LUTRATE 1 MONTH DEPOT 3.75 MG POWDER AND SOLVENT FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Lutrate 1 month Depot 3.75 mg powder and solvent for prolonged-release suspension for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 3.75 mg of leuprorelin acetate (equivalent to 3.57 mg leuprorelin free base).

1 ml of reconstituted suspension contains 1.875 mg of leuprorelin acetate.

Excipients with known effect:

Each vial contains from 1.3 to 2.2 mg (<1 mmol) of sodium (as carmellose sodium).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

Powder: white to off-white powder.

Solvent: clear transparent solution (pH 5.0 – 7.0).

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) As neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.

(vi) Management of estrogen dependant gynaecological disorders including the management of pain and lesions associated with endometriosis.

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

(viii) As treatment in pre- and perimenopausal women with advanced breast cancer suitable for hormonal manipulation.

(ix) As adjuvant treatment in combination with tamoxifen or an aromatase inhibitor, of endocrine responsive early stage breast cancer in pre- and perimenopausal women at higher risk of disease recurrence (young age, high grade tumour, lymph node involvement). In women who have received chemotherapy, premenopausal status must be confirmed after completion of chemotherapy.

(x) Preservation of ovarian function in pre-menopausal women with neoplastic disease undergoing chemotherapy treatment that can cause premature ovarian insufficiency. Lutrate 1 month Depot is not a replacement for standard fertility preservation methods. Treatment with a GnRH analogue should be proposed after careful evaluation, in each case, of the benefit/risk profile.

In children:

Treatment of central precocious puberty (girls under 9 years of age, boys under 10 years of age). (See section 5.1)

4.2 Posology and method of administration

Posology

The usual recommended dose of Lutrate 1 month Depot is 3.75 mg presented as a one month depot injection and administered as a single intramuscular injection every month.

The dose of Lutrate 1 month Depot allowing the continuous release of leuprorelin acetate during one month is incorporated in a depot formulation. The lyophilized powder should be reconstituted and administered as a single intramuscular injection at monthly intervals. Intra-arterial or intravenous administration must be avoided. The vial of Lutrate 1 month Depot microsphere powder should be reconstituted immediately prior to administration by intramuscular injection. As with other drugs administered regularly by injection, the injection site should be varied periodically.

Lutrate 1 month Depot therapy should not be discontinued when remission or improvement occurs.

Response to Lutrate 1 month Depot therapy should be monitored measuring serum levels of testosterone as well as prostate-specific antigen (PSA) periodically. Clinical studies have shown that testosterone levels increased during the first 4 days of treatment in the majority of non-orchiectomised patients. They then decreased and reached castrate levels by 3–4 weeks. Once attained, castrate levels (defined as concentration of testosterone less than 0.5 ng/mL) 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.

Lutrate 1 month Depot should be administered as monthly intramuscular injections. In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of castrate-resistant prostate cancer. Reference should be made to relevant guidelines.

Treatment options for vasomotor symptoms and bone mineral density loss should be considered.

Endometriosis:

The recommended dose is 3.75mg administered as a single intramuscular injection every month for a period of up to 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 Lutrate 1 month Depot taking into account the risks and benefits of each treatment. If Lutrate 1 month Depot is coadministered with HRT, treatment may be extended for up to 12 months in women with chronic symptomatic endometriosis.

Preoperative management of uterine fibroids:

The recommended dose is 3.75mg administered as a single intramuscular injection every month usually for 3–4 months but for a maximum of 6 months.

Advanced breast cancer:

The recommended dose is 3.75 mg administered as a single intramuscular injection every month.

Early breast cancer:

The recommended dose is 3.75 mg administered as a single intramuscular injection every month in combination with tamoxifen or an aromatase inhibitor.

In women receiving chemotherapy, leuprorelin should be commenced after completion of chemotherapy, once pre-menopausal status has been confirmed (see section 4.4).

The recommended treatment duration for adjuvant treatment in combination with other hormonotherapy is up to 5 years.

In combination with aromatase inhibitor for advanced and early breast cancer: Treatment with leuprorelin must be initiated at least 6–8 weeks before starting aromatase inhibitor treatment. A minimum of two injections of leuprorelin (with an interval of 1 month between injections) should be administered before commencement of aromatase inhibitor treatment.

Ovarian suppression should be confirmed by low blood concentrations of FSH and estradiol prior to starting aromatase inhibitor treatment and measurements should be repeated every three months during combination therapy with leuprorelin and an aromatase inhibitor (see section 4.4).

During treatment with an aromatase inhibitor, leuprorelin must not be interrupted to avoid rebound increases in circulating estrogens in premenopausal wo­men.

Preservation of ovarian function :

The recommended dose is 3.75 mg administered as a single subcutaneous or intramuscular injection. Patients should receive this dose 2 weeks before starting chemotherapy to allow time to achieve suppression of the sex hormone levels and then continue with monthly administration of Lutrate 1 month Depot for the duration of the chemotherapy treatment.

The treatment of children with leuprorelin acetate should be under the overall supervision of the paediatric endocrinologist.

The dosing scheme needs to be adapted individually.

The recommended starting dose is dependent on the body weight.

Children with a body weight > 20 kg:

The usual recommended dose of Lutrate 1 month Depot is 3.75 mg of leuprorelin acetate presented as a one-month depot injection and administered as a single intramuscular injection every month (the dose corresponds to 2 ml of reconstituted drug product (i.e. entire dose of drug product (see section 6.6))

Children with a body weight <20 kg:

In these rare cases the following dosage should be administered according to the clinical activity of the central precocious puberty: 1.88 mg leuprorelin acetate presented as a one-month depot injection and administered as a single intramuscular injection every month (the dose corresponds to 1 ml of reconstituted drug product (see section 6.6). The remainder of the suspension should be discarded. The child's weight gain should be monitored.

Depending on the activity of the central precocious puberty, it may be necessary to increase the dosage in the presence of inadequate suppression (clinical evidence e.g. spotting or inadequate gonadotropin suppression in the GnRH test). The minimal effective monthly dose to be administered should then be determined by means of the GnRH test.

It is recommended to use the lowest volumes possible for injections in children in order to decrease the inconvenience which is associated with the intramuscular injection.

Sterile abscesses at the injection site often occurred when leuprorelin acetate was administered intramuscularly at higher than the recommended dosages. Therefore, in such cases the absorption of leuprorelin acetate from the depot can be decreased (see section 4.4).

The duration of treatment depends on the clinical parameters at the start of treatment or during the course of treatment (final height prognosis, growth velocity, bone age and/or bone age acceleration) and is decided by the treating paediatrician together with the legal guardian and, if appropriate, the treated child. The bone age should be monitored during treatment at 6–12 month intervals.

In girls with bone maturation of older than 12 years and boys with bone maturation of older than 13 years discontinuation of treatment should be considered taking into account the clinical parameters.

In girls, pregnancy should be excluded before the start of treatment. The occurrence of pregnancy during treatment cannot be generally excluded. In such cases, medical advice should be sought.

Note:

The administration interval should be 30 ± 2 days in order to prevent the recurrence of precocious puberty symptoms.

Renal/hepatic impairment

The pharmacokinetics of Lutrate 1 month Depot in hepatically and renally impaired patients has not been determined.

Elderly

As for adults.

Method of administration

Lutrate 1 month Depot should be prepared, reconstituted and administered only by healthcare professionals who are familiar with these procedures.

Lutrate 1 month Depot must be administered via the intramuscular route only. Do not administer by any other route. If it is administered subcutaneously by mistake, the patient should be closely monitored since no data about other administration routes apart from intramuscular is available for Lutrate 1 month Depot. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindi­cations

Hypersensitivity to leuprorelin, any of the excipients (listed in section 6.1) or to other synthetic gonadotrophin releasing hormone (Gn-RH) analogues or Gn-RH derivatives.

Reports of anaphylactic reactions to synthetic GnRH or GnRH agonist analogues have been reported in the medical literature.

Previous orchiectomy.

Lutrate 1 month Depot must not be used as the only treatment in patients with prostate cancer and with evidence of spinal cord compression or spinal metastases.

Lutrate 1 month Depot is contraindicated in women who are or may become pregnant while receiving the drug.

Lutrate 1 month Depot should not be used in women who are breast-feeding or who have undiagnosed abnormal vaginal bleeding.

In the pre- and perimenopausal breast cancer setting: Initiation of aromatase inhibitor treatment before adequate ovarian suppression with leuprorelin has been achieved (see sections 4.2 and 4.4).

Lutrate 1-month Depot is contraindicated in:

Pregnancy and breast feeding

Undiagnosed vaginal bleeding

4.4 Special warnings and precautions for use

Lutrate 1 month Depot injectable suspension must be prepared at the time of use and, after reconstitution, used immediately

Treatment should be discontinued immediately if the patient develops any signs or symptoms suggestive of anaphylaxis/a­naphylactic reaction (dyspnoea, asthma, rhinitis, angioneurotic oedema or glottis, hypotension, urticaria, rash, pruritus or interstitial pneumonitis). Patients should be informed before starting treatment, warning them to discontinue it and consult their doctor if any of the above mentioned symptoms occur. Patients who have experienced a hypersensitivity reaction to leuprorelin should be closely monitored and should not be rechallenged with Lutrate 1 month Depot.

Seizures have been reported with the administration of leuprorelin acetate. These cases were observed in patients with a history of seizures, epilepsy, cerebrovascular disorders, anomalies or central nervous system tumours and in patients with concomitant medications that have been associated with seizures for example bupropion and selective inhibitors of serotonin reuptake (SSRIs). Seizures in patients in the absence of the any medical conditions mentioned above have also been reported.

There is an increased risk of incident depression (which may be severe) in patients undergoing treatment with GnRH agonists, such as leuprorelin acetate. Patients should be informed accordingly and treated as appropriate if symptoms occur.

Epidemiological data have shown that during androgen deprivation therapy changes in the metabolic condition (e.g. reduction in glucose tolerance or aggravation of preexisting diabetes) as well as an increased risk for cardiovascular diseases may occur. However, prospective data did not confirm the link between treatment with GnRH analogues and an increase in cardiovascular mortality. Patients at high risk for metabolic or cardiovascular diseases should be appropriately monitored. Diabetic patients may require more frequent monitoring of blood glucose during treatment with Lutrate 1 month Depot.

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

Fractured spine and paralysis have been reported with leuprorelin treatment

Sportsmen should take precaution as Lutrate 1 month Depot contains an ingredient which may give a positive test result in doping controls.

In the initial stages of Lutrate 1 month Depot treatment, as occurs during treatment with other GnRH agonists, a transient rise in levels of testosterone may occur. In some cases, this may be associated with a „flare“ or exacerbation of the tumour growth resulting in temporary worsening of prostate cancer symptoms. These symptoms usually subside on continuation of therapy (see section 4.8). „Flare“ may manifest itself as systemic or neurological symptoms in some cases (i.e. bone pain). 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. Also, cases of orchiatrophy and gynecomastia have been described with other GnRH agonists.

In patients treated with leuprorelin acetate, isolated cases of urethral obstruction (with or without haematuria) and spinal cord compression or metastatic vertebral lesions have been observed, which may contribute to paralysis with or without fatal complications. Patients at risk of urethral obstruction, spinal cord compression or metastatic vertebral lesions 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.

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with an LHRH agonist. Adding anti-androgenic therapy to the treatment regimen reduces bone loss, but increases the risk of other adverse effects such as clotting problems and oedema. If an anti-androgen is used over a prolonged period, due attention should be paid to the contraindications and precautions associated with its extended use. Patients at risk or with a medical history of osteoporosis should be considered carefully and closely supervised during treatment with leuprorelin acetate (see section 4.8).

Response to Lutrate 1 month Depot therapy should be monitored by clinical parameters and by measuring testosterone and PSA serum levels periodically.

Patients may experience metabolic changes (e.g. glucose intolerance or worsening of existing diabetes), hypertension, weight changes and cardiovascular disorders. 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 Lutrate 1 month Depot. Patients at high risk for metabolic or cardiovascular diseases should be carefully assessed before commencing treatment and adequately monitored during androgen deprivation therapy. Therapy with leuprorelin acetate results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprorelin acetate therapy may be affected.

Increased prothrombin time has been reported in patients under treatment with leuprorelin acetate.

Leuprorelin acetate should be used with precautions in the presence of, cardiovascular disease (including congestive heart failure condition), thromboembolism, oedema, depression and pituitary adenomas.

Leuprorelin acetate should be used with caution in patients with known bleeding disorders, thrombocytopenia or on treatment with anticoagulants.

Androgen deprivation therapy may prolong the QT interval.

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval (see section 4.5) physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Lutrate 1 month Depot.

Before starting treatment with leuprorelin acetate, pregnancy must be excluded (see section 4.3).

Since menstruation should stop with effective doses of Lutrate 1 month Depot, the patient should notify her physician if regular menstruation persists.

During treatment with leuprorelin acetate patients should be instructed to prevent conception e.g. with the use of non-hormonal methods until return of menses.”

Abnormal bleeding

Prior to administration of Lutrate 1 month Depot, undiagnosed vaginal bleeding must be investigated, diagnosis confirmed and relevant management initiated.

Initial increase in sex steroids

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.

Uterine fibroid diagnosis

In the case of uterine 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 techniques as appropriate, before Lutrate 1 month Depot therapy is instituted.

Uterine  fibroids

In women with submucous fibroids there have been reports of severe vaginal bleeding following administration of leuprorelin 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.

Cervical Resistance

Lutrate 1 month Depot may cause an increase in uterine cervical resistance, which may result in difficulty in dilating the cervix for intrauterine surgical procedures.

Bone density in patients with endometriosis or uterine fibroids

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 event responsible for limiting the duration of therapy to 6 months. The generally accepted level of bone loss with LHRH analogues such as Lutrate 1 month Depot is 5%. In clinical studies the levels varied between 2.3% and 15.7% depending on the method of measurement. During one 6 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, Lutrate 1 month Depot therapy may pose an additional risk. In these patients, the risks and benefits must be weighed carefully before therapy with Lutrate 1 month Depot is instituted.

In women receiving GnRH analogues for the treatment of uterine fibroids, the duration of administration of leuprorelin acetate should be limited to 6 months, as its use is associated with an increased risk of bone mineral loss (see Bone density, section 4.4). If it is necessary to resume administration of leuprorelin acetate, changes in bone parameters should be closely followed

Endometriosis

In women receiving GnRH analogues for the treatment of endometriosis, the duration of administration of leuprorelin acetate should be limited to 6 months, as its use is associated with an increased risk of bone mineral loss.

In women receiving GnRH analogues, the addition of HRT (an estrogen and progestogen) has been shown to reduce bone mineral density loss and vasomotor symptoms. Therefore, if appropriate, HRT may be co-administered with leuprorelin acetate, taking into account the risks and benefits of each medicinal product, for up to 12 months if clinically appropriate. If it is necessary to resume administration of leuprorelin acetate, changes in bone parameters should be closely followed.

Advanced and early breast cancer:

In order to ensure adequate ovarian suppression in pre- and perimenopausal women, treatment with leuprorelin should be administered for at least 6–8 weeks prior to commencement of an aromatase inhibitor, and monthly leuprorelin injections should be administered on schedule and without interruption throughout aromatase inhibitor treatment.

Women who are premenopausal at breast cancer diagnosis and who become amenorrhoeic following chemotherapy may or may not have continued estrogen production from the ovaries. Irrespective of menstrual status, premenopausal status should be confirmed following chemotherapy and before commencement of leuprorelin, by blood concentrations of estradiol and FSH within the reference ranges for premenopausal women, in order to avoid unnecessary treatment with leuprorelin in the event of a chemotherapy-induced menopause.

Following commencement of leuprorelin, it is important to confirm adequate ovarian suppression (gonadotrophin analogue induced menopause) by serial assessment of circulating FSH, and estradiol if this subset of women is to be considered for therapy with an aromatase inhibitor, in accordance with current clinical practice recommendations. Accordingly, ovarian suppression should be confirmed by low blood concentrations of FSH and estradiol prior to starting aromatase inhibitor treatment and measurements should be repeated every three months during combination therapy with leuprorelin and an aromatase inhibitor. This is to avoid aromatase inhibitor-induced rebound increase in circulating estrogen, with consequential implications for the breast cancer. Of note, circulating FSH levels are lowered in response to gonadotrophin analogue-induced ovarian suppression (induced menopause), unlike in a natural menopause where FSH levels are elevated.

Patients who have discontinued leuprorelin treatment should also discontinue aromatase inhibitors within 1 month of the last leuprorelin administration.

Particular attention should also be paid to the prescribing information of coadministered medicinal products, such as aromatase inhibitors, tamoxifen, CDK4/6 inhibitors, for relevant safety information when administered in combination with leuprorelin.

Bone mineral density should be assessed before starting treatment with leuprorelin, particularly in women who have additional risk factors for osteoporosis. These patients should be closely monitored and treatment for, or prophylaxis of, osteoporosis should be initiated when appropriate.

The risk of musculoskeletal disorders (including joint or musculoskeletal pain) when a GnRH agonist is used in combination with either an aromatase inhibitor or tamoxifen is approximately 89% with the aromatase inhibitor and approximately 76% with tamoxifen.

Hypertension has been reported as a targeted adverse event at a very common frequency with GnRH agonist in combination with either exemestane or tamoxifen.

Premenopausal women with breast cancer receiving GnRH agonist in combination with either exemestane or tamoxifen should have regular monitoring of cardiovascular risk factors and blood pressure.

Hyperglycaemia and diabetes were reported as targeted adverse events at a common frequency with a GnRH agonist in combination with either exemestane or tamoxifen. Premenopausal women with breast cancer receiving a GnRH agonist in combination with either exemestane or tamoxifen should have regular monitoring of risk factors for diabetes with blood glucose monitoring on a regular basis and appropriate antidiabetic treatment initiated, if appropriate, according to national guidelines.

Depression has been reported to occur in approximately 50% of patients treated with a GnRH agonist in combination with either tamoxifen or exemestane, but less than 5% of patients had severe depression (grade 3–4). Patients should be informed accordingly and treated as appropriate if symptoms occur. Patients with known depression or depression history should be carefully monitored during therapy.

Treatment of premenopausal women with endocrine responsive early stage breast cancer with leuprorelin in combination with tamoxifen or an aromatase inhibitor should follow a careful individual appraisal of the risks and benefits.

Before starting the therapy, a precise diagnosis of idiopathic and/or neurogenic central precocious puberty is necessary. In girls, pregnancy must be excluded (see section 4.3).

The therapy is a long-term treatment, adjusted individually. Lutrate 1 month Depot should be administered as precisely as possible in regular monthly periods. An exceptional delay of the injection date for a few days (30 ± 2 days) does not influence the results of the therapy.

In the event of a sterile abscess at the injection site (mostly reported after i.m. injection of higher than the recommended dosage) the absorption of leuprorelin acetate from the depot can be decreased. In this case the hormonal parameters (testosterone, oestradiol) should be monitored at 2-week intervals (see section 4.2).

The treatment of children with progressive brain tumours should follow a careful individual appraisal of the risks and benefits.

The occurrence of vaginal bleeding, spotting and discharge after the first injection may occur as a sign of hormone withdrawal in girls. Vaginal bleeding beyond the first/second month of treatment needs to be investigated.

Bone mineral density (BMD) may decrease during GnRH therapy for central precocious puberty. However, after cessation of treatment subsequent bone mass accrual is preserved and peak bone mass in late adolescence does not seem to be affected by treatment.

Slipped femoral epiphysis can be seen after withdrawal of GnRH treatment. The suggested theory is that the low concentrations of estrogen during treatment with GnRH agonists weakens the epiphysial plate. The increase in growth velocity after stopping the treatment subsequently results in a reduction of the shearing force needed for displacement of the epiphysis.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium- free’.

4.5 Interaction with other medicinal products and other forms of interaction

No pharmacokinetic-based drug-drug interaction studies have been conducted with leuprorelin acetate. However, because leuprorelin acetate is a peptide that is primarily degraded by peptidase and not by Cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, pharmacokinetic drug interactions would not be expected to occur.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Lutrate 1 month Depot with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy:

Lutrate 1 month Depot is contraindicated for use in pregnant women. Before starting treatment with Lutrate 1 month Depot, pregnancy must be excluded.

There have been reports of foetal malformation when leuprorelin injection has been given during pregnancy. Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy.

Breast-feeding:

It is not known whether leuprorelin acetate is excreted in human milk; therefore, Lutrate 1 month Depot must not be used in women who are breast-feeding. See section 4.3 Contraindi­cations.

When used monthly at the recommended dose, Lutrate 1 month Depot usually inhibits ovulation and stops menstruation. Contraception is not ensured, however, by taking Lutrate 1 month Depot and therefore, patients should use non-hormonal methods of contraception during treatment and after cessation of treatment until the return of menses.

Fertility:

Studies in animals have shown reproductive toxicity (see section 5.3).

Patients should be advised that if they miss successive doses of Lutrate 1 month Depot, 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.

In girls with central precocious puberty: See section 4.3 Contraindi­cations.

4.7 Effects on ability to drive and use machines

No specific studies on the effects of Lutrate 1 month Depot on the ability to drive and use machines have been performed. However, the ability to drive and use machines may be impaired due to visual disturbances and dizziness.

4.8 Undesirable effects

Adverse reactions seen with Lutrate 1 month Depot are due mainly to the specific pharmacological action, namely increases and decreases in certain hormone levels.

Unless otherwise specified, the following safety profile of Lutrate 1 month Depot is based on the results of a phase III clinical trial in which prostate cancer patients were treated with six intramuscular monthly doses of Lutrate 1 month Depot and followed up for total a period of 26 weeks. Most of the treatment-related AEs reported were the usual ones associated with testosterone suppressing therapy.

The most commonly reported adverse reactions with Lutrate 1 month Depot are hot flushes, injection site pain, injection site irritation, night sweats and headache.

The following adverse reactions from clinical investigations were listed below by system organ class and in order of decreasing incidence (very common: >1/10; common: >1/100 to <1/10; uncommon: > 1/1,000 to < 1/100 and not known (cannot be estimated from the available data)).

Table 1. Number and frequency of ADRs during Lutrate 1 month Depot 3.75 mg

therapy.

* In a post-marketing study the frequency of mood changes and depression in long term users was common.

In terms of severity, 98% of all treatment-related AEs were mild or moderate. Eighty-nine percentage (89%) of the hot flushes were reported as mild and nine percentage (9%) as moderate. Two cases of hot flushes (0.2%) were reported as severe.

A total of 35 local adverse reactions (LAR) at the injection site were reported by 29 patients (18.1%) during the study.

Local adverse reactions after Lutrate 1 month Depot 3.75mg are those typically reported with other similar products administered via intramuscular injection. Injection site pain, injection site irritation, injection site discomfort, injection site bruising and erythema were the most commonly reported. Uncommonly reported reactions were injection site reaction, swelling, injury and haemorrhage (Table 2)

Table 2. Frequency of patients with local adverse reactions during Lutrate 1 month Depot therapy.

*Subjects may fall into more than one category; LAR: local adverse reaction; SOC: System Organ Class.

In the presence of repeated administrations of Lutrate 1 month Depot, swelling (0.6%), pain (0.6%), bruising (0.6%) and irritation (0.6%) were reported as recurrent local adverse reactions. These events were all reported as not serious and mild. No patient discontinued therapy due to local adverse events.

In a phase I clinical trial (CRO-02–43) carried out in healthy subjects with Leuprolide Depot GP-Pharm 7.5 mg administered at single dose, one case of injection site induration was reported.

Other adverse events which have been reported to occur with leuprorelin acetate treatment include impotence, decrease in libido (both pharmacological consequences of testosterone deprivation), peripheral oedema, pulmonary embolism, palpitations, myalgia, muscle weakness, chills, dyspnoea, peripheral vertigo, rash, amnesia, visual disturbances , skin sensation, anaemia, hypersensitivity reactions (including rash, pruritus, urticaria, wheezing, fever, chills and anaphylactic reactions), weight fluctuation, decreased appetite, dizziness, parasthesiae, paralysis (see Section 4.4), seizure, hypertension, hypotension (see Section 4.4 and 4.5), hepatic function abnormal, hepatic function test abnormal (usually transient), bone pain, weakness of lower extremities, spinal fracture , reduction in bone mineral density, osteoporosis (including spinal fracture, see Section 4.4), urinary tract obstruction, testicular atrophy and gynaecomastia. Pituitary apoplexy has been reported following initial administration in patients with pituitary adenoma Infarction of pre-existing pituitary adenomas has been reported rarely after administration of both short and long acting LHRH agonists. There have been rare reports of thrombocytopenia and leucopoenia. Metabolic syndrome (including hypertension, dyslipidemia, insulin resistance, abnormal glucose tolerance)

Those adverse events occurring most frequently with leuprorelin 1 month Depot 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).

Vaginal haemorrhage may occur during therapy due to acute degeneration of submucous fibroids (see section 4.4).

The following adverse reactions from clinical investigations were listed below by system organ class and in order of decreasing incidence (very common: >1/10; common: >1/100 to <1/10; uncommon: > 1/1,000 to < 1/100, very rare> 1/10,000 to < 1/1,000 and not known (cannot be estimated from the available data)).

Table 3: Number and frequency of ADRs during leuprorelin 1 month Depot therapy in women.

In women with early breast cancer treated with a GnRH agonist in combination with tamoxifen or an aromatase inhibitor, the following side effects have been seen:

Very common: Nausea, fatigue, musculoskeletal disorders, osteoporosis, hot flushes, hyperhidrosis, insomnia, depression, libido decreased, vulvovaginal dryness, dyspareunia, urinary incontinence, hypertension.

Common: Diabetes mellitus, hyperglycaemia, injection site reaction, hypersensitivity fracture, embolism.

Uncommon: myocardial ischaemia, cerebral ischaemia, central nervous system haemorrhage.

Rare: QT prolongation

In the initial phase of therapy, a short-term increase as flare-up of the sex hormone level occurs, followed by a decrease to values within the pre-pubertal range. Due to this pharmacological effect, adverse events may occur particularly at the beginning of treatment.

The following adverse reactions from clinical investigations were listed below by system organ class and in order of decreasing incidence (common: >1/100 to <1/10; uncommon: > 1/1,000 to < 1/100, very rare: > 1/10,000 to < 1/1,000 and not known (cannot be estimated from the available data)).

Table 4: Number and frequency of ADRs during leuprorelin 1 month Depot therapy in pediatrics.

In general, the occurrence of vaginal spotting with continued treatment (subsequent to possible withdrawal bleeding in the first month of treatment) should be assessed as a sign of potential underdosage. The pituitary suppression should then be determined by an LHRH test

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA yellow card scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There is no clinical experience with the effects of an acute overdose of Lutrate 1 month Depot or leuprorelin acetate. In clinical trials using daily subcutaneous leuprorelin acetate in patients with prostate cancer, doses as high as 20 mg/day for up to two years caused no AEs differing from those observed with the 1 mg/day dose.

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 over dosage, the patient should be monitored closely and management should be symptomatic and supportive.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Endocrine therapy. Hormones and related agents. Gonadotropin-releasing hormones analogues; ATC code: L02AE02.

Mechanism of action

The chemical name of Leuprorelin acetate is 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-L-prolyl-ethylamide.

Leuprorelin acetate is inactive when given orally due to poor membrane permeability and an almost complete inactivation by intestinal proteolytic enzymes.

Leuprorelin acetate has potent GnRH agonist properties when given during short-term and intermittent therapy, however, when administered in a continuous, nonpulsatile manner, LHRH analogues induce inhibition of gonadotropin secretion and suppression of ovarian and testicular steroidogenesis. This effect is reversible on discontinuation of therapy.

Pharmacodynamic effects

Upon binding to pituitary LHRH receptors, leuprorelin acetate produces an initial increase in circulating levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in both men and women. In men, testosterone levels initially raised in response to early LH release, fall to castrate levels in about 2–4 weeks.. As a result, Leydig cells in the testes cease to produce testosterone, and the serum testosterone concentration declines to a castration level (less than 0.5 ng/mL) in about two to four weeks after initiation of treatment. Estradiol levels will decrease to postmenopausal levels in premenopausal women within one month of initiating treatment.

Clinical efficacy and safety

In an open-label, multicentre, multiple dose clinical study of Lutrate 1 month Depot, 160 patients with prostate cancer and no previous systemic cancer therapy, hormonal therapy for the treatment of prostate cancer, previous prostatic surgery neither previous orchiectomy, were enrolled. The objectives were to determine the efficacy and safety of Lutrate 1 month Depot when given to prostate cancer patients who could benefit from androgen deprivation therapy. Lutrate 1 month Depot was administered intramuscularly in 6 monthly doses.

Testosterone levels were monitored at different days during 168 days. As expected, after the first injection the mean testosterone levels rapidly increased from baseline levels (4.119±1.341 ng/mL), reaching peak levels (Cmax) of 6.598±2.249 ng/mL at the third day. After peaking, testosterone levels fell, and by day 21, 78.7% of the evaluable patients had achieved medical castration (defined as testosterone less than 0.5 ng/mL). By Day 28, 96.8% of the patients had achieved castrate levels, and 73.1% had reached levels of <0.2 ng/mL (Figure 1).

Figure 1. Mean (±SD) testosterone plasma levels during treatment with six monthly IM injections of Lutrate 1 month Depot 3.75 mg

Time (days)

Secondary efficacy endpoints included determination of serum LH, FSH and PSA concentrations. By day 14 and day 4 after the first Lutrate 1 month Depot injection, mean LH and FSH serum levels had decreased below the baseline concentrations. Concentrations remained well below baseline values from day 28 until the end of the study. During the treatment, mean PSA serum levels gradually decreased (first month) and then remained constantly below baseline level until the end of the study. However, a wide inter-individual variation in PSA concentrations was observed throughout the study.

The frequency of the acute on chronic response was 10.5 % and the frequency of testosterone breakthrough response was 11.8 %. No drug-related adverse events suggestive of a clinical testosterone flare (urinary retention, spinal cord compression, or exacerbation of bone pain) were reported in any of the patients showing a testosterone breakthrough effect.

Women (preservation of ovarian function):

In six observational studies monthly leuprorelin administered with chemotherapy appeared to have a protective effect (as assessed by clinical measures and symptoms of premature ovarian insufficiency) on subsequent ovarian function. In a prospective randomised controlled study in young premenopausal women with hormone receptor (HR) positive and HR negative breast cancer undergoing chemotherapy, concurrent treatment with monthly leuprorelin reduced the risk of developing premature ovarian insufficiency.

Reversible suppression of pituitary gonadotropin release occurs, with a subsequent decrease in oestradiol (E2) or testosterone levels to values in the pre-pubertal range.

Initial gonadal stimulation (flare-up) may cause vaginal bleeding in girls who are already post-menarchal at start of treatment.

Withdrawal bleeding may occur at the start of treatment. The bleeding normally stops as treatment continues.

The following therapeutic effects can be demonstrated:

– Suppression of basal and stimulated gonadotropin levels to pre-pubertal levels.

– Suppression of prematurely increased sexual hormone levels to pre-pubertal levels and arrest of premature menstruation;

– Arrest/involution of somatic pubertal development (Tanner stages);

– Improvement/nor­malisation of the ratio of chronological age to bone age;

– Prevention of progressive bone age acceleration;

– Decrease of growth velocity and its normalization;

– Increase in final height.

Treatment result is the suppression of the pathologically, prematurely activated hypothalamic-pituitary-gonadal axis according to pre-pubertal age.

In a long-term clinical trial in children treated with leuprorelin at doses up to 15mg monthly for > 4 years resumption of pubertal progression were observed after cessation of treatment. Follow up of 20 female subjects to adulthood showed normal menstrual cycles in 80% and 12 pregnancies in 7 of the 20 subjects including multiple pregnancies for 4 subjects.

5.2 Pharmacokinetic properties

Studies submitted with leuprorelin depot formulations 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

Absorption

Following three once-monthly injections of Lutrate 1 month Depot in a sample of prostate cancer patients (N=12), maximal leuprorelin acetate plasma concentration was similar among the three cycles. After first administration (Days 0–28), Cmax was 13,145.6±3,070­.6 pg/ml. Median time to achieve Cmax (Tmax) was 0.04 days, corresponding to 0.96 h (range 0.96 – 4.08 h).

Distribution

No drug distribution study was conducted with Lutrate 1 month Depot. However, in healthy male volunteers, the mean steady-state volume of distribution of leuprorelin acetate following bolus intravenous (IV) 1.0 mg dose was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.

Elimination

No drug metabolism or excretion study was conducted with Lutrate 1 month Depot.

Leuprorelin is expected to be metabolised to smaller inactive peptides that may be excreted or further catabolised.

In healthy male volunteers, a 1.0 mg bolus of leuprorelin acetate administered IV revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model.

Following administration of leuprorelin acetate to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.

Special Populations

Renal/hepatic impairment

The pharmacokinetics of the drug in hepatically and renally impaired patients has not been determined.

In Children

There appears to be no significant difference between the routes of administration (im vs sc) in biological effectiveness or pharmacokinetics. However, the following information related only to SC administration and Lutrate 1 month Depot is only for IM use.

Figure 1 presents leuprorelin serum levels after a single s.c. administration of leuprorelin acetate depot at a dosage of 30 jig/kg body weight. Peak serum levels are reached sixty minutes after administration (7.81 ± 3.59 ng/m)l. The AUC0–672 is 105.78 ± 52.40 ng x hr/ml.

Figure1: Leuprorelin serum levels after single s.c. administration of 30 microgram/kg body weight of leuprorelin acetate as Depot formulation (n=6) (Mean ± SD)

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

Excipients of the lyophilizate (vial):

Polysorbate 80

Mannitol (E-421)

Carmellose sodium (E-466)

Triethyl citrate

Poly (DL-lactide-co-glycolide) (PLGA)

Excipients of the solvent (prefilled syringe):

Mannitol (E-421)

Sodium hydroxide (for pH adjustment) Hydrochloric acid (for pH adjustment) Water for injection

6.2 Incompati­bilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

No other solvent other than the sterile solvent provided for Lutrate 1 month Depot can be used for the reconstitution of Lutrate 1 month Depot powder.

6.3 Shelf life

3 years unopened.

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

6.4 Special precautions for storage

Do not store above 25o C. Do not freeze.

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

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

The commercial kit includes:

1. One (1) type I glass vial containing 3.75 mg of leuprorelin acetate as a freeze-dried powder, sealed with a bromobutyl stopper and an aluminium flip-off cap.

2. One (1) type I glass prefilled syringe containing 2 ml of solvent sealed with an elastomer cap.

3. One (1) polycarbonate / HDPE adaptor system including one (1) sterile 20 gauge needle.

6.6 Special precautions for disposal

Method of administration

The vial of Lutrate 1 month Depot should be reconstituted immediately prior to administration by single intramuscular injection. Make sure an aseptic technique is followed.

The reconstituted product is a suspension of milky, white colour appearance.

7   MARKETING AUTHORISATION HOLDER

8 MARKETING AUTHORISATION NUMBER(S)

PL 25859/0007

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

04/03/2020