PRO-CURE 5 MG

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS REGULATIONS

(PREPARATIONS) 1986

This medicine can be sold under doctor's prescription only

PRO-CURE

®

5 mg

Tablets

Each tablet contains:

Finasteride 5 mg

For a list of inactive ingredients see section 6.1 "What PRO-CURE 5 mg contains". See also section 2.6

“Important information about some of the ingredients of PRO-CURE 5 mg.

Read all of this leaflet carefully before you start taking this medicine.

This leaflet contains concise information about PRO-CURE 5 mg. If you have any further questions,

ask your doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if

their ailment seems similar to yours.

The condition which PRO-CURE 5 mg is prescribed occurs only in men. This medicine is not

intended for women or children.

1. WHAT PRO-CURE 5 MG IS AND WHAT IT IS USED FOR?

Therapeutic group: 5α-reductase inhibitor

For the treatment and control of benign prostatic hyperplasia (BPH) to cause regression of the enlarged

prostate, and by this improve urinary flow and improve symptoms associated with BPH. PRO-CURE 5 mg

reduces the risk of acute urinary retention and the need for prostate surgery.

2. BEFORE YOU TAKE PRO-CURE 5 MG

2.1 Do not take PRO-CURE 5 mg if you:

are a woman and you are or may potentially be pregnant. Women should also not handle crushed

or broken tablets of PRO- CURE 5 mg (see also section 2.5 "pregnancy").

This medicine is not intended for women or children.

are hypersensitive (allergic) to finasteride or any of the other ingredients of PRO-CURE 5 mg

(for a list of inactive ingredients, see section 6.1).

2.2 Special warnings concerning use of PRO-CURE 5 MG

Before starting treatment with PRO-CURE 5 mg, tell your doctor if:

you are suffering, or have suffered in the past, from impaired function of the liver.

PRO-CURE 5 mg can affect a blood test called PSA. If you have a PSA test done, tell your doctor

that you are taking PRO-CURE 5 mg.

you are sensitive to any type of food or medicine.

2.3 Taking other medicines

If you are taking or have recently taken other medicines, including non-prescription medicines

and nutritional supplements, you should inform the attending doctor or pharmacist.

2.4 Taking PRO-CURE 5 mg with food

You may take PRO-CURE 5 mg with or without food.

2.5 Pregnancy

PRO-CURE 5 mg is for use by MEN only.

Women who are or may potentially be pregnant must not use PRO-CURE 5 mg. They should also not

handle crushed or broken tablets of PRO-CURE 5 mg.

If a woman who is pregnant with a male baby absorbs the active ingredient in PRO-CURE 5 mg after

oral use or through the skin, it may cause the male baby to be born with abnormalities of the sex

organs. PRO-CURE 5 mg tablets are coated and will prevent contact with the active ingredient

during normal handling, provided that the tablets are not broken or crushed. If a woman who is

pregnant comes into contact with the active ingredient in PRO-CURE 5 mg, a doctor should be

consulted.

2.6 Important information about some of the ingredients of PRO-CURE 5 mg

PRO-CURE 5 mg contains lactose.

2.7 Additional warnings

BPH develops over a long period of time. Some patients show early improvement in symptoms, but you

may need to take PRO-CURE 5 mg for at least six months to see if it improves your symptoms. Whether or

not you notice any improvement or change in symptoms, therapy with PRO-CURE 5 mg may reduce your

risk for a sudden inability to pass urine and the need for surgery. You must visit your doctor regularly for

periodic check-ups and evaluation of your progress.

Your doctor has prescribed PRO-CURE 5 mg for symptomatic BPH and not for cancer — but a man can

have BPH and prostate cancer at the same time. Doctors usually recommend that men be checked for

prostate cancer once a year when they turn 50 (or 40 if a family member has had prostate cancer). These

checks should continue while you take PRO-CURE 5 mg.

PRO-CURE 5 mg is not a treatment for prostate cancer.

3.

HOW TO TAKE PRO-CURE 5 MG ?

Always take PRO-CURE 5 mg as instructed by the doctor. You should check with your doctor or

pharmacist if you are not sure.

The dosage and method of treatment will be determined by the doctor only.

The usually recommended dose unless otherwise prescribed by your doctor is: one tablet once a day.

Swallow the medicine with a small amount of water, with or without food.

Do not exceed the recommended dose.

To avoid forgetting to take PRO-CURE 5 mg, it may be helpful to take it at the same time every day.

Remember that it took many years for your prostate to grow large enough to cause your symptoms. PRO-

CURE 5 mg can treat your symptoms and control the disease only if you continue to take it over the long

term.

If you take more PRO-CURE 5 mg than you should

If you have taken an overdose, or if a child has accidentally swallowed the medicine, proceed immediately

to a hospital emergency room and bring the package of the medicine with you.

If you forget to take PRO-CURE 5 mg

If you forgot to take this medicine at the specific time, do not take a double dose. Take the next

dose at the usual time.

Complete the full course of treatment as instructed by the doctor.

Even if there is an improvement in your health, do not discontinue use of this medicine before consulting

your doctor.

How can you contribute to the success of the treatment?

Even though the prostate shrinks, you may NOT notice an improvement in urine flow or symptoms. You

may need to take PRO-CURE 5 mg for six (6) months or more to see whether it improves your symptoms.

Do not take medicines in the dark! Check the label and the dose each time you take your medicine. Wear

glasses if you need them.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. SIDE EFFECTS

Like all medicines, PRO-CURE 5 mg can cause side effects, in some of the users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

Refer to the doctor as soon as possible, if you develop any of the following signs:

any changes in your breasts such as lumps, pain or nipple discharge.

Additional side effects

As with any medicine, in addition to the desired effect of the medicine, adverse reactions may occur during

the course of treatment with this medicine, for example: impotence (an inability to have an erection), or less

desire for sex.

Some men taking PRO-CURE 5 mg may have changes or problems with ejaculation, such as a decrease in

the amount of semen released during sex. This decrease in the amount of semen does not appear to

interfere with normal sexual function. In some cases these side effects went away while the patient

continued to take PRO-CURE 5 mg.

In addition, some men may have breast swelling and/or tenderness. You should promptly report to your

doctor any changes in your breasts such as lumps, pain or nipple discharge.

Some men have reported allergic reactions such as rash, itching, hives, and swelling of the lips, tongue,

throat and face; testicular pain; an inability to have an erection that continued after stopping the medication;

problems with ejaculation that continued after stopping the medication; male infertility and/or poor quality of

semen. Improvement in the quality of semen has been reported after stopping the medication; depression;

decrease in sex drive that continued after stopping the medication.

In rare cases, male breast cancer has been reported.

In the event that you experience side effects not mentioned in this leaflet, or if there is a change in your

general health, consult your doctor immediately.

What you need to know while taking PRO-CURE 5 mg:

About Prostate-Specific Antigen (PSA). Your doctor may have done a blood test called PSA for the

screening of prostate cancer. Because PRO-CURE 5 mg decreases PSA levels, you should tell your

doctor(s) that you are taking PRO-CURE 5 mg. Changes in PSA levels will need to be evaluated by your

doctor(s). Any increase in follow-up PSA levels from their lowest point may signal the presence of prostate

cancer and should be evaluated, even if the test results are still within the normal range. You should also

tell your doctor if you have not been taking PRO-CURE 5 mg as prescribed because this may affect the

PSA test results. For more information, talk to your doctor.

PRO-CURE 5 mg may increase the chance of a more serious form of prostate cancer.

If any of the side effects gets serious or if you suffer from side effects not mentioned in this leaflet, consult

your doctor.

5. HOW TO STORE PRO-CURE 5 mg?

Avoid Poisoning! This medicine, as all other medicines, must be stored in a safe place out of the

reach and sight of children and/or infants, in order to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by a doctor!

Do not use PRO-CURE 5 mg after the expiry date (exp. date) which is stated on the pack. The

expiry date refers to the last day of the indicated month.

Storage conditions: Store in the original package below 30°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how

to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

6.1 What PRO-CURE 5 mg contains

The active substance is: finasteride.

Each tablet contains 5 mg of finasteride.

In addition to the active ingredient the medicine also contains inactive ingredients:

Lactose

monohydrate,

microcrystalline

cellulose,

pregelatinized

starch,

sodium

starch

glycolate,

hydroxypropyl cellulose, hydroxypropyl methylcellulose, titanium dioxide, magnesium stearate, talc,

docusate sodium, FD&C Blue 2 aluminum lake and yellow ferric oxide.

Each tablet contains 106.4 mg lactose monohydrate.

6.2 What PRO-CURE 5 mg looks like and contents of the pack

PRO-CURE 5 mg is available as blue, apple-shaped film-coated tablets, one side engraved 72, the

other side plain.

Pack size: 28 tablets in blisters.

Marketing authorization holder:

Merck, Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121, Petah-Tikva 49170.

Manufacturer: Merck Sharp & Dohme UK Ltd., Cramlimgton, UK

This Leaflet was checked and approved by the Ministry of Health on May 2015

Drug registration no. listed in the official registry of the Ministry of Health:

113 61 27940

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights

do not include all the information needed to use PRO- CURE

safely and effectively. See full prescribing information for PRO-

CURE.

PRO-CURE (finasteride) Tablets

--------------------------- RECENT MAJOR CHANGES ---------------------------

----------------------------INDICATIONS AND USAGE ----------------------------

PRO-CURE, is a

5α-reductase inhibitor, indicated for the treatment

and control

of symptomatic benign prostatic hyperplasia (BPH) in men

with an enlarged prostate to (1.1):

Reduce the risk of acute urinary retention

Reduce the risk of the need for surgery including transurethral

resection of the prostate (TURP) and prostatectomy.

Limitations of Use: PRO-CURE is not approved for the prevention of

prostate cancer (1.3).

----------------------- DOSAGE AND ADMINISTRATION -----------------------

PRO-CURE may be administered with or without meals (2).

Monotherapy: One tablet (5 mg) taken once a day (2.1).

Combination with Doxazosin: One tablet (5 mg) taken once a day in

combination with the alpha-blocker doxazosin (2.2).

--------------------- DOSAGE FORMS AND STRENGTHS ---------------------

5-mg film-coated tablets (3).

------------------------------ CONTRAINDICATIONS -------------------------------

Hypersensitivity to any components of this product (4).

Women who are or may potentially be pregnant (4, 5.4, 8.1, 16).

----------------------- WARNINGS AND PRECAUTIONS -----------------------

PRO-CURE

reduces

serum

prostate

specific

antigen

(PSA)

levels by approximately 50%. However, any confirmed increase

in PSA while on PRO-CURE may signal the presence of prostate

cancer and should be evaluated, even if those values are still

within

normal

range

taking

5α-reductase

inhibitor (5.1).

PRO-CURE may increase the risk of high-grade prostate cancer

(5.2, 6.1).

Women should not handle crushed or broken PRO-CURE tablets

when they are pregnant or may potentially be pregnant due to

potential risk to a male fetus

(5.3, 8.1, 16).

PRO-CURE

indicated

pediatric

patients

women (5.4, 8.1, 8.3, 8.4, 12.3).

Prior

initiating

treatment

with

PRO-CURE

BPH,

consideration should be given to other urological conditions that

may cause similar symptoms (5.6).

------------------------------ ADVERSE REACTIONS ------------------------------

The drug-related adverse reactions, reported in ≥1% in patients treated

with PRO-CURE and greater than in patients treated with placebo over

a 4-year study are: impotence, decreased libido, decreased volume of

ejaculate, breast enlargement, breast tenderness and rash (6.1).

See 17 for PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION: CONTENTS*

1

INDICATIONS AND USAGE

Monotherapy

Combination with Alpha-Blocker

Limitations of Use

2

DOSAGE AND ADMINISTRATION

Monotherapy

Combination with Alpha-Blocker

3

DOSAGE FORMS AND STRENGTHS

4

CONTRAINDICATIONS

5

WARNINGS AND PRECAUTIONS

Effects on Prostate Specific Antigen (PSA) and the Use of

PSA in Prostate Cancer Detection

Increased Risk of High-Grade Prostate Cancer

Exposure of Women — Risk to Male Fetus

Pediatric Patients and Women

Effect on Semen Characteristics

Consideration of Other Urological Conditions

6

ADVERSE REACTIONS

Clinical Trials Experience

Postmarketing Experience

7

DRUG INTERACTIONS

Cytochrome

P450-Linked

Drug

Metabolizing

Enzyme

System

Other Concomitant Therapy

8

USE IN SPECIFIC POPULATIONS

Pregnancy

Nursing Mothers

Pediatric Use

Geriatric Use

Hepatic Impairment

Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

12.2

Pharmacodynamics

12.3

Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1

Monotherapy

14.2

Combination with Alpha-Blocker Therapy

14.3

Summary of Clinical Studies

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1

Increased Risk of High-Grade Prostate Cancer

17.2

Exposure of Women — Risk to Male Fetus

17.3

Additional Instructions

*Sections or subsections omitted from the full prescribing information

are not listed.

FULL PRESCRIBING INFORMATION

1

INDICATIONS AND USAGE

1.1

Monotherapy

PRO-CURE

is indicated for the treatment and control of symptomatic benign prostatic hyperplasia (BPH)

and for the prevention of urologic events to:

-Reduce the risk of acute urinary retention

-Reduce the risk of the need for surgery including transurethral resection of the prostate (TURP) and

prostatectomy.

- Pro-Cure causes regression of the enlarged prostate, improves urinary flow and improves the

symptoms associated with BPH.

Patients with an enlarged prostate are the appropriate candidates for therapy with Pro-Cure.

1.2

Limitations of Use

PRO-CURE is not approved for the prevention of prostate cancer.

2

DOSAGE AND ADMINISTRATION

PRO-CURE may be administered with or without meals.

2.1

Monotherapy

The recommended dose of PRO-CURE is one tablet (5 mg) taken once a day [see Clinical Studies

(14.1)].

2.2

PRO-CURE

3

DOSAGE FORMS AND STRENGTHS

5-mg blue, modified apple-shaped, film-coated tablets, one side engraved 72, the other side plain

4

CONTRAINDICATIONS

PRO-CURE is contraindicated in the following:

Hypersensitivity to any component of this medication.

Pregnancy. Finasteride use is contraindicated in women when they are or may potentially be

pregnant. Because of the ability of Type II 5α-reductase inhibitors to inhibit the conversion of

testosterone to 5α-dihydrotestosterone (DHT), finasteride may cause abnormalities of the

external genitalia of a male fetus of a pregnant woman who receives finasteride. If this drug is

used during pregnancy, or if pregnancy occurs while taking this drug, the pregnant woman

should be apprised of the potential hazard to the male fetus. [See also Warnings and

Precautions (5.3), Use in Specific Populations (8.1), How Supplied/Storage and Handling (16)

and

Patient

Counseling

Information

(17.2).]

female

rats,

doses

finasteride

administered during pregnancy have produced abnormalities of the external genitalia in male

offspring.

5

WARNINGS AND PRECAUTIONS

5.1

Effects on Prostate Specific Antigen (PSA) and the Use of PSA in Prostate Cancer

Detection

In clinical studies, PRO-CURE reduced serum PSA concentration by approximately 50% within six

months of treatment. This decrease is predictable over the entire range of PSA values in patients with

symptomatic BPH, although it may vary in individuals.

interpretation

serial

PSAs

taking

PRO-CURE,

baseline

should

established at least six months after starting treatment and PSA monitored periodically thereafter. Any

confirmed increase from the lowest PSA value while on PRO-CURE may signal the presence of prostate

cancer and should be evaluated, even if PSA levels are still within the normal range for men not taking a

5α-reductase inhibitor. Non-compliance with PRO-CURE therapy may also affect PSA test results. To

interpret an isolated PSA value in patients treated with PRO-CURE for six months or more, PSA values

should be doubled for comparison with normal ranges in untreated men. These adjustments preserve the

utility of PSA to detect prostate cancer in men treated with PRO-CURE.

PRO-CURE may also cause decreases in serum PSA in the presence of prostate cancer.

The ratio of free to total PSA (percent free PSA) remains constant even under the influence of PRO-

CURE. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men

undergoing finasteride therapy, no adjustment to its value appears necessary.

5.2

Increased Risk of High-Grade Prostate Cancer

Men aged 55 and over with a normal digital rectal examination and PSA ≤3.0 ng/mL at baseline taking

finasteride 5 mg/day in the 7-year Prostate Cancer Prevention Trial (PCPT) had an increased risk of

Gleason score 8-10 prostate cancer (finasteride 1.8% vs placebo 1.1%). [See Indications and Usage (1.3)

and Adverse Reactions (6.1).] Similar results were observed in a 4-year placebo-controlled clinical trial

with another 5α-reductase inhibitor (dutasteride, AVODART) (1% dutasteride vs 0.5% placebo). 5α-

reductase inhibitors may increase the risk of development of high-grade prostate cancer. Whether the

effect of 5α-reductase inhibitors to reduce prostate volume, or study-related factors, impacted the results

of these studies has not been established.

5.3

Exposure of Women — Risk to Male Fetus

Women should not handle crushed or broken PRO-CURE tablets when they are pregnant or may

potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential

risk to a male fetus. PRO-CURE tablets are coated and will prevent contact with the active ingredient

during

normal

handling,

provided

that

tablets

have

been

broken

crushed.

[See

Contraindications

(4),

Use

in

Specific

Populations

(8.1),

Clinical

Pharmacology

(12.3),

How

Supplied/Storage and Handling (16) and Patient Counseling Information (17.2).]

5.4

Pediatric Patients and Women

PRO-CURE is not indicated for use in pediatric patients [see Use in Specific Populations (8.4) and

Clinical Pharmacology (12.3)] or women [see also Warnings and Precautions (5.3), Use in Specific

Populations (8.1), Clinical Pharmacology (12.3), How Supplied/Storage and Handling (16) and Patient

Counseling Information (17.2)].

5.5

Effect on Semen Characteristics

Treatment with PRO-CURE for 24 weeks to evaluate semen parameters in healthy male volunteers

revealed no clinically meaningful effects on sperm concentration, mobility, morphology, or pH. A 0.6 mL

(22.1%) median decrease in ejaculate volume with a concomitant reduction in total sperm per ejaculate

observed.

These

parameters

remained

within

normal

range

were

reversible

upon

discontinuation of therapy with an average time to return to baseline of 84 weeks.

5.6

Consideration of Other Urological Conditions

Prior to initiating treatment with PRO-CURE, consideration should be given to other urological

conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.

Patients with large residual urinary volume and/or severely diminished urinary flow should be carefully

monitored for obstructive uropathy. These patients may not be candidates for finasteride therapy.

6

ADVERSE REACTIONS

6.1

Clinical Trials Experience

PRO-CURE is generally well tolerated; adverse reactions usually have been mild and transient.

4-Year Placebo-Controlled Study (PLESS)

In PLESS, 1524 patients treated with PRO-CURE and 1516 patients treated with placebo were

evaluated for safety over a period of 4 years. The most frequently reported adverse reactions were

related to sexual function. 3.7% (57 patients) treated with PRO-CURE and 2.1% (32 patients) treated with

placebo discontinued therapy as a result of adverse reactions related to sexual function, which are the

most frequently reported adverse reactions.

Table 1 presents the only clinical adverse reactions considered possibly, probably or definitely drug

related by the investigator, for which the incidence on PRO-CURE was ≥1% and greater than placebo

over the 4 years of the study. In years 2-4 of the study, there was no significant difference between

treatment groups in the incidences of impotence, decreased libido and ejaculation disorder.

Table 1

Drug-Related Adverse Experiences

Year 1

Years 2, 3 and 4*

Finasteride

Placebo

Finasteride

Placebo

Impotence

Decreased

Libido

Decreased

Volume of

Ejaculate

Ejaculation

Disorder

Breast

Enlargement

Breast

Tenderness

Rash

*Combined Years 2-4

N = 1524 and 1516, finasteride vs placebo, respectively

Phase III Studies and 5-Year Open Extensions

The adverse experience profile in the 1-year, placebo-controlled, Phase III studies, the 5-year open

extensions, and PLESS were similar.

Medical Therapy of Prostatic Symptoms (MTOPS) Study

In the MTOPS study, 3047 men with symptomatic BPH were randomized to receive PRO-CURE

5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the combination of PRO-CURE 5 mg/day and

doxazosin 4 or 8 mg/day (n=786), or placebo (n=737) for 4 to 6 years. [See Clinical Studies (14.2).]

The incidence rates of drug-related adverse experiences reported by

2% of patients in any treatment

group in the MTOPS Study are listed in Table 2.

The individual adverse effects which occurred more frequently in the combination group compared to

either drug alone were: asthenia, postural hypotension, peripheral edema, dizziness, decreased libido,

rhinitis, abnormal ejaculation, impotence and abnormal sexual function (see Table 2). Of these, the

incidence of abnormal ejaculation in patients receiving combination therapy was comparable to the sum

of the incidences of this adverse experience reported for the two monotherapies.

Combination therapy with finasteride and doxazosin was associated with no new clinical adverse

experience.

Four patients in MTOPS reported the adverse experience breast cancer. Three of these patients were

on finasteride only and one was on combination therapy. [See Long Term Data.]

The MTOPS Study was not specifically designed to make statistical comparisons between groups for

reported adverse experiences. In addition, direct comparisons of safety data between the MTOPS study

and previous studies of the single agents may not be appropriate based upon differences in patient

population, dosage or dose regimen, and other procedural and study design elements.

Table 2

Incidence ≥2% in One or More Treatment Groups

Drug-Related Clinical Adverse Experiences in MTOPS

Adverse Experience

Placebo

Doxazosin

4 mg or 8 mg*

Finasteride

Combination

(N=737)

(N=756)

(N=768)

(N=786)

Body as a whole

Asthenia

15.7

16.8

Headache

Cardiovascular

Hypotension

Postural Hypotension

16.7

17.8

Metabolic and Nutritional

Peripheral Edema

Nervous

Dizziness

17.7

23.2

Libido Decreased

10.0

11.6

Somnolence

Respiratory

Dyspnea

Rhinitis

Urogenital

Abnormal Ejaculation

14.1

Gynecomastia

Impotence

12.2

14.4

18.5

22.6

Sexual Function Abnormal

*Doxazosin dose was achieved by weekly titration (1 to 2 to 4 to 8 mg). The final tolerated dose (4 mg or 8 mg) was administered at end-Week 4.

Only those patients tolerating at least 4 mg were kept on doxazosin. The majority of patients received the 8-mg dose over the duration of the study.

Long-Term Data

High-Grade Prostate Cancer

The PCPT trial was a 7-year randomized, double-blind, placebo-controlled trial that enrolled 18,882

men ≥55 years of age with a normal digital rectal examination and a PSA ≤3.0 ng/mL. Men received

either PRO-CURE (finasteride 5 mg) or placebo daily. Patients were evaluated annually with PSA and

digital rectal exams. Biopsies were performed for elevated PSA, an abnormal digital rectal exam, or the

end of study. The incidence of Gleason score 8-10 prostate cancer was higher in men treated with

finasteride (1.8%) than in those treated with placebo (1.1%) [see Indications and Usage (1.3) and

Warnings and Precautions (5.2)]. In a 4-year placebo-controlled clinical trial with another 5α-reductase

inhibitor (dutasteride, AVODART), similar results for Gleason score 8-10 prostate cancer were observed

(1% dutasteride vs 0.5% placebo).

No clinical benefit has been demonstrated in patients with prostate cancer treated with PRO-CURE.

Breast Cancer

During the 4- to 6-year placebo- and comparator-controlled MTOPS study that enrolled 3047 men,

there were 4 cases of breast cancer in men treated with finasteride but no cases in men not treated with

finasteride. During the 4-year, placebo-controlled PLESS study that enrolled 3040 men, there were 2

cases of breast cancer in placebo-treated men but no cases in men treated with finasteride. During the 7-

year placebo-controlled Prostate Cancer Prevention Trial (PCPT) that enrolled 18,882 men, there was 1

case of breast cancer in men treated with finasteride, and 1 case of breast cancer in men treated with

placebo. There have been postmarketing reports of male breast cancer with the use of finasteride

relationship between long-term use of finasteride and male breast neoplasia is currently unknown.

Sexual Function

There is no evidence of increased sexual adverse experiences with increased duration of treatment

with PRO-CURE. New reports of drug-related sexual adverse experiences decreased with duration of

therapy.

6.2

Postmarketing Experience

The following additional adverse effects have been reported in post-marketing experience with PRO-

CURE and/or finasteride at lower doses. Because these reactions are reported voluntarily from a

population of uncertain size, it is not always possible to reliably estimate their frequency or establish a

causal relationship to drug exposure:

- hypersensitivity reactions, such as pruritus, urticaria, and angioedema (including swelling of the lips,

tongue, throat and face)

- testicular pain

- : sexual dysfunction (erectile dysfunction and ejaculation disorders) that continued after discontinuation

of treatment..

- male infertility and/or poor seminal quality -. Normalization or improvement of seminal quality has been

reported after discontinuation of finasteride.

- depression

- decreased libido that continued after discontinuation of treatment

DRUG INTERACTIONS

7.1

Cytochrome P450-Linked Drug Metabolizing Enzyme System

No drug interactions of clinical importance have been identified. Finasteride does not appear to affect

the cytochrome P450-linked drug metabolizing enzyme system. Compounds that have been tested in

man have included antipyrine, digoxin, propranolol, theophylline, and warfarin and no clinically meaningful

interactions were found.

7.2

Other Concomitant Therapy

Although specific interaction studies were not performed, PRO-CURE was concomitantly used in

clinical studies with acetaminophen, acetylsalicylic acid, α-blockers, angiotensin-converting enzyme

(ACE)

inhibitors,

analgesics,

anti-convulsants,

beta-adrenergic

blocking

agents,

diuretics,

calcium

channel blockers, cardiac nitrates, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs

(NSAIDs), benzodiazepines, H

antagonists and quinolone anti-infectives without evidence of clinically

significant adverse interactions.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Pregnancy Category X. [See Contraindications (4).]

PRO-CURE is contraindicated for use in women who are or may become pregnant. PRO-CURE is a

Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a

hormone necessary for normal development of male genitalia. In animal studies, finasteride caused

abnormal development of external genitalia in male fetuses. If this drug is used during pregnancy, or if the

patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to

the male fetus.

Abnormal male genital development is an expected consequence when conversion of testosterone to

5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those

reported in male infants with genetic 5α-reductase deficiency. Women could be exposed to finasteride

through contact with crushed or broken PRO-CURE tablets or semen from a male partner taking PRO-

CURE. With regard to finasteride exposure through the skin, PRO-CURE tablets are coated and will

prevent skin contact with finasteride during normal handling if the tablets have not been crushed or

broken. Women who are pregnant or may become pregnant should not handle crushed or broken PRO-

CURE tablets because of possible exposure of a male fetus. If a pregnant woman comes in contact with

crushed or broken PRO-CURE tablets, the contact area should be washed immediately with soap and

water. With regard to potential finasteride exposure through semen, two studies have been conducted in

men receiving PRO-CURE 5 mg/day that measured finasteride concentrations in semen [see Clinical

Pharmacology (12.3)].

In an embryo-fetal development study, pregnant rats received finasteride during the period of major

organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86

times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of

0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100%

of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17

days of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral

maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day),

male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and

transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats

that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day).

No abnormalities were observed in female offspring at any maternal dose of finasteride.

No developmental abnormalities were observed in the offspring of untreated females mated with

finasteride treated male rats that received approximately 61 times the MRHD (based on AUC at animal

dose of 80 mg/kg/day). Slightly decreased fertility was observed in male offspring after administration of

about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late

gestation and lactation. No effects on fertility were seen in female offspring under these conditions.

No evidence of male external genital malformations or other abnormalities were observed in rabbit

fetuses exposed to finasteride during the period of major organogenesis (gestation days 6-18) at maternal

oral doses up to 100 mg/kg /day, (finasteride exposure levels were not measured in rabbits). However,

this study may not have included the critical period for finasteride effects on development of male external

genitalia in the rabbit.

fetal

effects

maternal

finasteride

exposure

during

period

embryonic

fetal

development

were

evaluated

rhesus

monkey

(gestation

days

20-100),

species

development period more predictive of specific effects in humans than the studies in rats and rabbits.

Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated

maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of

pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male

fetuses. In confirmation of the relevance of the rhesus model for human fetal development, oral

administration of a dose of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated

blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external

genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no

finasteride-related abnormalities were observed in female fetuses at any dose.

8.3

Nursing Mothers

PRO-CURE is not indicated for use in women.

It is not known whether finasteride is excreted in human milk.

8.4

Pediatric Use

PRO-CURE is not indicated for use in pediatric patients.

Safety and effectiveness in pediatric patients have not been established.

8.5

Geriatric Use

Of the total number of subjects included in PLESS, 1480 and 105 subjects were 65 and over and 75

and over, respectively. No overall differences in safety or effectiveness were observed between these

subjects and younger subjects, and other reported clinical experience has not identified differences in

responses between the elderly and younger patients. No dosage adjustment is necessary in the elderly

[see Clinical Pharmacology (12.3) and Clinical Studies (14)].

8.6

Hepatic Impairment

Caution should be exercised in the administration of PRO-CURE in those patients with liver function

abnormalities, as finasteride is metabolized extensively in the liver [see Clinical Pharmacology (12.3)].

8.7

Renal Impairment

No dosage adjustment is necessary in patients with renal impairment [see Clinical Pharmacology

(12.3)].

10

OVERDOSAGE

Patients have received single doses of PRO-CURE up to 400 mg and multiple doses of PRO-CURE

up to 80 mg/day for three months without adverse effects. Until further experience is obtained, no specific

treatment for an overdose with PRO-CURE can be recommended.

Significant lethality was observed in male and female mice at single oral doses of 1500 mg/m

(500

mg/kg) and in female and male rats at single oral doses of 2360 mg/m

(400 mg/kg) and 5900 mg/m

(1000 mg/kg), respectively.

11

DESCRIPTION

PRO-CURE (finasteride), a synthetic 4-azasteroid compound, is a specific inhibitor of steroid Type II

5α-reductase,

intracellular

enzyme

that

converts

androgen

testosterone

into

5α-dihydrotestosterone (DHT).

Finasteride

4-azaandrost-1-ene-17-carboxamide,

N-(1,1-dimethylethyl)-3-oxo-,(5α,17β)-.

empirical formula of finasteride is C

and its molecular weight is 372.55. Its structural formula is:

Finasteride is a white crystalline powder with a melting point near 250°C. It is freely soluble in

chloroform and in lower alcohol solvents, but is practically insoluble in water.

PRO-CURE (finasteride) tablets for oral administration are film-coated tablets that contain 5 mg of

finasteride

following

inactive

ingredients:

hydrous

lactose,

microcrystalline

cellulose,

pregelatinized starch, sodium starch glycolate, hydroxypropyl cellulose LF, hydroxypropyl methylcellulose,

titanium dioxide, magnesium stearate, talc, docusate sodium, FD&C Blue 2 aluminum lake and yellow

iron oxide.

12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

The development and enlargement of the prostate gland is dependent on the potent androgen,

5α-dihydrotestosterone (DHT). Type II 5α-reductase metabolizes testosterone to DHT in the prostate

gland, liver and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei

of these organs.

Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with which it slowly forms a

stable enzyme complex. Turnover from this complex is extremely slow (t

30 days). This has been

demonstrated both in vivo and in vitro. Finasteride has no affinity for the androgen receptor. In man, the

5α-reduced steroid metabolites in blood and urine are decreased after administration of finasteride.

12.2

Pharmacodynamics

man,

single

5-mg

oral

dose

PRO-CURE

produces

rapid

reduction

serum

concentration, with the maximum effect observed 8 hours after the first dose. The suppression of DHT is

maintained throughout the 24-hour dosing interval and with continued treatment. Daily dosing of PRO-

CURE at 5 mg/day for up to 4 years has been shown to reduce the serum DHT concentration by

approximately 70%. The median circulating level of testosterone increased by approximately 10-20% but

remained within the physiologic range. In a separate study in healthy men treated with finasteride 1 mg

per day (n=82) or placebo (n=69), mean circulating levels of testosterone and estradiol were increased by

approximately 15% as compared to baseline, but these remained within the physiologic range.

In patients receiving PRO-CURE 5 mg/day, increases of about 10% were observed in luteinizing

hormone (LH) and follicle-stimulating hormone (FSH), but levels remained within the normal range. In

healthy volunteers, treatment with PRO-CURE did not alter the response of LH and FSH to gonadotropin-

releasing hormone indicating that the hypothalamic-pituitary-testicular axis was not affected.

In patients with BPH, PRO-CURE has no effect on circulating levels of cortisol, prolactin, thyroid-

stimulating hormone, or thyroxine. No clinically meaningful effect was observed on the plasma lipid profile

(i.e., total cholesterol, low density lipoproteins, high density lipoproteins and triglycerides) or bone mineral

density.

Adult males with genetically inherited Type II 5α-reductase deficiency also have decreased levels of

DHT. Except for the associated urogenital defects present at birth, no other clinical abnormalities related

to Type II 5α-reductase deficiency have been observed in these individuals. These individuals have a

small prostate gland throughout life and do not develop BPH.

In patients with BPH treated with finasteride (1-100 mg/day) for 7-10 days prior to prostatectomy, an

approximate 80% lower DHT content was measured in prostatic tissue removed at surgery, compared to

placebo; testosterone tissue concentration was increased up to 10 times over pretreatment levels, relative

to placebo. Intraprostatic content of PSA was also decreased.

In healthy male volunteers treated with PRO-CURE for 14 days, discontinuation of therapy resulted in

a return of DHT levels to pretreatment levels in approximately 2 weeks. In patients treated for three

months, prostate volume, which declined by approximately 20%, returned to close to baseline value after

approximately three months of discontinuation of therapy.

12.3

Pharmacokinetics

Absorption

In a study of 15 healthy young subjects, the mean bioavailability of finasteride 5-mg tablets was 63%

(range 34-108%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV)

reference dose. Maximum finasteride plasma concentration averaged 37 ng/mL (range, 27-49 ng/mL) and

was reached 1-2 hours postdose. Bioavailability of finasteride was not affected by food.

Distribution

Mean steady-state volume of distribution was 76 liters (range, 44-96 liters). Approximately 90% of

circulating finasteride is bound to plasma proteins. There is a slow accumulation phase for finasteride

after multiple dosing. After dosing with 5 mg/day of finasteride for 17 days, plasma concentrations of

finasteride were 47 and 54% higher than after the first dose in men 45-60 years old (n=12) and

70 years

old (n=12), respectively. Mean trough concentrations after 17 days of dosing were 6.2 ng/mL (range, 2.4-

9.8 ng/mL) and 8.1 ng/mL (range, 1.8-19.7 ng/mL), respectively, in the two age groups. Although steady

state was not reached in this study, mean trough plasma concentration in another study in patients with

BPH (mean age, 65 years) receiving 5 mg/day was 9.4 ng/mL (range, 7.1-13.3 ng/mL; n=22) after over a

year of dosing.

Finasteride has been shown to cross the blood brain barrier but does not appear to distribute

preferentially to the CSF.

In 2 studies of healthy subjects (n=69) receiving PRO-CURE 5 mg/day for 6-24 weeks, finasteride

concentrations in semen ranged from undetectable (<0.1 ng/mL) to 10.54 ng/mL. In an earlier study using

a less sensitive assay, finasteride concentrations in the semen of 16 subjects receiving PRO-CURE

5 mg/day ranged from undetectable (<1.0 ng/mL) to 21 ng/mL. Thus, based on a 5-mL ejaculate volume,

the amount of finasteride in semen was estimated to be 50- to 100-fold less than the dose of finasteride

g) that had no effect on circulating DHT levels in men [see also Use in Specific Populations (8.1)].

Metabolism

Finasteride is extensively metabolized in the liver, primarily via the cytochrome P450 3A4 enzyme

subfamily.

metabolites,

t-butyl

side

chain

monohydroxylated

monocarboxylic

acid

metabolites, have been identified that possess no more than 20% of the 5

-reductase inhibitory activity of

finasteride.

Excretion

In healthy young subjects (n=15), mean plasma clearance of finasteride was 165 mL/min (range, 70-

279 mL/min) and mean elimination half-life in plasma was 6 hours (range, 3-16 hours). Following an oral

dose of

C-finasteride in man (n=6), a mean of 39% (range, 32-46%) of the dose was excreted in the

urine in the form of metabolites; 57% (range, 51-64%) was excreted in the feces.

The mean terminal half-life of finasteride in subjects

70 years of age was approximately 8 hours

(range, 6-15 hours; n=12), compared with 6 hours (range, 4-12 hours; n=12) in subjects 45-60 years of

age. As a result, mean AUC

(0-24 hr)

after 17 days of dosing was 15% higher in subjects

70 years of age

than in subjects 45-60 years of age (p=0.02).

Table 3

Mean (SD) Pharmacokinetic Parameters

in Healthy Young Subjects (n=15)

Mean (

Bioavailability

63% (34-108%)*

Clearance (mL/min)

165 (55)

Volume of Distribution (L)

76 (14)

Half-Life (hours)

6.2 (2.1)

*Range

Pediatric

Finasteride pharmacokinetics have not been investigated in patients <18 years of age.

Finasteride is not indicated for use in pediatric patients [see Warnings and Precautions (5.4), Use in

Specific Populations (8.4)].

Gender

Finasteride is not indicated for use in women [see Contraindications (4), Warnings and Precautions

(5.3 and 5.4), Use in Specific Populations (8.1), How Supplied/Storage and Handling (16) and Patient

Counseling Information (17.2)].

Geriatric

No dosage adjustment is necessary in the elderly. Although the elimination rate of finasteride is

decreased in the elderly, these findings are of no clinical significance. [See Clinical Pharmacology (12.3)

and Use in Specific Populations (8.5).]

Table 4

Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5

mg/day in Older Men

Mean (

45-60 years old (n=12)

70 years old (n=12)

AUC (ng

hr/mL)

389 (98)

463 (186)

Peak Concentration (ng/mL)

46.2 (8.7)

48.4 (14.7)

Time to Peak (hours)

1.8 (0.7)

1.8 (0.6)

Half-Life (hours)*

6.0 (1.5)

8.2 (2.5)

*First-dose values; all other parameters are last-dose values

Race

The effect of race on finasteride pharmacokinetics has not been studied.

Hepatic Impairment

The effect of hepatic impairment on finasteride pharmacokinetics has not been studied. Caution

should

exercised

administration

PRO-CURE

those

patients

with

liver

function

abnormalities, as finasteride is metabolized extensively in the liver.

Renal Impairment

No dosage adjustment is necessary in patients with renal impairment. In patients with chronic renal

impairment,

with

creatinine

clearances

ranging

from

55 mL/min,

AUC,

maximum

plasma

concentration, half-life, and protein binding after a single dose of

C-finasteride were similar to values

obtained in healthy volunteers. Urinary excretion of metabolites was decreased in patients with renal

impairment. This decrease was associated with an increase in fecal excretion of metabolites. Plasma

concentrations of metabolites were significantly higher in patients with renal impairment (based on a 60%

increase in total radioactivity AUC). However, finasteride has been well tolerated in BPH patients with

normal renal function receiving up to 80 mg/day for 12 weeks, where exposure of these patients to

metabolites would presumably be much greater.

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of a tumorigenic effect was observed in a 24-month study in Sprague-Dawley rats

receiving doses of finasteride up to 160 mg/kg/day in males and 320 mg/kg/day in females. These doses

produced respective systemic exposure in rats of 111 and 274 times those observed in man receiving the

recommended human dose of 5 mg/day. All exposure calculations were based on calculated AUC

(0-24 hr)

for animals and mean AUC

(0-24 hr)

for man (0.4 µghr/mL).

In a 19-month carcinogenicity study in CD-1 mice, a statistically significant (p≤0.05) increase in the

incidence of testicular Leydig cell adenomas was observed at 228 times the human exposure (250

mg/kg/day). In mice at 23 times the human exposure, estimated (25 mg/kg/day) and in rats at 39 times

the human exposure (40 mg/kg/day) an increase in the incidence of Leydig cell hyperplasia was

observed. A positive correlation between the proliferative changes in the Leydig cells and an increase in

serum LH levels (2- to 3-fold above control) has been demonstrated in both rodent species treated with

high doses of finasteride. No drug-related Leydig cell changes were seen in either rats or dogs treated

with finasteride for 1 year at 30 and 350 times (20 mg/kg/day and 45 mg/kg/day, respectively) or in mice

treated for 19 months at 2.3 times the human exposure, estimated (2.5 mg/kg/day).

No evidence of mutagenicity was observed in an in vitro bacterial mutagenesis assay, a mammalian

cell mutagenesis assay, or in an in vitro alkaline elution assay. In an in vitro chromosome aberration

assay, using Chinese hamster ovary cells, there was a slight increase in chromosome aberrations. These

concentrations correspond to 4000-5000 times the peak plasma levels in man given a total dose of 5 mg.

In an in vivo chromosome aberration assay in mice, no treatment-related increase in chromosome

aberration was observed with finasteride at the maximum tolerated dose of 250 mg/kg/day (228 times the

human exposure) as determined in the carcinogenicity studies.

In sexually mature male rabbits treated with finasteride at 543 times the human exposure (80

mg/kg/day) for up to 12 weeks, no effect on fertility, sperm count, or ejaculate volume was seen. In

sexually mature male rats treated with 61 times the human exposure (80 mg/kg/day), there were no

significant effects on fertility after 6 or 12 weeks of treatment; however, when treatment was continued for

up to 24 or 30 weeks, there was an apparent decrease in fertility, fecundity and an associated significant

decrease in the weights of the seminal vesicles and prostate. All these effects were reversible within

6 weeks of discontinuation of treatment. No drug-related effect on testes or on mating performance has

been seen in rats or rabbits. This decrease in fertility in finasteride-treated rats is secondary to its effect

on accessory sex organs (prostate and seminal vesicles) resulting in failure to form a seminal plug. The

seminal plug is essential for normal fertility in rats and is not relevant in man.

14

CLINICAL STUDIES

14.1

Monotherapy

PRO-CURE 5 mg/day was initially evaluated in patients with symptoms of BPH and enlarged prostates

by digital rectal examination in two 1-year, placebo-controlled, randomized, double-blind studies and their

5-year open extensions.

PRO-CURE was further evaluated in the PRO-CURE Long-Term Efficacy and Safety Study (PLESS),

a double-blind, randomized, placebo-controlled, 4-year, multicenter study. 3040 patients between the

ages of 45 and 78, with moderate to severe symptoms of BPH and an enlarged prostate upon digital

rectal examination, were randomized into the study (1524 to finasteride, 1516 to placebo) and 3016

patients were evaluable for efficacy. 1883 patients completed the 4-year study (1000 in the finasteride

group, 883 in the placebo group).

Effect on Symptom Score

Symptoms were quantified using a score similar to the American Urological Association Symptom

Score, which evaluated both obstructive symptoms (impairment of size and force of stream, sensation of

incomplete bladder emptying, delayed or interrupted urination) and irritative symptoms (nocturia, daytime

frequency, need to strain or push the flow of urine) by rating on a 0 to 5 scale for six symptoms and a 0 to

4 scale for one symptom, for a total possible score of 34.

Patients in PLESS had moderate to severe symptoms at baseline (mean of approximately 15 points

on a 0-34 point scale). Patients randomized to PRO-CURE who remained on therapy for 4 years had a

mean (

1 SD) decrease in symptom score of 3.3 (

5.8) points compared with 1.3 (

5.6) points in the

placebo group. (See Figure 1.) A statistically significant improvement in symptom score was evident at

1 year in patients treated with PRO-CURE vs placebo (–2.3 vs –1.6), and this improvement continued

through Year 4.

Results seen in earlier studies were comparable to those seen in PLESS. Although an early

improvement in urinary symptoms was seen in some patients, a therapeutic trial of at least 6 months was

generally necessary to assess whether a beneficial response in symptom relief had been achieved. The

improvement in BPH symptoms was seen during the first year and maintained throughout an additional

5 years of open extension studies.

Effect on Acute Urinary Retention and the Need for Surgery

In PLESS, efficacy was also assessed by evaluating treatment failures. Treatment failure was

prospectively defined as BPH-related urological events or clinical deterioration, lack of improvement

and/or the need for alternative therapy. BPH-related urological events were defined as urological surgical

intervention and

acute

urinary

retention

requiring

catheterization.

Complete

event

information was

available for 92% of the patients. The following table (Table 5) summarizes the results.

Table 5

All Treatment Failures in PLESS

Patients (%)*

Event

Placebo

N=1503

Finasteride

N=1513

Relative

Risk

†

95% CI

P

Value

†

All Treatment

Failures

37.1

26.2

0.68

(0.57 to 0.79)

<0.001

Baseline

Year 1

Year 2

Year 3

Year 4

Mean Change from Baseline ± 1 SE

Placebo

Finasteride

1296

1314

1438

1437

1101

1153

1047

Figure 1

Symptom Score in PLESS

Surgical

Interventions

for BPH

10.1

0.45

(0.32 to 0.63)

<0.001

Acute Urinary

Retention

Requiring

Catheterization

0.43

(0.28 to 0.66)

<0.001

consecutive

symptom

scores

Bladder Stone

Incontinence

Renal Failure

Discontinuation

due to

worsening of

BPH, lack of

improvement,

or to receive

other medical

treatment

21.8

13.3

*patients with multiple events may be counted more than once for each type of event

†Hazard ratio based on log rank test

Compared with placebo, PRO-CURE was associated with a significantly lower risk for acute urinary

retention or the need for BPH-related surgery [13.2% for placebo vs 6.6% for PRO-CURE; 51% reduction

in risk, 95% CI: (34 to 63%)]. Compared with placebo, PRO-CURE was associated with a significantly

lower risk for surgery [10.1% for placebo vs 4.6% for PRO-CURE; 55% reduction in risk, 95% CI: (37 to

68%)] and with a significantly lower risk of acute urinary retention [6.6% for placebo vs 2.8% for PRO-

CURE; 57% reduction in risk, 95% CI: (34 to 72%)]; see Figures 2 and 3.

Observation Time (Month)

Finasteride

Placebo

Percent of Patients

Figure 2

Percent of Patients Having Surgery for BPH,

Including TURP

Placebo Group

No. of events, cumulative

No. at risk, per year

1503

1454

1374

1314

Finasteride Group

No. of events, cumulative

No. at risk, per year

1513

1483

1438

1410

Effect on Maximum Urinary Flow Rate

In the patients in PLESS who remained on therapy for the duration of the study and had evaluable

urinary flow data, PRO-CURE increased maximum urinary flow rate by 1.9 mL/sec compared with 0.2

mL/sec in the placebo group.

There was a clear difference between treatment groups in maximum urinary flow rate in favor of PRO-

CURE by month 4 (1.0 vs 0.3 mL/sec) which was maintained throughout the study. In the earlier 1-year

studies, increase in maximum urinary flow rate was comparable to PLESS and was maintained through

the first year and throughout an additional 5 years of open extension studies.

Effect on Prostate Volume

In PLESS, prostate volume was assessed yearly by magnetic resonance imaging (MRI) in a subset of

patients. In patients treated with PRO-CURE who remained on therapy, prostate volume was reduced

compared with both baseline and placebo throughout the 4-year study. PRO-CURE decreased prostate

volume by 17.9% (from 55.9 cc at baseline to 45.8 cc at 4 years) compared with an increase of 14.1%

(from 51.3 cc to 58.5 cc) in the placebo group (p<0.001). (See Figure 4.)

Results seen in earlier studies were comparable to those seen in PLESS. Mean prostate volume at

baseline ranged between 40-50 cc. The reduction in prostate volume was seen during the first year and

maintained throughout an additional five years of open extension studies.

Placebo Group

No. of events, cumulative

No. at risk, per year

1503

1454

1398

1347

Finasteride Group

No. of events, cumulative

No. at risk, per year

1513

1487

1449

1421

Observation Time (Month)

Finasteride

Placebo

Percent of Patients

Figure 3

Percent of Patients Developing Acute Urinary Retention

(Spontaneous and Precipitated)

Prostate Volume as a Predictor of Therapeutic Response

A meta-analysis combining 1-year data from seven double-blind, placebo-controlled studies of similar

design, including 4491 patients with symptomatic BPH, demonstrated that, in patients treated with PRO-

CURE, the magnitude of symptom response and degree of improvement in maximum urinary flow rate

were greater in patients with an enlarged prostate at baseline.

14.2

Combination with Alpha-Blocker Therapy

The Medical Therapy of Prostatic Symptoms (MTOPS) Trial was a double-blind, randomized,

placebo-controlled, multicenter, 4- to 6-year study (average 5 years) in 3047 men with symptomatic BPH,

who were randomized to receive PRO-CURE 5 mg/day (n=768), doxazosin 4 or 8 mg/day (n=756), the

combination of PRO-CURE 5 mg/day and doxazosin 4 or 8 mg/day (n=786), or placebo (n=737). All

participants underwent weekly titration of doxazosin (or its placebo) from 1 to 2 to 4 to 8 mg/day. Only

those who tolerated the 4 or 8 mg dose level were kept on doxazosin (or its placebo) in the study. The

participant’s final tolerated dose (either 4 mg or 8 mg) was administered beginning at end-Week 4. The

final doxazosin dose was administered once per day, at bedtime.

The mean patient age at randomization was 62.6 years (

7.3 years). Patients were Caucasian (82%),

African American (9%), Hispanic (7%), Asian (1%) or Native American (<1%). The mean duration of BPH

symptoms was 4.7 years (

4.6 years). Patients had moderate to severe BPH symptoms at baseline with a

mean AUA symptom score of approximately 17 out of 35 points. Mean maximum urinary flow rate was

10.5 mL/sec (

2.6 mL/sec). The mean prostate volume as measured by transrectal ultrasound was

36.3 mL (

20.1 mL). Prostate volume was

20 mL in 16% of patients,

50 mL in 18% of patients and

between 21 and 49 mL in 66% of patients.

The primary endpoint was a composite measure of the first occurrence of any of the following five

outcomes: a

4 point confirmed increase from baseline in symptom score, acute urinary retention, BPH-

related renal insufficiency (creatinine rise), recurrent urinary tract infections or urosepsis, or incontinence.

Compared to placebo, treatment with PRO-CURE, doxazosin, or combination therapy resulted in a

reduction in the risk of experiencing one of these five outcome events by 34% (p=0.002), 39% (p<0.001),

and 67% (p<0.001), respectively. Combination therapy resulted in a significant reduction in the risk of the

primary endpoint compared to treatment with PRO-CURE alone (49%; p≤0.001) or doxazosin alone

(46%; p≤0.001). (See Table 6.)

Table 6

Count and Percent Incidence of Primary Outcome Events

by Treatment Group in MTOPS

Treatment Group

Placebo

Doxazosin

Finasteride

Combination

Total

N=737

N=756

N=768

N=786

N=3047

Placebo ( ) n =

Finasteride ( ) n =

Figure 4

Prostate Volume in PLESS

Baseline

Year 1

Year 2

Year 3

Year 4

Mean Percent Change from Baseline ± 1 SE

Event

N (%)

N (%)

N (%)

N (%)

N (%)

AUA 4-point rise

100 (13.6)

59 (7.8)

74 (9.6)

41 (5.2)

274 (9.0)

Acute urinary retention

18 (2.4)

13 (1.7)

6 (0.8)

4 (0.5)

41 (1.3)

Incontinence

8 (1.1)

11 (1.5)

9 (1.2)

3 (0.4)

31 (1.0)

Recurrent UTI/urosepsis

2 (0.3)

2 (0.3)

0 (0.0)

1 (0.1)

5 (0.2)

Creatinine rise

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

Total Events

128 (17.4)

85 (11.2)

89 (11.6)

49 (6.2)

351 (11.5)

The majority of the events (274 out of 351; 78%) was a confirmed

4 point increase in symptom score,

referred to as symptom score progression. The risk of symptom score progression was reduced by 30%

(p=0.016), 46% (p<0.001), and 64% (p<0.001) in patients treated with PRO-CURE, doxazosin, or the

combination, respectively, compared to patients treated with placebo (see Figure 5). Combination therapy

significantly reduced the risk of symptom score progression compared to the effect of PRO-CURE alone

(p<0.001) and compared to doxazosin alone (p=0.037).

Figure 5

Cumulative Incidence of a 4-Point Rise in AUA Symptom Score by Treatment Group

Treatment with PRO-CURE, doxazosin or the combination of PRO-CURE with doxazosin, reduced

the mean symptom score from baseline at year 4. Table 7 provides the mean change from baseline for

AUA symptom score by treatment group for patients who remained on therapy for four years.

Table 7

Change From Baseline in AUA Symptom Score

by Treatment Group at Year 4 in MTOPS

Placebo

N=534

Doxazosin

N=582

Finasteride

N=565

Combination

N=598

Baseline Mean (SD)

16.8 (6.0)

17.0 (5.9)

17.1 (6.0)

16.8 (5.8)

Mean Change

Symptom

Score

(SD)

-4.9 (5.8)

-6.6 (6.1)

-5.6 (5.9)

-7.4 (6.3)

Comparison to

Placebo (95% CI)

-1.8

(-2.5, -1.1)

-0.7

(-1.4, 0.0)

-2.5

(-3.2, -1.8)

Percent with Event

Years from Randomization

Combination

Finasteride

Doxazosin

Placebo

Comparison to

Doxazosin alone (95%

-0.7

(-1.4, 0.0)

Comparison to

Finasteride alone (95%

-1.8

(-2.5, -1.1)

The results of MTOPS are consistent with the findings of the 4-year, placebo-controlled study PLESS

[see Clinical Studies (14.1)] in that treatment with PRO-CURE reduces the risk of acute urinary retention

and the need for BPH-related surgery. In MTOPS, the risk of developing acute urinary retention was

reduced by 67% in patients treated with PRO-CURE compared to patients treated with placebo (0.8% for

PRO-CURE and 2.4% for placebo). Also, the risk of requiring BPH-related invasive therapy was reduced

by 64% in patients treated with PRO-CURE compared to patients treated with placebo (2.0% for PRO-

CURE and 5.4% for placebo).

14.3

Summary of Clinical Studies

The data from these studies, showing improvement in BPH-related symptoms, reduction in treatment

failure (BPH-related urological events), increased maximum urinary flow rates, and decreasing prostate

volume, suggest that PRO-CURE arrests the disease process of BPH in men with an enlarged prostate.

16

HOW SUPPLIED/STORAGE AND HANDLING

PRO-CURE tablets 5 mg are blue, modified apple-shaped, film-coated tablets, one side engraved 72,

the other side plain

Storage and Handling

Store in the original package, below 30°C.

Women should not handle crushed or broken PRO-CURE tablets when they are pregnant or may

potentially be pregnant because of the possibility of absorption of finasteride and the subsequent potential

risk to a male fetus [see Warnings and Precautions (5.3), Use in Specific Populations (8.1) and Patient

Counseling Information (17.2)].

17

PATIENT COUNSELING INFORMATION

See Approved Patient Labeling (Patient Information).

17.1

Increased Risk of High-Grade Prostate Cancer

Patients should be informed that there was an increase in high-grade prostate cancer in men treated

with 5α-reductase inhibitors indicated for BPH treatment, including PRO-CURE, compared to those

treated with placebo in studies looking at the use of these drugs to prevent prostate cancer [see

Indications and Usage (1.3), Warnings and Precautions (5.2), and Adverse Reactions (6.1)].

17.2

Exposure of Women – Risk to Male Fetus

Physicians should inform patients that women who are pregnant or may potentially be pregnant should

not handle crushed or broken PRO-CURE tablets because of the possibility of absorption of finasteride

and the subsequent potential risk to the male fetus. PRO-CURE tablets are coated and will prevent

contact with the active ingredient during normal handling, provided that the tablets have not been broken

or crushed. If a woman who is pregnant or may potentially be pregnant comes in contact with crushed or

broken PRO-CURE tablets, the contact area should be washed immediately with soap and water [see

Contraindications (4), Warnings and Precautions (5.3), Use in Specific Populations (8.1) and How

Supplied/Storage and Handling (16)].

17.3

Additional Instructions

Physicians should inform patients that the volume of ejaculate may be decreased in some patients

during treatment with PRO-CURE. This decrease does not appear to interfere with normal sexual

function. However, impotence and decreased libido may occur in patients treated with PRO-CURE [see

Adverse Reactions (6.1)].

Physicians should instruct their patients to promptly report any changes in their breasts such as lumps,

pain or nipple discharge. Breast changes including breast enlargement, tenderness and neoplasm have

been reported [see Adverse Reactions (6.1)].

Physicians should instruct their patients to read the patient package insert before starting therapy with

PRO-CURE and to reread it each time the prescription is renewed so that they are aware of current

information for patients regarding PRO-CURE.

Manufactured by Merck, Sharp & Dohme UK Ltd., Shotton Lane, Cramlington, Northumberland, England

License holder: Merck, Sharp & Dohme (Israel-1996) Company Ltd., P.O.Box 7121 Petah-Tikva, 49170,

Israel.

The format of this leaflet was determined by the Ministry of Health and its content was checked and

approved in May 2015