Pericyazine 10mg Tablets

1. Name Of The Medicinal Product

Pericyazine 10mg Tablets

2. Qualitative And Quantitative Composition

Pericyazine 10mg

3. Pharmaceutical Form

Pericyazine 10mg Tablets: Circular, very pale lime-yellow tablet, with one face impressed 'S172' and a break-line on reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

a) In adults with schizophrenia or other psychoses, for the treatment of symptoms or prevention of relapse.

b) In anxiety, psychomotor agitation, violent or dangerously impulsive behaviour. Pericyazine is used as an adjunct to the short-term management of these conditions.

4.2 Posology And Method Of Administration

Route of administration: oral .

Dosage requirement varies with the individual and the severity of the condition being treated. Initial dosage should be low with progressive increases until the desired response is obtained, after which dosage should be adjusted to maintain control of the symptoms.

Severe conditions

Indication (a)

Adults: Initially 75 mg per day in divided doses. Dosage should be increased by 25 mg per day at weekly intervals until the optimum effect is achieved. Maintenance therapy would not normally be expected to exceed 300 mg per day.

Elderly: Initially 15-30 mg per day in divided doses. If this is well tolerated the dosage may be increased if necessary for optimum control of behaviour.

Mild or moderate conditions

Indication (b)

Adults: Initially 15-30 mg daily, divided into two portions with a larger dose being given in the evening.

Elderly: 5-10 mg per day is suggested as a starting dose. It may be divided so that a larger portion is given in the evening. Half or quarter the normal adult dose may be sufficient for maintenance therapy.

Pericyazine tablets are not recommended for children.

4.3 Contraindications

See use in pregnancy below. Known hypersensitivity to pericyazine or to any of the other ingredients.

4.4 Special Warnings And Precautions For Use

Neuroleptics should be avoided in patients with liver or renal dysfunction, Parkinson's disease, hypothyroidism, cardiac failure, phaeochromocytoma, myasthenia gravis, prostrate hypertrophy. It should be avoided in patients known to be hypersensitive to phenothiazines or with a history of narrow angle glaucoma or agranulocytosis. It should be used with caution in the elderly, particularly during very hot or very cold weather (risk of hyper-hypothermia).

Close monitoring is required in patients with epilepsy or a history of seizures, as phenothiazines may lower the seizure threshold.

As agranulocytosis may occur rarely, regular monitoring of the complete blood count is recommended.

It is imperative that treatment be discontinued in the event of unexplained fever, as this may be a sign of neuroleptic malignant syndrome (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity). Signs of autonomic dysfunction, such as sweating and arterial instability, may precede the onset of hyperthermia and serve as early warning signs. Although neuroleptic malignant syndrome may be idiosyncratic in origin, dehydration and organic brain disease are predisposing factors.

The occurrence of unexplained infections or fever may be evidence of blood dyscrasia (see section 4.8 below), and requires immediate haematological investigation.

Acute withdrawal symptoms, including nausea, vomiting and insomnia, have very rarely been reported following the abrupt cessation of high doses of neuroleptics. Relapse may also occur, and the emergence of extrapyramidal reactions has been reported. Therefore, gradual withdrawal is advisable.

In schizophrenia, the response to neuroleptic treatment may be delayed. If treatment is withdrawn, the recurrence of symptoms may not become apparent for some time.

Neuroleptic phenothiazines may potentiate QT interval prolongation which increases the risk of onset of serious ventricular arrhythmias of the torsade de pointes type, which is potentially fatal (sudden death). QT prolongation is exacerbated, in particular, in the presence of bradycardia, hypokalaemia, and congenital or acquired (i.e. drug induced) QT prolongation. The risk-benefit should be fully assessed before pericyazine treatment is commenced. If the clinical situation permits, medical and laboratory evaluations (e.g. biochemical status and ECG) should be performed to rule out possible risk factors (e.g. cardiac disease; family history of QT prolongation; metabolic abnormalities such as hypokalaemia, hypocalcaemia or hypomagnesaemia; starvation; alcohol abuse; concomitant therapy with other drugs known to prolong the QT interval) before initiating treatment withpericyazine and during the initial phase of treatment, or as deemed necessary during the treatment (see also sections 4.5 & 4.8).

Avoid concomitant treatment with other neuroleptics (see section 4.5).

Stroke: In randomised clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded. Pericyazine should be used with caution in patients with stroke risk factors.

As with all antipsychotic drugs, Pericyazine should not be used alone where depression is predominant. However, it may be combined with antidepressant therapy to treat those conditions in which depression and psychosis coexist.

Because of the risk of photosensitisation, patients should be advised to avoid exposure to direct sunlight.

In those frequently handling preparations of phenothiazines, the greatest care must be taken to avoid contact of the drug with the skin, since contact skin sensitisation occurs rarely.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with pericyazine and preventive measures undertaken.

Hyperglycaemia or intolerance to glucose has been reported in patients with pericyazine.

Patients with an established diagnosis of diabetes mellitus or with risk factors for the development of diabetes who are started on pericyazine, should get appropriate glycaemic monitoring during treatment (see section 4.8).

Increased Mortality in Elderly people with Dementia

Data from two large observational studies showed that elderly people with dementia who are treated with conventional (Typical) antipyschotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.

Pericyazine is not licensed for the treatment of dementia-related behavioural disturbances.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interactions of phenothiazine neuroleptics:

The CNS depressant actions of neuroleptic agents may be intensified (additively) by alcohol, barbiturates and other sedatives. Respiratory depression may occur.

The hypotensive effect of most antihypertensive drugs, especially alpha adrenoceptor blocking agents may be exaggerated by neuroleptics.

There is an increased risk of arrhythmias when neuroleptics are used with concomitant QT prolonging drugs (including certain antiarrhythmics, antidepressants, and other antipsychotics) and drugs causing electrolyte imbalance (see sections 4.4 and 4.8).

The mild anticholinergic effect of neuroleptics may be enhanced by other anticholinergic drugs, possibly leading to constipation, heat stroke, etc.

The action of some drugs may be opposed by neuroleptics; these include amfetamine, levodopa, clonidine, guanethidine, adrenaline.

Where treatment for neuroleptic-induced extrapyramidal symptoms is required, anticholinergic antiparkinsonian agents should be used in preference to levodopa, since neuroleptics antagonise the antiparkinsonian action of dopaminergics.

Anticholinergic agents may reduce the antipsychotic effect of neuroleptics.

Some drugs interfere with absorption of neuroleptic agents: antacids, anti-Parkinson drugs, lithium. Increases or decreases in the plasma concentrations of a number of drugs, e.g: propranolol, phenobarbital have been observed but were not of clinical significance. High doses of neuroleptics may reduce the response to hypoglycaemic agents the dosage of which might have to be raised.

In patients treated concurrently with neuroleptics and lithium, there have been rare reports of neurotoxicity.

Adrenaline must not be used in patients overdosed with neuroleptics.

Simultaneous administration of desferrioxamine and prochlorperazine has been observed to induce a transient metabolic encephalopathy characterised by loss of consciousness for 48-72 hours. It is possible this may occur with Pericyazine since it shares many of the pharmacological properties of prochlorperazine.

There is an increased risk of agranulocytosis when neuroleptics are used concurrently with drugs with myelosuppressive potential, such as carbamazepine or certain antibiotics and cytotoxics.

4.6 Pregnancy And Lactation

There is inadequate evidence of the safety of pericyazine in human. There is evidence with some neuroleptics of harmful effects in animals. Like other drugs pericyazine should be avoided in pregnancy unless the physician considers it essential. It may occasionally prolong labour and at such a time should be withheld until the cervix is dilated 3-4 cm. Possible adverse effects on the foetus include lethargy or paradoxical hyperexcitability, tremor and low Apgar score.

Phenothiazines may be excreted in milk, therefore breastfeeding should be suspended during treatment.

4.7 Effects On Ability To Drive And Use Machines

Patients should be warned about drowsiness during early days of treatment, and advised not to drive or operate machinery. The elderly are particularly susceptible to postural hypotension.

4.8 Undesirable Effects

Liver function: jaundice, occurs in a very small percentage of patients taking neuroleptics. A premonitory sign may be a sudden onset of fever after one to three weeks of treatment followed by the development of jaundice. Neuroleptic jaundice has the biochemical and other characteristics of obstructive (cholestatic) jaundice and is associated with obstruction of the canaliculi by bile thrombi; the frequent presence of an accompanying eosinophilia indicates the allergic nature of this phenomenon. Liver injury has been reported very rarely in patients treated with pericyazine. Treatment should be withheld on the development of jaundice.

Cardiorespiratory: hypotension, usually postural, commonly occurs. Elderly or volume depleted subjects are particularly susceptible.

ECG changes, include QT prolongation (as with other neuroleptics), ST depression, U-Wave and T-Wave changes. Cardiac arrhythmias, including ventricular arrhythmias and atrial arrhythmias, a-v block, ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest have been reported during neuroleptic phenothiazine therapy, possibly related to dosage. Pre-existing cardiac disease, old age, hypokalaemia and concurrent tricyclic antidepressants may predispose.

There have been isolated reports of sudden death, with possible cases of cardiac origin (see section 4.4, above), as well as cases of unexplained sudden death, in patients receiving neuroleptic phenothiazines.

Respiratory depression is possible in susceptible patients.

Blood picture: a mild leukopenia occurs in up to 30% of patients on prolonged high dosage of neuroleptics; agranulocytosis may occur rarely; it is not dose-related.

Extrapyramidal: acute dystonias or dyskinesias, usually transitory are commoner in children and young adults, and usually occur within the first four days of treatment or after dosage increases.

	• Akathisia characteristically occurs after large initial doses.
	• Parkinsonism is commoner in adults and the elderly. It usually develops after weeks or months of treatment. One or more of the following may be seen: tremor, rigidity, akinesia, or other features of Parkinsonism. Commonly just tremor.
	• Tardive dyskinesia: if this occurs it is usually, but not necessarily after prolonged or high dosage. It can even occur after treatment has been stopped. Dosage should therefore be kept low whenever possible.

Skin and eyes: contact skin sensitisation may occur rarely in those frequently handling preparations of phenothiazines (see section 4.4, above. Skin rashes of various kinds may also be seen in patients treated with the drug. Patients on high dosage should be warned that they may develop photosensitivity in sunny weather and should avoid exposure to direct sunlight.

Endocrine: hyperprolactinaemia which may result in galactorrhoea, gynaecomastia, amenorrhoea; impotence.

Priapism has very rarely been reported in patients treated with pericyazine.

Neuroleptic malignant syndrome (hyperthermia, rigidity autonomic dysfunction and altered consciousness) may occur with any neuroleptic.

Minor side effects are nasal stuffiness, dry mouth, insomnia, agitation

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs (see also section 4.4).

Intolerance to glucose, hyperglycaemia (see section 4.4).

4.9 Overdose

Toxicity and treatment of overdosage:

Symptoms of neuroleptic overdosage include drowsiness or loss of consciousness, hypotension, tachycardia, ECG changes, ventricular arrhythmias and hypothermia. Severe extrapyramidal dyskinesias may occur.

If the patient is seen sufficiently soon (up to 6 hours) after ingestion of a toxic dose, gastric lavage may be attempted. Pharmacological induction of emesis is unlikely to be of any use. Activated charcoal should be given. There is no specific antidote. Treatment is supportive.

Generalised vasodilatation may result in circulatory collapse; raising the patient's legs may suffice; in severe cases, volume expansion by intravenous fluids may be needed; infusion fluids should be warmed before administration in order not to aggravate hypothermia.

Positive inotropic agents such as dopamine may be tried if fluid replacement is insufficient to correct the circulatory collapse. Peripheral vasoconstrictor agents are not generally recommended; avoid the use of adrenaline.

Ventricular or supraventricular tachy-arrhythmias usually respond to restoration of normal body temperature and correction of circulatory or metabolic disturbances. If persistent or life threatening, appropriate anti-arrhythmic therapy may be considered. Avoid lidocaine, and as far as possible long acting, anti-arrhythmic drugs.

Pronounced central nervous system depression requires airway maintenance or, in extreme circumstances, assisted respiration. Severe dystonic reactions usually respond to procyclidine (5-10 mg) or orphenedrine (20-40 mg) administered intramuscularly or intravenously. Convulsions should be treated with intravenous diazepam.

Neuroleptic malignant syndrome should be treated with cooling. Dantrolene sodium may be tried.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pericyazine is a neuroleptic with cardiovascular and antihistamine effects similar to those of chlorpromazine, but it has a stronger antiserotonin effect and a powerful central sedative effect.

5.2 Pharmacokinetic Properties

Kinetics: there is little information about plasma concentrations, distribution and excretion in humans. The rate of metabolism and excretion of phenothiazines decreases in old age.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose anhydrous USP, Microcrystalline cellulose (E460), Sodium starch glycollate, Magnesium stearate BP, Colloidal silicon dioxide (E551), Methyl hydroxybenzoate BP (E218).

6.2 Incompatibilities

None known.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

Protect from light.

6.5 Nature And Contents Of Container

Securitainer or HDPE bottle containing 500 tablets.

PVDC coated UPVC aluminium foil blister containing 84 tablets.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS, UK

8. Marketing Authorisation Number(S)

PL 17780/0459

9. Date Of First Authorisation/Renewal Of The Authorisation

17 July 2009

10. Date Of Revision Of The Text

6 April 2010

Legal status

POM

Lumizyme

Generic Name: alglucosidase alfa (Intravenous route)

al-gloo-KOE-si-dase AL-fa

Intravenous route(Powder for Solution)

Myozyme(R): Life-threatening anaphylactic reactions have been observed in patients during alglucosidase alfa infusion. Appropriate supportive measures should be readily available during treatment. Patients with compromised cardiac or respiratory function may be at risk of serious acute exacerbation due to infusion reactions, and require additional monitoring .

Intravenous route(Powder for Solution)

Lumizyme(TM): Life-threatening anaphylactic reactions, severe allergic reactions, and immune-mediated reactions have been observed in some patients during alglucosidase alfa infusions. Appropriate medical support should be readily available when alglucosidase alfa is administered. Because of the potential risk of rapid disease progression in Pompe disease patients less than 8 years of age, alglucosidase alfa is available only through a restricted distribution program called the LUMIZYME ACE Program. Only prescribers and healthcare facilities enrolled in the program may prescribe, dispense, or administer alglucosidase alfa. Alglucosidase alfa may be administered only to patients who are enrolled in and meet all the conditions of the LUMIZYME ACE Program. To enroll in the LUMIZYME ACE Program call 1-800-745-4447 .

Commonly used brand name(s)

In the U.S.

• Lumizyme


• Myozyme

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Enzyme Replacement

Pharmacologic Class: Enzyme

Uses For Lumizyme

Alglucosidase alfa injection is an enzyme that treats Pompe disease, which is also called glycogen storage disease type II. Alglucosidase alfa contains a human enzyme called acid alpha-glucosidase. This enzyme helps with the digestion and absorption of glycogen. People with Pompe disease are not able to make enough of this enzyme.

The Lumizyme™ form of this medicine is only available under a special restricted distribution program called Lumizyme™ ACE (Alglucosidase alfa Control and Education) program.

This medicine is available only with your doctor's prescription.

Before Using Lumizyme

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of alglucosidase alfa injection in children.

Geriatric

No information is available on the relationship of age to the effects of alglucosidase alfa injection in the geriatric population.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Breathing problems or


• Cardiac hypertrophy (heart is larger than normal) or


• Heart rhythm problems (e.g., arrhythmia) or


• Lung disease—Use with caution. May make these conditions worse.

Proper Use of alglucosidase alfa

This section provides information on the proper use of a number of products that contain alglucosidase alfa. It may not be specific to Lumizyme. Please read with care.

A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed in one of your veins.

This medicine must be given slowly, so the needle will remain in place for a few hours. You may also receive medicines to help prevent possible allergic reactions to the injection.

Precautions While Using Lumizyme

It is very important that your doctor check the progress of you or your child at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

This medicine may cause chest pain; fever; chills; itching; hives or a rash; a fast heartbeat; flushing of the face; dizziness, fainting, or lightheadedness; trouble with breathing; or swelling of the face, tongue, and throat within a few hours after it is given. Check with your doctor or nurse right away if you or your child have any of these symptoms.

This medicine may cause serious types of allergic reactions, including anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you or your child have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth after receiving this medicine.

Lumizyme Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Blue lips, fingernails, or skin


• body aches or pain


• chest discomfort or pain


• chills


• cough


• difficult or labored breathing


• difficulty with breathing


• difficulty with swallowing


• dizziness


• dry, red, hot, or irritated skin


• ear congestion


• fast, pounding, or irregular heartbeat or pulse


• feeling of warmth


• fever


• headache


• hives


• increased sweating


• irregular, fast, slow, or shallow breathing


• itching


• lightheadedness, dizziness, or fainting


• loss of voice


• nasal congestion


• pain


• pale skin


• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue


• rapid shallow breathing


• redness of the face, neck, arms, and occasionally, upper chest


• redness or pain at the catheter site


• runny nose


• shakiness in the legs, arms, hands, or feet


• shortness of breath


• skin rash


• slow or irregular heartbeat


• sneezing


• sore throat


• swollen, painful, or tender lymph glands in the neck, armpit, or groin


• tightness in the chest


• trembling or shaking of the hands or feet


• troubled breathing


• troubled breathing with exertion


• unusual bleeding or bruising


• unusual tiredness or weakness


• wheezing

Less common

• Blood in the urine


• convulsions


• decreased urine


• dry mouth


• increased thirst


• loss of appetite


• mood changes


• muscle pain or cramps


• nausea or vomiting


• numbness or tingling in the hands, feet, or lips


• pain in the groin or genitals


• sharp back pain just below the ribs

Incidence not known

• Blue-green to black skin discoloration


• blurred vision


• confusion


• dilated neck veins


• extreme fatigue


• heart stops


• inability to speak


• no breathing


• no pulse or blood pressure


• pain, redness, swelling, or sloughing of the skin at the place of injection


• seizures


• severe or sudden headache


• severe pain in the chest


• slurred speech


• sudden and severe weakness in the arm or leg on one side of the body


• sudden onset of severe breathing difficulty


• swelling of the face, fingers, feet, or lower legs


• temporary blindness


• unconscious


• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Abdominal or stomach pain


• acid or sour stomach


• belching


• body aches or pain


• change in hearing


• congestion


• constipation


• dryness or soreness of the throat


• ear discomfort or pain


• ear drainage


• earache


• feeling of constant movement of self or surroundings


• general feeling of discomfort or illness


• heartburn


• hives or welts


• hoarseness


• indigestion


• muscle or bone pain, stiffness, or tightness


• muscle twitching


• redness of the skin


• redness or swelling in the ear


• sensation of spinning


• sore mouth or tongue


• stomach discomfort, upset, or pain


• stuffy nose


• tender, swollen glands in the neck


• trouble with swallowing


• upper abdominal or stomach pain


• voice changes


• white patches in the mouth or on the tongue

Less common

• Bloody nose


• sleepiness or unusual drowsiness

Incidence not known

• Burning, dry, or itching eyes


• discharge, excessive tearing


• muscle spasm


• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: Lumizyme side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More Lumizyme resources

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

• Lumizyme Consumer Overview


• Lumizyme MedFacts Consumer Leaflet (Wolters Kluwer)


• Lumizyme Prescribing Information (FDA)


• Alglucosidase Alfa Professional Patient Advice (Wolters Kluwer)


• Alglucosidase Alfa Monograph (AHFS DI)


• Myozyme Prescribing Information (FDA)


• Myozyme Consumer Overview

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Estradiol Patch

Estradiol Transdermal System

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER

Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.

There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)

CARDIOVASCULAR AND OTHER RISKS

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

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

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

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

Estradiol Patch Description

The Estradiol Transdermal System, is designed to release estradiol continuously upon application to intact skin. Six (6.5, 9.375, 12.5, 15, 18.75 and 25 cm2) systems are available to provide nominal in vivo delivery of 0.025, 0.0375, 0.05, 0.06, 0.075 or 0.1 mg respectively of estradiol per day. The period of use is 7 days. Each system has a contact surface area of either 6.5, 9.375, 12.5, 15, 18.75 or 25 cm2, and contains 2, 2.85, 3.8, 4.55, 5.7 or 7.6 mg of estradiol USP respectively. The composition of the systems per unit area is identical. Estradiol USP is a white, crystalline powder, chemically described as estra-1,3,5(10)-triene-3, 17ß-diol. It has an empirical formula of C18H24O2 and molecular weight of 272.39. The structural formula is:

The Estradiol Transdermal System comprises three layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent polyethylene film, and (2) an acrylate adhesive matrix containing estradiol USP. A protective liner (3) of siliconized or fluoropolymer-coated polyester film is attached to the adhesive surface and must be removed before the system can be used.

The active component of the system is estradiol. The remaining components of the system (acrylate copolymer adhesive, fatty acid esters, and polyethylene backing) are pharmacologically inactive.

Estradiol Patch - Clinical Pharmacology

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

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

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

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

Pharmacokinetics

Absorption

The Estradiol Transdermal System continuously releases estradiol which is transported across intact skin leading to sustained circulating levels of estradiol during a 7-day treatment period. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route.

In a bioavailability study, the 6.5 cm2 Estradiol Transdermal System was studied with the 12.5 cm2 system as reference. The mean estradiol levels in serum from the two sizes are shown in Figure 1.

Figure 1 Mean Serum 17ß-Estradiol Concentrations vs. Time Profile following Application of a 6.5 cm2 and 12.5 cm2 Estradiol Transdermal System

Dose proportionality was demonstrated for the 6.5 cm2 Estradiol Transdermal System as compared to the 12.5 cm2 system in a 2-week crossover study with a 1-week washout period between the two-transdermal systems in 24 postmenopausal women.

Dose proportionality was also demonstrated for the 12.5 cm2 and 25 cm2 Estradiol Transdermal Systems in a 1-week study conducted in 54 postmenopausal women. The mean steady state levels (Cavg) of the estradiol during the application of 25 cm2 and 12.5 cm2 systems on the abdomen were about 80 and 40 pg/mL, respectively.

In a 3 week multiple application study in 24 postmenopausal women, the 25 cm2 Estradiol Transdermal System produced average peak estradiol concentrations (Cmax) of approximately 100 pg/mL. Trough values at the end of each wear interval (Cmin) were approximately 35 pg/mL. Nearly identical serum curves were seen each week, indicating little or no accumulation of estradiol in the body. Serum estrone peak and trough levels were 60 and 40 pg/mL, respectively.

In a single dose, randomized, crossover study conducted to compare the effect of site of application, 38 postmenopausal women wore a single 25 cm2 Estradiol Transdermal System for 1 week on the abdomen and buttocks. The estradiol serum concentration profiles are shown in Figure 2. Cmax and Cavg values were, respectively, 25% and 17% higher with the buttock application than with the abdomen application.

Figure 2 Observed Mean (± S.E.) Estradiol Serum Concentrations for a One Week Application of the Estradiol Transdermal System (25 cm2) to the abdomen and buttocks of 38 postmenopausal women

Table 1 provides a summary of estradiol pharmacokinetic parameters determined during evaluation of the Estradiol Transdermal System.

Table 1 Pharmacokinetic Summary (Mean Estradiol Values)

System Delivery Rate	Surface Area (cm2)	Application Site	No. of Subjects	Dosing	Cmax (pg/mL)	Cmin (pg/mL)	Cavg (pg/mL)
0.025	6.5	Abdomen	24	Single	32	17	22
0.05	12.5	Abdomen	102	Single	71	29	41
0.1	25	Abdomen	139	Single	147	60	87
0.1	25	Buttock	38	Single	174	71	106

The relative standard deviation of each pharmacokinetic parameter after application to the abdomen averaged 50%, which is indicative of the considerable intersubject variability associated with transdermal drug delivery. The relative standard deviation of each pharmacokinetic parameter after application to the buttock was lower than that after application to the abdomen (e.g., for Cmax 39% vs 62%, and for Cavg 35% vs 48%).

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens.

Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

Metabolism

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

Excretion

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

Special Populations:

Geriatric: There have not been sufficient numbers of geriatric patients involved in clinical studies utilizing the Estradiol Transdermal System to determine whether those over 65 years of age differ from younger subjects in their response to the system.

Pediatric: No pharmacokinetic study for the Estradiol Transdermal System has been conducted in a pediatric population.

Gender: The Estradiol Transdermal System is indicated for use in women only.

Race: No studies were done to determine the effect of race on the pharmacokinetics of the Estradiol Transdermal System.

Patients with Renal Impairment: Total estradiol serum levels are higher in postmenopausal women with end stage renal disease (ESRD) receiving maintenance hemodialysis than in normal subjects at baseline and following oral doses of estradiol. Therefore, conventional transdermal estradiol doses used in individuals with normal renal function may be excessive for postmenopausal women with ESRD receiving maintenance hemodialysis.

Patients with Hepatic Impairment: Estrogens may be poorly metabolized in patients with impaired liver function and should be administered with caution.

Drug Interactions

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

Adhesion

An open-label study of adhesion potentials of placebo transdermal systems that correspond to the 6.5 cm2 and 12.5 cm2 sizes of the Estradiol Transdermal System was conducted in 112 healthy women of 45-75 years of age. Each woman applied both transdermal systems weekly, on the upper outer abdomen, for 3 consecutive weeks. It should be noted that lower abdomen and upper quadrant of the buttock are the approved sites of application for the system.

The adhesion assessment was done visually on Days 2, 4, 5, 6, 7 of each week of transdermal system wear. A total of 1654 adhesion observations were conducted for 333 transdermal systems of each size.

Of these observations, approximately 90% showed essentially no lift for both the 6.5 cm2 and 12.5 cm2 transdermal systems. Of the total number of transdermal systems applied, approximately 5% showed complete detachment for each size. Adhesion potentials of the 18.75 cm2 and 25cm2 sizes of transdermal systems (0.075 mg/day and 0.1 mg/day) have not been studied.

Clinical Studies

Effects on vasomotor symptoms

A study of 214 women 25 to 74 years old met the qualification criteria and were randomly assigned to one of the three treatment groups: 72 to the 0.05 mg Estradiol Patch, 70 to the 0.1 mg Estradiol Patch, and 72 to placebo. Potential subjects were postmenopausal women in good general health who experienced vasomotor symptoms. Natural menopause patients had not menstruated for at least 12 months and surgical menopause patients had undergone bilateral oophorectomy at least 4 weeks before evaluation for study entry. In order to enter the 11-week treatment phase of the study, potential subjects must have experienced a minimum of five moderate to severe hot flushes per week, or a minimum of 15 hot flushes of any severity per week, for 2 consecutive weeks. Women wore the patches in a cyclical fashion (three weeks on and one week off).

During treatment, all subjects used diaries to record the number and severity of hot flushes. Subjects were monitored by clinic visits at the end of weeks 1, 3, 7, and 11 and by telephone at the end of weeks 4, 5, 8, and 9.

Adequate data for the analysis of efficacy was available from 191 subjects. The results are presented as the mean ± SD number of flushes in each of the 3 treatment weeks of each 4-week cycle. In the 0.05 mg estradiol group, the mean weekly hot flush rate across all treatment cycles decreased from 46 ± 6.5 at baseline to 20 ± 3 (-67.0%). The 0.1 mg estradiol group had a decline in the mean weekly hot flush rate from 52 ± 4.4 at baseline to 16 ± 2.4 (-72%). In the placebo group, the mean weekly hot flush rate declined from 53 ± 4.5 at baseline to 46 ± 6.5 (-18.1%). Compared with placebo, the 0.05 mg and 0.1 mg estradiol groups showed a statistically significantly larger mean decrease in hot flushes across all treatment cycles (P<0.05). When the response to treatment was analyzed for each of the three cycles of therapy, similar statistically significant differences were observed between both estradiol treatment groups and the placebo group during all treatment cycles.

In a double-blind, placebo-controlled, randomized study of 187 women receiving the Estradiol Transdermal System 0.025 mg/day or placebo continuously for up to three 28-day cycles, the 0.025 mg/day dosage was shown to be statistically better than placebo at weeks 4 and 12 for relief of both the frequency and severity of moderate-to-severe vasomotor symptoms.

Table 2 Mean Change from Baseline in the Number of Moderate-to-Severe Vasomotor Symptoms (ITT)

Treatment Group	Statistics	Week 4	Week 8	Week 12
E2 TDS	N	82	84	68
	Mean	-6.45	-7.69	-7.56
	SD	4.65	4.76	4.64
Placebo	N	83	71	65
	Mean	-5.11	-5.98	-5.98
	SD	7.43	8.63	9.69
	p-Value	<0.002		<0.003

A second active-control trial of 193 randomized subjects was supportive of the placebo-controlled trial.

Effects on bone mineral density

A two-year clinical trial enrolled a total of 175 healthy, hysterectomized, postmenopausal, non-osteoporotic (i.e., lumbar spine bone mineral density >0.9 gm/cm2) women at 10 study centers in the United States. 129 subjects were allocated to receive active treatment with 4 different doses of Estradiol Patches (6.5, 12.5, 15, 25 cm2) and 46 subjects were allocated to receive placebo patches. 77% of the randomized subjects (100 on active drug and 34 on placebo) contributed data to the analysis of percent change of A-P spine bone mineral density (BMD), the primary efficacy variable (see Figure 3). A statistically significant overall treatment effect at each timepoint was noted, implying bone preservation for all active treatment groups at all timepoints, as opposed to bone loss for placebo at all timepoints.

Figure 3 Mean Percent Change from Baseline in Lumbar Spine (A-P View) Bone Mineral Density By Treatment and Time last observation carried forward

Percent change in BMD of the total hip (see Figure 4) was also statistically significantly different from placebo for all active treatment groups. The results of the measurements of biochemical markers supported the finding of efficacy for all doses of transdermal estradiol. Serum osteocalcin levels decreased, indicative of a decrease in bone formation, at all timepoints for all active treatment doses, statistically significantly different from placebo (which generally rose). Urinary deoxypyridinoline and pyridinoline changes also suggested a decrease in bone turnover for all active treatment groups.

Figure 4 Mean Percent Change from Baseline in Total Hip by Treatment and Time last observation carried forward

Footnote: This figure is based on 74% of the randomized subjects (95 on active drug and 34 on placebo).

Women’s Health Initiative Studies

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

The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 3 below:

Table 3 Relative and Absolute Risk Seen in the CE/MPA Substudy of WHIa

Eventc	Relative Risk CE/MPA vs placebo at 5.2 Years (95% CI*)	Placebo n = 8102	CE/MPA n = 8506
		Absolute Risk per 10,000 Person-years
CHD events	1.29 (1.02-1.63)	30	37
Non-fatal MI	1.32 (1.02-1.72)	23	30
CHD death	1.18 (0.70-1.97)	6	7
Invasive breast cancerb	1.26 (1.00-1.59)	30	38
Stroke	1.41 (1.07-1.85)	21	29
Pulmonary embolism	2.13 (1.39-3.25)	8	16
Colorectal cancer	0.63 (0.43-0.92)	16	10
Endometrial cancer	0.83 (0.47-1.47)	6	5
Hip fracture	0.66 (0.45-0.98)	15	10
Death due to causes other than the events above	0.92 (0.74-1.14)	40	37
Global Index c	1.15 (1.03-1.28)	151	170
Deep vein thrombosis d	2.07 (1.49-2.87)	13	26
Vertebral fractures d	0.66 (0.44-0.98)	15	9
Other osteoporotic fractures d	0.77 (0.69-0.86)	170	131

a adapted from JAMA, 2002; 288:321-333

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

c a subset of the events was combined in a "global index", defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes

d not included in Global Index

* nominal confidence intervals unadjusted for multiple looks and multiple comparisons

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

Women’s Health Initiative Memory Study

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

After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See BOXED WARNINGS and WARNINGS, Dementia and PRECAUTIONS, Geriatric Use.)

Indications and Usage for Estradiol Patch

The Estradiol Transdermal System is indicated in the:

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


2. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with the menopause. When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.


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


4. Prevention of postmenopausal osteoporosis. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medications should be carefully considered.

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

Contraindications

The Estradiol Transdermal System should not be used in women with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.


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


3. Known or suspected estrogen-dependent neoplasia.


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


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


6. Liver dysfunction or disease.


7. Known hypersensitivity to its ingredients.


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

Warnings

(See BOXED WARNING.)

Cardiovascular Disorders

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

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

Coronary Heart Disease and Stroke

In the Women’s Health Initiative (WHI) study, an increased risk of stroke was observed in women receiving oral CE compared to placebo.

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

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

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

6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall.

Venous Thromboembolism (VTE)

In the Women’s Health Initiative (WHI) study, an increased risk of deep vein thrombosis was observed in women receiving CE compared to placebo.

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

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

Malignant Neoplasms

Endometrial Cancer

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

Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Breast Cancer

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

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

In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 vs. 33 cases per

10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups.

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

Dementia

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

Gallbladder Disease

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

Hypercalcemia

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

Visual Abnormalities

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

Precautions

General

Addition of a Progestin When a Woman Has Not Had a Hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone treatment. These include a possible increased risk of breast cancer.

Elevated Blood Pressure

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

Hypertriglyceridemia

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

Impaired liver function and past history of cholestatic jaundice

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

Hypothyroidism

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

Fluid Retention

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

Hypocalcemia

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

Ovarian Cancer

The CE/MPA sub-study of WHI reported that estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE/MPA versus placebo was 1.58 (95% confidence interval 0.77-3.24) but was not statistically significant. The absolute risk for CE/MPA versus placebo was 4.2 versus 2.7 cases per 10,000 women-years. In some epidemiological studies, the use of estrogen alone

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