can be

reduced

progestin,

such

norethindrone

acetate, is given regularly for a certain number of

days

with

your

estrogen

replacement

therapy.

Each

cycle

progestin

administration

should

induce a periodic bleeding, during which time the

inner lining of the uterus is shed., This protects

against endometrial hyperplasia.

When it should not be used

Certain medical conditions may be aggravated by

estrogens and progestins, therefore these hormones

should not be used at all under these conditions.

ESTRACOMB* should not be used under these

conditions:

if you are pregnant or think you may be

pregnant. Since pregnancy may be possible

early in menopause while you are still having

spontaneous periods, the use of

non-hormonal birth control should be

discussed with your physician at this time. If

you take estrogen during pregnancy, there is

a small risk of your unborn child having birth

defects.

if you are breast-feeding. Ask your doctor or

pharmacist for advice.

if you currently have or have ever had cancer

of the breast, or uterus or endometrium

(lining of the womb) or any other cancer

which is sensitive to estrogens

if you have been diagnosed with endometrial

hyperplasia (overgrowth of the lining of the

uterus)

if you have unexplained changes in

unexpected or unusual genital bleeding that

has not been investigated.

if you have active thrombophlebitis

(inflamed varicose veins)

if you currently have a problem with

abnormal blood clots forming in your blood

vessels or have ever had such a problem in

the past. This may cause painful

inflammation of the veins (thrombophlebitis)

or blockage of a blood vessel in the legs

(deep vein thrombosis), lungs (pulmonary

embolism) or other organs

if you have ever had a heart attack, coronary

heart disease or stroke

if you currently have a serious liver disease

if you have migraine

if you have had partial or complete loss of

vision due to blood vessel disease in the eye.

if you have a disease of blood pigment called

porphyria

if you have ever had any unusual allergic

reaction to estrogens or any other component

of ESTRACOMB* (see

What the medicinal

ingredient are and What the nonmedicinal

ingredients are

ESTRACOMB* is not a contraceptive, nor will it

restore fertility.

Talk to your doctor if you have any further

questions or if you think that any of the above may

apply to you.

What the medicinal ingredient are:

ESTRACOMB* contains two types of transdermal

therapeutic systems (patches) that are used in

sequence. The round patch is called

ESTRADERM* 50 (ESTRADERM*) and the

twin patch is called ESTRAGEST* 250/50

(ESTRAGEST*).

ESTRADERM* contains a natural estrogen

hormone,

estradiol

, while ESTRAGEST*

contains

estradiol

as well as a progestin,

norethindrone acetate (NETA).

What the nonmedicinal ingredients are:

cellulose

compounds,

ethanol,

ethylene-vinyl

acetate copolymer, light mineral oil, polyester and

polyisobutylene.

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 40 of 47

What dosage forms it comes in:

ESTRACOMB*

package

contains

four

ESTRADERM*

patches

(two

patches

week)

four

ESTRAGEST*

250/50

patches

(two patches per week) for a 28-day treatment

cycle.

Breast cancer

The results of the WHI trial indicated an increased

risk of breast cancer in post-menopausal women

taking

combined

estrogen

plus

progestin

compared to women taking placebo.

results

trial

indicated

difference

risk

breast

cancer

postmenopausal women with prior hysterectomy

taking

estrogen-alone

compared to women taking

placebo.

Estrogens with or without progestins should not be

taken by women who have a personal history of

breast cancer.

In addition, women with a family history of breast

cancer or women with a history of breast lump,

breast biopsies or abnormal mammograms (breast

x-rays) should consult with their doctor before

starting hormone replacement therapy.

Women

should

have

mammogram

before

starting

regular

intervals

during

treatment as recommended by their doctor.

Regular

breast

examinations

doctor

regular breast self-examination are recommended

for all women. You should review technique for

breast self-examination with your doctor.

Overgrowth of the lining of the uterus and

cancer of the uterus

estrogen-alone

therapy

post

menopausal

women

still

have

uterus

increases

risk

developing

endometrial

hyperplasia

(overgrowth

lining

uterus), which increases the risk of endometrial

cancer (cancer of the lining of the uterus).

The purpose of adding a progestin medication to

estrogen

therapy

reduce

risk

endometrial hyperplasia.

should

discuss

progestin

therapy

risk

factors

endometrial

hyperplasia

endometrial carcinoma with your doctor. You

should

also

report

unexpected

unusual

vaginal bleeding to your doctor.

If you have had your uterus removed, you are not

at risk of developing endometrial hyperplasia or

endometrial

carcinoma.

Progestin

therapy

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

The Women’s Health Initiative (WHI) trial is a

large clinical study that assessed the benefits and

risks

oral

combined

estrogen

plus

progestin

therapy and oral

estrogen-alone

therapy compared

with placebo (a pill with no active ingredients) in

postmenopausal women.

trial

indicated

increased

risk

myocardial infarction (heart attack), stroke, breast

cancer, pulmonary emboli (blood clots in the lungs)

and deep vein thrombosis (blood clots in the large

veins)

postmenopausal

women

taking

oral

combined

estrogen plus progestin

The WHI trial indicated an increased risk of stroke

deep

vein

thrombosis

postmenopausal

women with prior hysterectomy (surgical removal

of the uterus) taking oral

estrogen-alone

Therefore,

should

highly

consider

following:

There

increased

risk

developing

invasive breast cancer, heart attack, stroke and

blood clots in both lungs and large veins with

the use of estrogen plus progestin therapy.

There is an increased risk of stroke and blood

clots

large

veins

with

estrogen-alone therapy.

Estrogens with or without progestins should

not be used for the prevention of heart disease

or stroke.

Estrogens with or without progestins should be

used at

the lowest effective dose

and for

the

shortest

period

of

time

possible.

Regular

medical follow-up is advised.

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 41 of 47

therefore not generally required in women who

have had a hysterectomy.

Ovarian cancer

In some studies, the use of estrogen-alone and

estrogen plus progestin therapies for 5 or more

years has been associated with an increased risk of

ovarian cancer.

Heart disease and Stroke

The results of the WHI trial indicated an increased

risk of stroke and coronary heart disease in post-

menopausal women taking combined

estrogen

plus progestin

compared to women taking placebo.

The results of the WHI trial indicated an increased

risk of stroke, but no difference in the risk of

coronary heart disease in post-menopausal women

with prior hysterectomy taking

estrogen alone

compared to women taking placebo.

Abnormal Blood Clotting

The results of the WHI trial indicated an increased

risk of blood clots in the lungs and large veins in

post

menopausal

women

taking

combined

estrogen

plus

progestin

compared

women

taking placebo.

The results of the WHI trial indicated an increased

risk

blood

clots

large

veins,

difference in the risk of blood clots in the lungs in

post-menopausal women with prior hysterectomy

taking

estrogen-alone

compared to women taking

placebo.

The risk of blood clots increases with age, if you

or a family member has had blood clots, if you

smoke or if you are severely overweight. The risk

of blood clots is also temporarily increased if you

immobilized

long

periods

time

following major surgery. You should discuss risk

factors

blood

clots

with

your

doctor

since

blood clots can be life-threatening or cause serious

disability.

Gallbladder disease

The use of estrogens by postmenopausal women

been

associated

with

increased

risk

gallbladder disease requiring surgery.

Dementia

Women’s

Health

Initiative

Memory

Study

(WHIMS) was a substudy of the WHI trial and

indicated an increased risk of dementia (loss of

memory

intellectual

function)

post-

menopausal women age 65 and over taking oral

combined

estrogen plus progestin

compared to

women taking placebo.

The WHIMS indicated no difference in the risk of

dementia in post-menopausal women age 65 and

over with prior hysterectomy taking oral

estrogen-

alone

compared to women taking placebo.

Before you use ESTRACOMB* talk to your

doctor or pharmacist if you:

have a history of allergy or intolerance to

any medications or other substances

have been told that you have a condition

called hereditary angioedema of if you

have had episodes of rapid swelling of the

hands, feet, face, lips, eyes, tongue, throat

(airway blockage) or digestive tract

have a personal history of breast disease

(including

breast

lumps)

and/or

breast

biopsies, or a family history of breast

cancer

have

experienced

unusual

undiagnosed vaginal bleeding

have

history

uterine

fibroids

endometriosis

have a history of liver disease or liver

tumours, jaundice (yellowing of the eyes

and/or skin) or itching related to estrogen

use or during pregnancy

have a history of migraine headache

have a history of high blood pressure

have a personal or family history of blood

clots,

personal

history

heart

disease or stroke

phlebitis (inflamed varicose veins)

have a history of kidney disease, asthma

or epilepsy (seizures)

have

history

bone

disease

(this

includes certain metabolic conditions or

cancers that can affect blood levels of

calcium and phosphorus)

have been diagnosed with diabetes

have been diagnosed with porphyria (a

disease of blood pigment)

have been diagnosed with lupus

gall bladder disease

depression

have been diagnosed with hearing loss

due to otosclerosis

have a history of high cholesterol or high

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 42 of 47

triglycerides

are pregnant or may be pregnant

are breastfeeding

have

hysterectomy

(surgical

removal of the uterus)

smoke

are undergoing surgery or need long bed

rest.

Ask your doctor and pharmacist to answer any

questions you may have.

INTERACTION WITH THIS MEDICATION

Tell your doctor or pharmacist if you are

taking or have recently taken any other

medicines. Remember also those not prescribed

by a doctor.

This particularly includes the following: anti-

anxiety medicines (e.g.barbiturates,

meprobamate), anti-epileptic medicines (e.g.

pheno barbital, phenytoin or carbamazepine), an

anti-inflammatory medicine called

phenylbutazone, antibiotics and other anti-

infective medicines (e.g. rifampicin, rifabutin,

nevirapine, efavirenz), and herbal medicines (e.g.

St John’s wort).

These medicines may be affected by

ESTRACOMB* or, conversely, they may affect

how well ESTRACOMB* works. Your doctor

may need to adjust the dose of your treatment.

PROPER USE OF THIS MEDICATION

Usual dose:

Each

ESTRACOMB*

pack

contains

four

ESTRADERM* and four ESTRAGEST* patches.

round

ESTRADERM*

patch

provides

estrogen,

estradiol.

twin

ESTRAGEST*

patch

provides

estradiol

progestin,

norethindrone

acetate

(NETA).

These

patches

contain and release different amounts of active

ingredient, as follows:

ESTRADERM*: 10 cm

round patch,

containing 4 mg estradiol and releasing

about 50 µg estradiol a day

ESTRAGEST*: 20 cm

goggle-shaped

patch, containing 10 mg estradiol and 30

mg norethindrone acetate, and releasing

about 50 µg estradiol and 250 µg NETA

a day

When ESTRACOMB* is applied to the skin, the

patches release small amounts of estradiol and

NETA, which pass directly through the skin into

your bloodstream.

All eight patches are to be used in a 28-day

treatment cycle.

Therapy

started

with

ESTRADERM*

patches

which

used

first

weeks

followed by the ESTRAGEST* patches for the

next 2 weeks (See Figure 1). The ESTRADERM*

ESTRAGEST*

patches

applied

twice

weekly on the same days of each week. Each

patch should be worn continuously for 3-4 days.

Regular cyclical bleeding usually starts towards

the end of the ESTRAGEST* application phase

(i.e., while you are wearing the 4th ESTRAGEST*

patch of that cycle). The duration of bleeding is

around 6 days. Bleeding is of light intensity or

spotting for 60-70% of this time. Tell your doctor

if you have heavy or irregular bleeding after a few

months of treatment.

As therapy with ESTRACOMB* is continuous,

next

treatment

cycle

started

with

ESTRADERM* immediately after removal of the

last

ESTRAGEST*

patch,

regardless

whether there is still bleeding (i.e., you will have a

patch on at all times).

It is important that you take your medication as

your physician has prescribed. Do not discontinue

or change your therapy without consulting your

physician first.

How And Where To Apply ESTRACOMB*

It is recommended that you change the site of

application

each

time

patch

applied.

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 43 of 47

However, each time you apply a patch you should

always apply it to the same area of your body (i.e.,

if the patch is applied to the buttocks, move the

patch from right side to left side, twice a week or

more if there is any redness under the patch).

1. Preparing The Skin

In order for the patch to stick, the skin should be

clean, dry and free of creams, lotions or oils. If

you wish, you may use body lotion after the patch

has been properly applied to the skin. The skin

should not be irritated or broken, since this may

alter the amount of hormone you get. Contact

with water (bath, pool, or shower) won't affect the

patch,

although

very

water

steam

loosen it and therefore should be avoided

(see

Helpful Hints)

2. Where To Apply The ESTRADERM* Or

ESTRAGEST* Patches

The buttock is the preferred place to apply the

patches. Other suitable application sites are the

side, lower back or lower abdomen (see Figure 1).

Change the site of application each time you put a

patch on. You can use the same spot more than

once but

not twice in a row

Figure 1

Avoid areas of the skin where clothing may rub

the patch off or areas where the skin is very hairy

or folded. Also avoid areas where the patch is

likely to be exposed to the sun since this may

affect how the patch works.

DO NOT APPLY THE PATCHES TO YOUR

BREAST

, since this may cause unwanted effects

and discomfort.

3. Opening The Pouch

Each ESTRADERM* or ESTRAGEST* patch is

individually sealed in a protective pouch.

Tear

open this pouch at the indented notch and remove

the patch (see Figures 2a and 2b). Do not use

scissors, as you may accidentally cut and destroy

the patch. There may or may not be bubbles in the

patch, but this is normal. Do not cut the twin

ESTRAGEST* patch in half.

Figure 2a

Figure 2b

4. Removing The Liner

One side of the patch has the adhesive that sticks

your

skin.

adhesive

covered

protective liner that must be removed.

To separate the patch from the liner, hold the patch

with your thumb on the smooth liner, your other

fingers on the patch. See positioning in Figure 3.

Press your thumb against your other fingers by

using the motion of snapping your fingers slowly.

Figure 3

This will allow you to easily separate the patch

and liner. Holding the

edge

of the patch you can

peel

away

liner

(Figure

Avoid

touching the adhesive.

Figure 4

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 44 of 47

Don't worry if the patch buckles slightly because

you can flatten it out after the liner has been

removed. Apply the patch soon after opening the

pouch and removing the liner.

5.

Applying

The

ESTRADERM*

And

ESTRAGEST* Patches

Apply the adhesive side to the spot you have

chosen. Press it firmly in place with the palm of

your hand for about 10 seconds, then run your

finger around the edge, making sure there is

good contact with the skin.

6. When And How To Remove The Patch

The ESTRADERM* and ESTRAGEST* patches

should be changed twice weekly. Always change it

on the same 2 days of the week. If you forget to

change it at the scheduled time, there is no cause

for alarm. Just change it as soon as possible and

continue

to follow your usual schedule.

After you remove the patch fold it in half with the

adhesive sides inwards.

Throw it away, safely

out of the reach of children or pets

Any adhesive left on your skin should rub off

easily. You can also use mineral oil, baby oil or

rubbing alcohol to remove adhesive from the skin.

Apply a new ESTRADERM* or ESTRAGEST*

patch on a different spot of clean, dry skin.

Helpful Hints

What to do if the patch falls off

Should a patch fall off in a very hot bath or

shower, shake the water off the patch. Dry your

skin completely and reapply the patch as soon as

possible (to a new area of skin) and continue your

regular schedule. Make sure you choose a clean,

lotion-free area of the skin. If it still does not stick

completely to your skin, then use a

new

patch. No

matter what day this happens, go back to changing

the patch on the same days as the initial schedule.

If hot baths, saunas or whirlpools are something

you enjoy and you find that the patch is falling off,

you may consider removing the patch

temporarily

while you are in the water. If you do remove the

patch temporarily, the adhesive side of the patch

should be placed on the protective liner that was

removed when originally applying the patch. Wax

paper may be used as an alternate to the liner.

This

prevents

contents

patch

from

emptying

evaporation

while

wearing it.

In addition to exposure to very hot water, there are

some other causes for the patch failing to stick. If

you are having patches fall off regularly, this could

be happening as a result of:

using any type of bath oil

using soaps with a high cream content

using skin moisturizers before applying the

patch

Patch adhesion may be improved if you avoid

using these products, and by cleansing the site of

application with rubbing alcohol before you apply

the patch.

What

to

do

if

your

skin

becomes

red

or

irritated under or around the patch

As with any product that covers the skin for a

period

time

(such

bandages),

ESTRADERM* and ESTRAGEST* patches can

produce some skin irritation in some women. This

varies according to the sensitivity of each woman.

Usually

this

redness

does not

pose

health

concern to you, but to reduce this problem, there

are some things that you may do:

choose the buttock as the site of application

change

site

application

ESTRADERM*

ESTRAGEST*

patch

every time a new patch is applied, usually

twice weekly

Experience with ESTRADERM* has shown that if

you allow the patch to be exposed to the air for

approximately 10 seconds after the protective liner

has been removed, skin redness may not occur.

If redness and/or itching continues, you should

consult your physician.

Overdose:

Symptoms

Overdosage

with

estrogen

cause

nausea,

breast

discomfort,

fluid

retention,

bloating

vaginal bleeding in women.

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 45 of 47

Progestin (norethindrone acetate) overdosage may

cause

depressed

mood,

tiredness,

acne

hirsutism.

If more medication has been taken than what has

been prescribed, remove the patch and contact

either

your

doctor,

hospital,

emergency

department immediately.

For management of a suspected drug overdose,

contact your regional Poison Control Center.

Treatment

Owing

mode

administration

(transdermal), plasma levels of estradiol-17ß and

norethindrone acetate can be rapidly reduced by

removal of the patch.

Missed Dose:

If you miss applying a patch, apply a new patch as

soon as you remember. No matter what day that

happens, go back to changing this patch on the

same day as your initial schedule.

Always Remember

Your doctor has prescribed ESTRACOMB* for

you after a careful review of your medical needs.

Use it only as directed and do not give it to anyone

else. Your doctor should re-examine you at least

once a year.

If you have any questions, contact your doctor or

pharmacist.

SSIDE

EFFECTS

AND

WHAT

TO

DO

ABOUT THEM

All medicines can have side effects. Sometimes

they are serious, most of the time they are not

.

Check with your doctor as soon as possible if any

of the following occur:, swelling of the lower legs,

ankles, fingers or abdomen due to fluid retention

(oedema) persisting for more than 6 weeks, change

in weight, change in your sex drive, easy bruising,

excessive

nose

bleeds,

painful

and/or

heavy

periods (may be signs of growth of fibroids in

uterus), back pain or menstrual period-like pain,

breast tenderness and excessive vaginal secretions

(may be a sign that too much estrogen is taken),

change in vaginal discharge (may be a sign that

much

estrogen

taken),

vaginal

thrush

(vaginal

fungal

infection

with

severe

itching,

vaginal discharge), intolerable breast tenderness,

persistent or severe skin irritation, itching under

the patch, reddening of the skin after the patch has

been removed; hair loss, excessive hairiness, rash,

itching, dryness or discoloration of the skin, spotty

darkening of the skin, particularly on the face or

abdomen (chloasma), acne, purple skin patches,

decline of memory or mental ability, headache,

nervousness, rapid change in mood, contact lens

discomfort, gall bladder disease (tendency to form

gall stones).

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 46 of 47

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Frequency

Symptom/possible

side effect

Talk to your

doctor or

pharmacist

Stop

taking

drug

and call

your

doctor

or

pharma-

cist

Only

if

severe

In

all

cases

Commo

n

Abdominal pain,

nausea or vomiting

x

Breast lump

x

Crushing chest

pain or chest

heaviness

x

Pain or swelling in

the leg

x

Persistent sad

mood

x

Sharp pain in the

chest, coughing

blood or sudden

shortness of breath

x

Sudden partial

or complete loss of

vision

x

Sudden severe

headache or

worsening of

headache,

vomiting,

dizziness, fainting,

disturbance of

vision or speech or

weakness or

numbness in an

arm or leg

x

Migraine

x

Unexpected

vaginal bleeding or

excessively heavy

bleeding

x

Uncommon

Yellowing

skin

eyes

(jaundice)

x

Signs

of

allergic

reaction:

sudden

troubled breathing,

tightness

chest, general rash,

swelling or itching

x

Increase

blood

pressure

x

This is not a complete list of side effects. For any

unexpected effects while taking ESTRACOMB*,

contact your doctor or pharmacist.

ESTRADERM* and ESTRAGEST* should be

stored in a cool dry place ( not above 25

C). Do

not freeze.

Store in the original package.

ESTRADERM* and ESTRAGEST* patches

should be kept out of the reach and sight of

children and pets before and after use.

Use ESTRACOMB* within 6 months of purchase

or before the expiry date shown on the pack,

whichever comes first.

Do not use any ESTRACOMB* pack that is

damaged or shows signs of tampering.

HOW TO STORE IT

IMPORTANT: PLEASE READ

ESTRACOMB*

Page 47 of 47

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through

Canada Vigilance Program

collects information on

serious and unexpected side effects of drugs. If you

suspect you have had a serious or unexpected reaction

to this drug you may notify Canada Vigilance:

Online: www.healthcanada.gc.ca/medeffect

Toll-free telephone:

1-866-234-2345

toll-free fax

1-866-678-6789

Postage Paid mail:

Canada Vigilance Program

Health Canada

AL 0701C

Ottawa ON K1A 0K9

NOTE: Should you require information related to

the management of the side effect, please contact

your health care provider. The Canada Vigilance

Program does not provide medical advice.

MORE INFORMATION

Please consult your doctor or pharmacist with any

questions or concerns you may have regarding

your individual condition.

This document plus the full product monograph,

prepared for health professionals can be found at:

http://www.novatis.ca

contacting

sponsor,

Novartis

Pharmaceuticals Canada Inc., at:

1-800-363-8883

This

leaflet

prepared

Novartis

Pharmaceuticals Canada Inc

Last revised: February 05, 2009

Novartis

Pharmaceuticals Canada Inc.

385 Bouchard Blvd

Dorval, Quebec H9S 1A9

* Registered trademark

3-11-2018

Janssen Issues Voluntary Nationwide Recall for one lot of ORTHO-NOVUM 1/35 and two lots of ORTHO-NOVUM 7/7/7 Due to Incorrect Veridate Dispenser Instructions

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Janssen Pharmaceuticals, Inc. has initiated a voluntary recall of one lot of ORTHO-NOVUM 1/35 (norethindrone / ethinyl estradiol) Tablets and two lots of ORTHO-NOVUM 7/7/7 (norethindrone / ethinyl estradiol) Tablets to the pharmacy level. The patient information provided inside affected packages of ORTHO-NOVUM does not include the appropriate instructions for the Veridate dispenser.

FDA - U.S. Food and Drug Administration

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FDA approves new vaginal ring for one year of birth control

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FDA - U.S. Food and Drug Administration

29-5-2018

TAYTULLA (norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules) by Allergan: Recall - Due to Out of Sequence Capsules

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Allergan recently identified, through a physician report, that four placebo capsules were placed out of order in a sample pack of TAYTULLA. Specifically, the first four days of therapy had four non-hormonal placebo capsules instead of active capsules. As a result of this packaging error, oral contraceptive capsules, that are taken out of sequence, may place the user at risk for contraceptive failure and unintended pregnancy. The reversing of the order may not be apparent to either new users or previous ...

FDA - U.S. Food and Drug Administration

29-5-2018

Allergan Issues Nationwide Voluntary Recall of TAYTULLA® Softgel Capsules 1mg/20mcg Sample Packs Due to Out of Sequence Capsules

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Allergan plc (NYSE:AGN) today issued a voluntary recall in the US market of one lot (Lot# 5620706, Expiry May-2019) of TAYTULLA® (norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules) 1mg/20mcg, 6x28 physicians sample pack, indicated for use by women to prevent pregnancy. Allergan recently identified, through a physician report, that four placebo capsules were placed out of order in a sample pack of TAYTULLA. Specifically, the first four days of therapy had four non-hormonal...

FDA - U.S. Food and Drug Administration