Prostap 3 DCS

1. Name Of The Medicinal Product

PROSTAP^® 3 DCS 11.25 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled syringe

2. Qualitative And Quantitative Composition

PROSTAP 3 Powder: contains 11.25 mg leuprorelin acetate (equivalent to 10.72 mg base).

Sterile Solvent: Each ml contains carmellose sodium 5 mg, mannitol (E421) 50 mg, polysorbate 80 1 mg, glacial acetic acid up to 0.05 mg in Water for Injections.

When reconstituted with Sterile Solvent, the suspension contains 11.25 mg/ml leuprorelin acetate.

For full list of excipients, see section 6.1

3. Pharmaceutical Form

Powder and solvent for suspension for injection in pre-filled syringe

Powder: A sterile, lyophilised, white, odourless powder.

Solvent: A clear, odourless, slightly viscous, sterile solvent.

4. Clinical Particulars

4.1 Therapeutic Indications

(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.

(See Section 5.1)

4.2 Posology And Method Of Administration

Prostate Cancer: The usual recommended dose is 11.25 mg presented as a three month depot injection and administered as a single subcutaneous injection at intervals of three months. The majority of patients will respond to this dosage. PROSTAP 3 therapy should not be discontinued when remission or improvement occurs. As with other drugs administered regularly by injection, the injection site should be varied periodically.

Response to PROSTAP 3 therapy should be monitored by clinical parameters and by measuring prostate-specific antigen (PSA) serum levels. Clinical studies with leuprorelin acetate 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. If a patient's response appears to be sub-optimal, then it would be advisable to confirm that serum testosterone levels have reached or are remaining at castrate levels. 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 11.25 mg administered as a single intramuscular injection every 3 months 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 3 taking into account the risks and benefits of each treatment.

Elderly: As for adults.

Children: PROSTAP 3 is not recommended in children under 18 years due to insufficient data on safety and efficacy in this patient group.

Administration

The pre-filled syringe of PROSTAP 3 microsphere powder should be reconstituted immediately prior to administration by subcutaneous or intramuscular injection.

To prepare for injection, screw the plunger rod into the end stopper until the end stopper begins to turn.

While holding the syringe upright, depress the plunger slowly by pushing the plunger rod until the middle stopper is at the blue line in the middle of the barrel.

NOTE: Pushing the plunger rod quickly or over the blue line will cause leakage of the suspension from the needle.

Gently tap the syringe on the palm keeping the syringe upright to thoroughly mix the particles to form a uniform suspension. The suspension will appear milky.

NOTE: Avoid hard tapping to prevent the generation of bubbles.

Remove the sheath and advance the plunger rod to expel the air from the syringe.

Inject the entire contents of the syringe subcutaneously or intramuscularly as you would for a normal injection

4.3 Contraindications

Hypersensitivity to the active substance, any of the excipients or to synthetic gonadotrophin releasing homone (Gn-RH) or Gn-RH derivatives.

Women: PROSTAP 3 is contra-indicated in women who are or may become pregnant while receiving the drug. PROSTAP 3 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 3 in men.

4.4 Special Warnings And Precautions For Use

As would be expected with this class of drug, development or aggravation of diabetes may occur, therefore diabetic patients may require more frequent monitoring of blood glucose during treatment with PROSTAP 3.

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 acetate 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 leuprorelin acetate.

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

When receiving GnRH analogues for the treatment of endometriosis, the addition of HRT (an oestrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms (see 'Posology and Method of Administration' section 4.2 for further information).

The induced hypo-oestrogenic 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-oestrogenaemia 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 3 is 5%. In clinical studies with PROSTAP 3 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 3 therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with PROSTAP 3 is instituted.

In women with submucous fibroids there have been reports of severe bleeding following administration of PROSTAP 3 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 3 may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.

Precautions

Men: Patients with urinary obstruction and patients with metastatic vertebral lesions should begin PROSTAP 3 therapy under close supervision for the first few weeks of treatment.

Women: Since menstruation should stop with effective doses of PROSTAP 3, the patient should notify her physician if regular menstruation persists.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

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 3, pregnancy must be excluded. There have been reports of foetal malformation when PROSTAP 3 has been given during pregnancy.

PROSTAP 3 should not be used in women who are breastfeeding.

When used 3-monthly at the recommended dose, PROSTAP 3 usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking PROSTAP 3 and therefore patients should use non-hormonal methods of contraception during treatment.

Patients should be advised that if they miss successive doses of PROSTAP 3, 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 apprised of this evidence and the potential for an unknown risk to the foetus.

4.7 Effects On Ability To Drive And Use Machines

PROSTAP 3 can influence the ability to drive and use machines due to visual disturbances and dizziness.

4.8 Undesirable Effects

Side effects seen with PROSTAP 3 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 Section 4.4).

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

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

Men: In cases where a "tumour flare" occurs after PROSTAP 3 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 3 therapy.

The administration of PROSTAP 3 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 3 are associated with hypo-oestrogenism; the most frequently reported are hot flushes, mood swings including depression (occasionally severe), and vaginal dryness. Oestrogen levels return to normal after treatment is discontinued.

The induced hypo-oestrogenic state results in a small loss in bone density over the course of treatment, some of which may not be reversible (see 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 Section 4.4).

4.9 Overdose

No case of overdose has been reported.

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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Gonadotrophin-Releasing Hormone Analogues

ATC code: L02AE 02

PROSTAP 3 contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring gonadotrophin releasing hormone (GnRH) which possesses greater potency than the natural hormone. Leuprorelin acetate 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.

Leuprorelin acetate is inactive when given orally.

A randomised, open-label, comparative multi-centre study was performed to compare the efficacy and safety of the 3.75 mg and 11.25 mg depots of leuprorelin acetate. 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 3.75 mg leuprorelin acetate on a monthly basis as treatment for metastatic prostate cancer, the long-term efficacy and safety of leuprorelin acetate 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 acetate 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 acetate 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 10ng/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 acetate (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 acetate in this setting.

5.2 Pharmacokinetic Properties

Leuprorelin acetate is well absorbed after subcutaneous and intramuscular injections. It binds to the LHRH receptors and is rapidly degraded. An initially high plasma level of leuprorelin acetate peaks at around 3 hours after a PROSTAP 3 subcutaneous injection, followed by a decrease to maintenance levels in 7 to 14 days. PROSTAP 3 provides continuous plasma levels for up to 117 days resulting in suppression of testosterone to below castration level within 4 weeks of the first injection in the majority of patients.

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

5.3 Preclinical Safety Data

Animal studies have shown that leuprorelin acetate has a high acute safety factor. No major overt toxicological problems have been seen during repeated administration. 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. No evidence of mutagenicity or teratogenicity has been shown. Animal reproductive studies showed increased foetal mortality and decreased foetal weights reflecting the pharmacological effects of this LHRH agonist.

6. Pharmaceutical Particulars

6.1 List Of Excipients

PROSTAP 3 Powder

Poly (D-L lactic acid)

Mannitol (E421)

Sterile Solvent

Carmellose sodium

Mannitol (E421)

Polysorbate 80

Glacial Acetic Acid (for pH adjustment)

Water for Injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years unopened.

Once reconstituted with sterile solvent, the suspension should be administered immediately.

6.4 Special Precautions For Storage

Do not store above 25^oC.

Do not refrigerate or freeze.

Store in the original container in order to protect from light.

6.5 Nature And Contents Of Container

One dual chamber pre-filled syringe containing 11.25 mg leuprorelin acetate powder in the front chamber and 1 ml of Sterile Solvent in the rear chamber.

1 x 23 gauge syringe needle

1 x syringe plunger

1 x injection site swab

6.6 Special Precautions For Disposal And Other Handling

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Takeda UK Limited

Takeda House

Mercury Park

Wooburn Green

High Wycombe

Bucks., HP10 0HH

UK

8. Marketing Authorisation Number(S)

16189/0013

9. Date Of First Authorisation/Renewal Of The Authorisation

28/04/2011

10. Date Of Revision Of The Text

28/04/2011