1. Name Of The Medicinal Product
PROSTAP® SR DCS 3.75 mg Powder and Solvent for Prolonged-release Suspension for Injection in Pre-filled Syringe
2. Qualitative And Quantitative Composition
PROSTAP SR Powder: contains 3.75 mg leuprorelin acetate (equivalent to 3.57 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 3.75 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.
(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)
4.2 Posology And Method Of Administration
Prostate Cancer: The usual recommended dose is 3.75 mg presented as a one month depot injection and administered as a single subcutaneous or intramuscular injection every month. The majority of patients will respond to a 3.75 mg dose. PROSTAP SR 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 SR therapy may be monitored by clinical parameters and by measuring serum levels of testosterone and acid phosphatase. 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 3.75 mg 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 SR taking into account the risks and benefits of each treatment.
Endometrial preparation prior to intrauterine surgery: A single 3.75 mg 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 3.75 mg 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: PROSTAP SR 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 SR 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 SR is contra-indicated in women who are or may become pregnant while receiving the drug. PROSTAP SR 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 SR 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 SR.
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: 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 SR 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 SR is 5%. In clinical studies with PROSTAP SR 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 SR therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with PROSTAP SR 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 SR 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 (5th percentile by DEXA scan) range, PROSTAP SR therapy should not be started.
In women with submucous fibroids there have been reports of severe bleeding following the administration of PROSTAP SR 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 SR 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 SR therapy under close supervision for the first few weeks of treatment.
Women: Since menstruation should stop with effective doses of PROSTAP SR, 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 SR, pregnancy must be excluded. There have been reports of foetal malformation when PROSTAP SR has been given during pregnancy.
PROSTAP SR should not be used in women who are breastfeeding.
When used monthly at the recommended dose, PROSTAP SR usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking PROSTAP SR and therefore patients should use non-hormonal methods of contraception during treatment.
Patients should be advised that if they miss successive doses of PROSTAP SR, 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 SR can influence the ability to drive and use machines due to visual disturbances and dizziness.
4.8 Undesirable Effects
Side effects seen with PROSTAP SR 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 SR 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 SR therapy.
The administration of PROSTAP SR 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 SR 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 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 SR contains leuprorelin acetate, a synthetic nonapeptide analogue of naturally occurring 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. 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 acetate 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.
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 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 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
Studies submitted show that single intramuscular or subcutaneous doses of leuprorelin acetate over the dose range 3.75 to 15 mg results in detectable levels of leuprorelin acetate for more than 28 days, good bioavailability, a consistent and predictable pharmacokinetic profile, and biological efficacy at plasma levels of less than 0.5 ng/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.
5.3 Preclinical Safety Data
A teratogenic effect has been observed in rabbits but not in rats.
6. Pharmaceutical Particulars
6.1 List Of Excipients
PROSTAP SR Powder
Gelatin
Copoly (DL lactic acid/glycolic acid) 72:25 mol%
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 25oC.
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 3.75 mg leuprorelin acetate powder in the front chamber and 1 ml of Sterile Solvent in the rear chamber.
1 x 25 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)
16189/0012
9. Date Of First Authorisation/Renewal Of The Authorisation
28/04/2011
10. Date Of Revision Of The Text
28/04/2011
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