LUTRATE DEPOT Powder and solvent for prolonged-release suspension for injection Ref.[6974] Active ingredients: Leuprorelin

In the initial stages of Lutrate 1 month Depot treatment, as occurs during treatment with other LHRH 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...). Also, cases of orchiatrophy and gynecomastia have been described with other LHRH agonists.

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.

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.

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.

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).

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.

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.

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.

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

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

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.

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).

Pregnancy

Lutrate 1 month Depot is not indicated for use in pregnant women.

Leuprorelin acetate injection may cause foetal harm when administered to a pregnant woman.

Therefore, the possibility exists that spontaneous abortion may occur if the drug is administered during pregnancy.

Breast-feeding

Lutrate 1 month Depot should not be used in women who are breast-feeding.

Fertility

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

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.

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).

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

Category SOC
Frequency: Preferred Term

Metabolism and nutrition disorders

Common: Decreased appetite

Uncommon: Hypercholesterolaemia, hyperlipidaemia

Psychiatric disorders

Uncommon: Sleep disorders, insomnia, libido decreased, mood changes, anorexia and depression*

Nervous system disorders

Common: Headache

Uncommon: Somnolence

Ear and labyrinth disorders

Uncommon: Vertigo

Vascular disorder

Very common: Hot flush

Gastrointestinal disorders

Uncommon: Abdominal pain lower, diarrhoea, nausea, vomiting

Hepatobiliary disorders

Uncommon: Hyperbilirubinaemia

Skin and subcutaneous tissue disorders

Common: Hyperhidrosis, night sweats, cold sweats

Uncommon: Periorbital edema, urticaria, pruritus,

Musculoskeletal and connective tissue disorders

Common: Back pain

Uncommon: Arthralgia, muscle spasms, pain in extremity

Renal and urinary disorders

Uncommon: Urinary retention, urinary incontinence, pollakiuria

Reproductive system and breast disorders

Common: Erectile dysfunction

Uncommon: Breast swelling, breast tenderness, ejaculation failure

General disorders and administration site conditions

Common: Fatigue, asthenia, pyrexia, local adverse reactions (see table 2)

Uncommon: Weakness, feeling hot and cold, feeling jittery

Investigations

Common: Weight gain

Uncommon: Increased AST, increased ALT, bilirubin increased, gamma-glutamyltransferase increased, electrocardiogram QT prolonged (see sections 4.4 and 4.5).

* 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 sitebruising 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 and skin sensation. 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. Changes in glucose tolerance have been reported.

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

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.