PROSTAP* SR Leuprorelin Acetate Depot Injection 3.75mg.

Each dose of PROSTAP SR Powder 3.75mg contains leuprorelin acetate equivalent to 3.57mg base.

Prolonged release powder for suspension for injection by subcutaneous or intramuscular administration after reconstitution with the Sterile Vehicle.

(i) Metastatic prostate cancer.

(ii) Locally advanced prostate cancer, as an alternative to surgical castration.

(iii) As an adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

(iv) As an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression.

(v) Management of endometriosis, including pain relief and reduction of endometriotic lesions.

(vi) Endometrial preparation prior to intrauterine surgical procedures including endometrial ablation or resection.

(vii) Preoperative management of uterine fibroids to reduce their size and associated bleeding.

(See Section 5.1)

Dosage

Prostate Cancer: The usual recommended dose is 3.75mg administered as a single subcutaneous or intramuscular injection every month. The majority of patients will respond to a 3.75mg dose. PROSTAP therapy should not be discontinued when remission or improvement occurs. As with other drugs administered chronically by injection, the injection site should be varied periodically.

Response to PROSTAP therapy may be monitored by clinical parameters and by measuring serum levels of testosterone and acid phosphatase. Clinical studies have shown that testosterone levels increased during the first 4 days of treatment in the majority of non-orchidectomised patients. They then decreased and reached castrate levels by 2-4 weeks. Once attained, castrate levels were maintained as long as drug therapy continued. Transient increases in acid phosphatase levels sometimes occur early in the treatment period but usually return to normal or near normal values by the 4th week of treatment.

Endometriosis: The recommended dose is 3.75mg administered as a single subcutaneous or intramuscular injection every month for a period of 6 months only. Treatment should be initiated during the first 5 days of the menstrual cycle.

In women receiving GnRH analogues for the treatment of endometriosis, the addition of hormone replacement therapy (HRT - an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms. Therefore if appropriate, HRT should be co-administered with PROSTAP taking into account the risks and benefits of each treatment.

Endometrial preparation prior to intrauterine surgery: A single 3.75mg subcutaneous or intramuscular injection 5-6 weeks prior to surgery. Therapy should be initiated during days 3 to 5 of the menstrual cycle.

Preoperative management of uterine fibroids: The recommended dose is 3.75mg administered as a single subcutaneous or intramuscular injection every month, usually for 3-4 months but for a maximum of six months.

Elderly: As for adults.

Children: Safety and efficacy in children have not been established.

Administration

The vial of PROSTAP SR microcapsule powder should be reconstituted immediately prior to administration by subcutaneous or intramuscular injection. Remove flip-cap from vial of PROSTAP SR Powder and cap from prefilled syringe containing 1ml of Sterile Vehicle. Ensure 23 gauge needle is fixed securely to the syringe and inject whole contents of syringe into vial of PROSTAP SR Powder using an aseptic technique. Remove the syringe/needle and keep aseptic. Shake vial gently for 15-20 seconds to produce a uniform cloudy suspension of PROSTAP.

Immediately draw up suspension into syringe taking care to exclude air bubbles. Change the needle on syringe using a 23 gauge needle if the suspension is to be administered subcutaneously or alternatively a 21 gauge needle for intramuscular administration. Having cleaned an appropriate injection site and ensured that the needle is fixed securely, administer the suspension by subcutaneous or intramuscular injection as appropriate taking care not to enter a blood vessel. Apply sterile dressing to injection site if required.

The injection should be given as soon as possible after mixing. If any settling of suspension occurs in vial or syringe, re-suspend by gentle shaking and administer immediately.

No other fluid can be used for reconstitution of PROSTAP SR Powder.

Hypersensitivity to any of the ingredients or to synthetic Gn-RH or Gn-RH derivatives.

Women: PROSTAP is contra-indicated in women who are or may become pregnant while receiving the drug. PROSTAP should not be used in women who are breastfeeding or have undiagnosed abnormal vaginal bleeding.

Men: There are no known contra-indications to the use of PROSTAP in men.

Development or aggravation of diabetes may occur, therefore diabetic patients may require more frequent monitoring of blood glucose during treatment with PROSTAP.

Hepatic dysfunction and jaundice with elevated liver enzyme have been reported. Therefore, close observation should be made and appropriate measures taken if necessary.

Spinal fracture, paralysis, hypotension and worsening of depression have been reported.

Men: In the initial stages of therapy, a transient rise in levels of testosterone, dihydrotestosterone and acid phosphatase may occur. In some cases, this may be associated with a "flare" or exacerbation of the tumour growth resulting in temporary deterioration of the patient's condition. These symptoms usually subside on continuation of therapy. "Flare" may manifest itself as systemic or neurological symptoms in some cases.

In order to reduce the risk of “flare”, an anti-androgen may be administered beginning 3 days prior to leuprorelin therapy and continuing for the first two to three weeks of treatment. This has been reported to prevent the sequelae of an initial rise in serum testosterone.

Patients at risk of ureteric obstruction or spinal cord compression should be considered carefully and closely supervised in the first few weeks of treatment. These patients should be considered for prophylactic treatment with anti-androgens. Should urological/neurological complications occur, these should be treated by appropriate specific measures.

If an anti-androgen is used over a prolonged period, due attention should be paid to the contra-indications and precautions associated with its extended use.

Whilst the development of pituitary adenomas has been noted in chronic toxicity studies at high doses in some animal species, this has not been observed in long term clinical studies with PROSTAP.

Women: When considering the preoperative treatment of fibroids it is mandatory to confirm the diagnosis of fibroids and exclude an ovarian mass, either visually by laparoscopy or by ultrasonography or other investigative technique, as appropriate, before PROSTAP therapy is instituted.

During the early phase of therapy, sex steroids temporarily rise above baseline because of the physiological effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed during the initial days of therapy, but these will dissipate with continued therapy.

The induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible. The extent of bone demineralisation due to hypo-estrogenaemia is proportional to time and, consequently, is the adverse event responsible for limiting the duration of therapy to 6 months. The generally accepted level of bone loss with LHRH analogues such as PROSTAP is 5%. In clinical studies with PROSTAP the levels varied between 2.3% and 15.7% depending on the method of measurement. During one six-month treatment period, this bone loss should not be important. In patients with major risk factors for decreased bone mineral content such as chronic alcohol and/or tobacco use, strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, PROSTAP therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with PROSTAP is instituted. This is particularly important in women with uterine fibroids where age related bone loss may have already begun to occur.

Therefore, before using PROSTAP for the preoperative treatment of uterine fibroids, patients with major risk factors for decreased bone mineral content (see above) should have their bone density measured and where results are below the normal (5^th percentile by DEXA scan) range, PROSTAP therapy should not be started.

In women with submucous fibroids there have been reports of severe bleeding following the administration of PROSTAP as a consequence of the acute degeneration of the fibroids. Patients should be warned of the possibility of abnormal bleeding or pain in case earlier surgical intervention is required.

PROSTAP may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.

In women receiving GnRH analogues for the treatment of endometriosis, the addition of HRT (an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms.

Precautions

Men: Patients with urinary obstruction and patients with metastatic vertebral lesions should begin PROSTAP therapy under close supervision for the first few weeks of treatment.

Women: Since menstruation should stop with effective doses of PROSTAP, the patient should notify her physician if regular menstruation persists.

None have been reported.

Safe use of leuprorelin acetate in pregnancy has not been established clinically.

Studies in animals have shown reproductive toxicity (see section 5.3). Before starting treatment with PROSTAP, pregnancy must be excluded. There have been reports of foetal malformation when Prostap has been given during pregnancy.

PROSTAP should not be used in women who are breastfeeding.

When used monthly at the recommended dose, PROSTAP usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking PROSTAP and therefore patients should use non-hormonal methods of contraception during treatment.

Patients should be advised that if they miss successive doses of PROSTAP, breakthrough bleeding or ovulation may occur with the potential for conception. Patients should be advised to see their physician if they believe they may be pregnant. If a patient becomes pregnant during treatment, the drug must be discontinued. The patient must be appraised of this evidence and the potential for an unknown risk to the foetus.

The ability to drive and use machines may be impaired due to visual disturbances and dizziness.

Very rare cases of pituitary apoplexy have been reported following initial administration in patients with pituitary adenoma.

Side effects seen with PROSTAP are due mainly to the specific pharmacological action, namely increases and decreases in certain hormone levels. Adverse events which have been reported infrequently include peripheral oedema, pulmonary embolism, hypertension, palpitations, fatigue, muscle weakness, diarrhoea, nausea, vomiting, anorexia, fever/chills, headache (occasionally severe), hot flushes, arthralgia, myalgia, dizziness, insomnia, depression, paraesthesia, visual disturbances, weight changes, hepatic dysfunction, jaundice, increases in liver function test values (usually transient) and irritation at the injection site. Changes in blood lipids and alteration of glucose tolerance have also been reported which may affect diabetic control. Thrombocytopenia and leucopenia have been reported rarely. Hypersensitivity reactions including rash, pruritus, urticaria, and rarely, wheezing or interstitial pneumonitis have also been reported. Anaphylactic reactions are rare.

Spinal fracture, paralysis, hypotension and worsening of depression have been reported(see 'Special Warnings and Precautions for Use' section 4.4).

A reduction in bone mass may occur with the use of GnRH agonists.

Men: In cases where a "tumour flare" occurs after PROSTAP therapy, an exacerbation may occur in any symptoms or signs due to disease, for example, bone pain, urinary obstruction, weakness of the lower extremities and paraesthesia. These symptoms subside on continuation of therapy.

Impotence and decreased libido will be expected with PROSTAP therapy.

The administration of PROSTAP is often associated with hot flushes and sometimes sweating.

Orchiatrophy and gynaecomastia have been reported occasionally.

Women: Those adverse events occurring most frequently with PROSTAP are associated with hypo-estrogenism; the most frequently reported are hot flushes, mood swings including depression (occasionally severe), and vaginal dryness. Estrogen levels return to normal after treatment is discontinued.

The induced hypo-estrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible (see 'Special Warnings and Precautions for Use' section 4.4).

Breast tenderness or change in breast size may occur occasionally. Hair loss has also been reported occasionally.

Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see 'Special Warnings and Precautions for Use' section 4.4).

There is no clinical experience with the effects of an acute overdose of PROSTAP. In animal studies, doses of up to 500 times the recommended human dose resulted in dyspnoea, decreased activity and local irritation at the injection site. In cases of overdose, the patients should be monitored closely and management should be symptomatic and supportive.

PROSTAP is a synthetic nonapeptide analogue of naturally occurring gonadotrophin releasing hormone (GnRH) which possesses greater potency than the natural hormone. PROSTAP is a peptide and therefore unrelated to the steroids. Chronic administration results in an inhibition of gonadotrophin production and subsequent suppression of ovarian and testicular steroid secretion. This effect is reversible on discontinuation of therapy.

Administration of leuprorelin acetate results in an initial increase in circulating levels of gonadotrophins which leads to a transient increase in gonadal steroid levels in both men and women. Continued administration of leuprorelin acetate results in a decrease of gonadotrophin and sex steroid levels. In men serum testosterone levels, initially raised in response to early luteinising hormone (LH) release, fall to castrate levels in about 2-4 weeks. Estradiol levels will decrease to postmenopausal levels in premenopausal women within one month of initiating treatment.

The drug is well absorbed from the subcutaneous or intramuscular route, binds to luteinising hormone releasing hormone (LHRH) receptors and is rapidly degraded. In this dose form, an initial high level of leuprorelin in the plasma is achieved within 3 hours followed by a drop over 24-48 hours to maintenance levels of 0.3-0.8ng/ml and a slow decline thereafter. Effective levels persist for 30-40 days after a single dose. PROSTAP is inactive when given orally.

A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the 3.75mg and 11.25mg depots of leuprorelin. 48% of patients included had locally advanced disease (T3N0M0), 52% of patients had metastatic disease. Mean serum testosterone level fell below the threshold for chemical castration (0.5 ng/ml) at one month of treatment, continuing to decrease thereafter and stabilising at a value below the castration threshold. The decline in serum PSA mirrored that of serum testosterone in both groups.

In an open, prospective clinical trial involving 205 patients receiving 3.75mg leuprorelin on a monthly basis as treatment for metastatic prostate cancer, the long-term efficacy and safety of leuprorelin was assessed. Testosterone levels were maintained below the castrate threshold over the 63-month follow up period. Median survival time exceeded 42.5 months for those receiving monotherapy and 30.9 months for those receiving leuprorelin in combination with anti-androgens (this difference relating to baseline differences between groups)

In a meta-analysis involving primarily patients with metastatic disease, no statistically significant difference in survival was found for patients treated with LHRH analogues compared with patients treated with orchidectomy.

In another randomised, open-label, multi-centre comparative trial, leuprorelin in combination with flutamide has been shown to significantly improve disease-free survival and overall survival when used as an adjuvant therapy to radiotherapy in 88 patients with high-risk localised (T1-T2 and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3-T4) prostate cancer. The optimum duration of adjuvant therapy has not been established. This US study used a higher dose of leuprorelin (7.5mg/month) which is therapeutically equivalent to the European licensed dose.

The use of a LHRH agonist may be considered after prostatectomy in selected patients considered at high risk of disease progression. There are no disease-free survival data or survival data with leuprorelin in this setting.

Studies submitted show that single intramuscular or subcutaneous doses of leuprorelin acetate over the dose range 3.75 to 15mg results in detectable levels of leuprorelin for more than 28 days, good bioavailability, a consistent and predictable pharmacokinetic profile, and biological efficacy at plasma levels of less than 0.5ng/ml. The pharmacokinetic profile is similar to that seen in animal studies using the compound, with an initial high level of drug released from the microcapsules during reconstitution and injection followed by a plateau over a 2-3 week period before levels gradually become undetectable. There appears to be no significant difference between the routes of administration (im vs sc) in biological effectiveness or pharmacokinetics.

The metabolism, distribution and excretion of leuprorelin acetate in humans have not been fully determined.

A teratogenic effect has been observed in rabbits but not in rats.

PROSTAP SR Powder:

Gelatin, copoly (DL-lactic acid/glycolic acid) 75:25 mol%, mannitol.

Sterile Vehicle:

Each ml contains carmellose sodium 5mg, mannitol 50mg and polysorbate 80 1mg in water for injections.

None reported.

36 months unopened.

Chemical and Physical in-use stability has been demonstrated for 24 hours at 25^oC.

From a microbiological point of view, once reconstituted with Sterile Vehicle, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8^oC, unless reconstitution has taken place in controlled and validated aseptic conditions.

Do not store above 25^oC. Store in the original container and protect from light.

Vials containing 3.75mg leuprorelin acetate as microcapsule powder.

Prefilled syringes containing 1ml of Sterile Vehicle.

PROSTAP SR Powder 3.75mg: A sterile, lyophilised, white odourless PLGA microcapsule powder for subcutaneous or intramuscular injection after reconstitution with the Sterile Vehicle (4 week depot injection).

PLGA = copoly (DL-lactic acid/glycolic acid) 75:25mol%.

Sterile Vehicle: Prefilled syringes containing 1ml of clear, colourless, slightly viscous, Sterile Vehicle for reconstitution of the microcapsules.

Takeda UK Limited

Takeda House

Mercury Park

Wooburn Green

High Wycombe

Bucks. HP10 0HH

UK

PL 16189/0008 PROSTAP SR.

PL 16189/0010 Sterile Vehicle.

16 December 2004

02/06/2010

* Registered Trademark of Takeda Chemical Industries.