Eligard 7.5 mg/22.5 mg/30 mg/45 mg

ELIGARD is indicated for the palliative treatment of advanced prostate cancer.

Posology

• ELIGARD is administered subcutaneously and provides continuous release of leuprolide acetate over a one-, three- or six-month treatment period.
• The injection delivers the dose of leuprolide acetate incorporated in a polymer formulation.

ELIGARD RECOMMENDED DOSING:

Method of administration

• Injection. Use aseptic technique throughout the procedure. The use of gloves is recommended during mixing and administration. Allow the product to reach room temperature before mixing. Once mixed, the product must be administered within 30 minutes or it should be discarded.

• ELIGARD is contraindicated in patients with hypersensitivity to leuprorelin acetate, GnRH agonist analogues or any of the excipients of ELIGARD listed in Section 6.1.
• Anaphylactic reactions to synthetic GnRH or GnRH agonist analogues have been reported in the literature.
• Pregnancy and lactation (see Section 4.6).
• ELIGARD is contraindicated in women and in paediatric patients.
• In patients who previously underwent orchiectomy (as with other GnRH agonists, ELIGARD does not result in further decrease of serum testosterone in case of surgical castration).
• As sole treatment in prostate cancer patients with spinal cord compression or evidence of spinal metastases (see also section 4.4).

Transient testosterone flare: ELIGARD causes a transient increase in serum concentrations of testosterone, dihydrotestosterone and acid phosphatase during the first week of treatment. Patients may experience worsening of symptoms or onset of new signs and symptoms during the first few weeks of treatment, including bone pain, neuropathy, haematuria, or bladder outlet obstruction (see section 4.8).

Other events: ELIGARD causes a transient increase in serum testosterone concentrations during the first one or two weeks of treatment. Therefore, potential exacerbation of signs and symptoms of the disease during the first few weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or haematuria. If these conditions are aggravated, it may lead to neurological problems such as weakness and/or paraesthesia of the lower limbs or worsening of urinary symptoms. Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.

Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

Cases of ureteral obstruction and/or spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with LH-RH agonists, such as ELIGARD. If spinal cord compression or ureteral obstruction develops, standard treatment of these complications should be instituted.

Hyperglycemia and diabetes: There is increased reporting of risk for hyperglycemia and developing diabetes and certain cardiovascular diseases (heart attack, sudden cardiac death, stroke) in men receiving GnRH agonists, such as ELIGARD, for prostate cancer; it is important for healthcare professionals to evaluate patients for risk factors for these diseases. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitoring of blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist is needed. Healthcare professionals should always carefully weigh the benefits and risks of using GnRH agonists, such as ELIGARD, before determining appropriate treatment for prostate cancer.

Cardiovascular: Androgen deprivation therapy may prolong the QT interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking medicines known to prolong the QT interval (see section 4.5). Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. Doctors should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating ELIGARD.

Laboratory tests: Response to ELIGARD may be monitored by measuring serum concentrations of testosterone and prostate-specific antigen (PSA) periodically. In the majority of patients, testosterone levels increased above baseline during the first week, declining thereafter to baseline levels or below by the end of the second week. Castrate levels were routinely reached within two to four weeks and once achieved was maintained for the duration of treatment.

Respiratory: There have been post-marketing reports of interstitial pneumonitis associated with leuprorelin use. Treatment should be discontinued immediately if the patient develops any signs or symptoms suggestive of interstitial lung disease.

Idiopathic intracranial hypertension: Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving leuprorelin. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, vision disturbances and tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of leuprorelin should be considered.

Severe cutaneous adverse reactions: Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), and Toxic epidermal necrolysis (TEN) which can be life-threatening or fatal, have been reported in association with leuprorelin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If signs and symptoms suggestive of these reactions appear, leuprorelin as contained in ELIGARD should be withdrawn immediately and an alternative treatment considered (as appropriate).

• No pharmacokinetic-based interaction studies were conducted with ELIGARD.
• Medicine/Laboratory test interactions:
• Therapy with ELIGARD results in suppression of the pituitary-gonadal system.
• Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after ELIGARD therapy may be affected.
• Since androgen deprivation treatment may prolong the QT interval, the concomitant use of ELIGARD with medicines known to prolong the QT interval or medicines able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) dysarrhythmic medicines, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated (see section 4.4).

Women of childbearing potential/ Contraception in males and females

No information available.

Pregnancy

ELIGARD is contraindicated in pregnancy (see section 4.3).

• ELIGARD is contraindicated in women and in paediatric patients and was not studied in women or children.
• ELIGARD can cause foetal harm when administered to pregnant women. Major foetal abnormalities were observed in rabbits but not in rats after administration of leuprolide acetate throughout gestation.
• There was increased foetal mortality and decreased foetal weights in rats and rabbits.
• The effects on foetal mortality are expected consequences of the alterations in hormonal levels brought about by ELIGARD.
• The possibility exists that spontaneous abortion may occur.

Breastfeeding

ELIGARD is contraindicated in lactation (see section 4.3).

Fertility

No information available.

ELIGARD may impair mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision, due to fatigue, dizziness and visual disturbances being possible side effects of treatment or resulting from the underlying disease.

Summary of the safety profile

During the clinical trials, injection sites were closely monitored. Local side effects at the injection site were as follows:

• Burning/ stinging sensation in 34, 6 % of injections for the 7,5 mg strength; 21,7 % of injections for the 22,5 mg strength; 20 % of injections for the 30 mg strength and 16 % of injections for the 45 mg strength.
• Pain in 4,3 % of injections for the 7,5 mg strength; 3,5 % of injections for the 22,5 mg strength; 2,3 % of injections for the 30 mg strength and 4,6 % of injections for the 45 mg strength.
• Erythema in 2,6 % of injections for the 7,5 mg strength; 0,9 % of injections for the 22,5 mg strength and 1,1 % of injections for the 30 mg strength.
• Bruising in 2,5 % of injections for the 7,5 mg strength; 1,7 % of injections for the 22,5 mg strength and 2,3 % of injections for the 45 mg strength.
• Pruritis in 1,4 % of injections for the 7,5 mg strength and 0,4 % of injections for the 22,5 mg strength.
• Induration in 0,4 % of injections for the 7,5 mg strength.
• Ulceration in 0,1 % of injections for the 7,5 mg strength.

The localised adverse events were non-recurrent over time. No patient discontinued therapy due to an injection site adverse event.

The following possibly or probably related systemic adverse events occurred during clinical trials of up to 6 months of treatment with ELIGARD and were reported in u2265 2 % of patients. Often, causality is difficult to assess in patients with metastatic prostate cancer. Reactions considered not product-related are excluded.

Body as a whole:

• Malaise and fatigue occurred in 17, 5 % of patients treated with the 7,5 mg strength; 6 % of patients treated with the 22,5 mg strength; 13,3 % of patients treated with the 30 mg strength and 11,7 % of patients treated with the 45 mg strength.
• Weakness occurred 3,6 % of patients treated with the 45 mg strength.

Nervous system disorders:

• Dizziness occurred in 3,3 % of patients treated with the 7,5 mg strength; and 4,4 % of patients treated with the 30 mg strength.

Vascular disorders:

• Hot flushes/ sweats occurred in 56,7 % of patients treated with the 7,5 mg strength; 56,4 % of patients treated with the 22,5 mg strength; 73,3 % of patients treated with the 30 mg strength and 57,7 % of patients treated with the 45 mg strength.

Renal/ urinary disorders:

• Urinary frequency occurred in 2,6 % of patients treated with the 22,5 mg strength and 2,2 % of patients treated with the 30 mg strength.
• Nocturia occurred in 2,2 % of patients treated with the 30 mg strength.

Gastro-intestinal disorders:

• Nausea occurred in 3,4 % of patients treated with the 22,5 mg strength and 2,2 % of patients treated with the 30 mg strength.
• Gastroenteritis/ colitis occurred in 2,5 % of patients treated with the 7,5 mg strength.

Skin and subcutaneous disorders:

• Pruritis occurred in 2,6 % of patients treated with the 22,5 mg strength.
• Clamminess occurred in 4,4 % of patients treated with the 30 mg strength.
• Night sweats occurred in 3,3 % of patients treated with the 30 mg strength and 2,7 % of patients treated with the 45 mg strength.
• Alopecia occurred in 2,2 % of patients treated with the 30 mg strength.

Musculoskeletal disorders:

• Arthralgia occurred in 3,4 % of patients treated with the 22,5 mg strength.
• Myalgia occurred in 2,2 % of patients treated with the 30 mg strength and 4,5 % of patients treated with the 45 mg strength.
• Pain in limbs occurred in 2,7 % of patients treated with the 45 mg strength.

Reproductive disorders:

• Testicular atrophy occurred in 5,0 % of patients treated with the 7,5 mg strength; 4,4 % of patients treated with the 30 mg strength and 7,2 % of patients treated with the 45 mg strength.
• Gynaecomastia occurred in 2,2 % of patients treated with the 30 mg strength and 3,6 % of patients treated with the 45 mg strength.
• Testicular pain occurred 2,2 % of patients treated with the 30 mg strength.

Psychiatric disorders:

• Decreased libido occurred in 3,3 % of patients treated with the 30 mg strength.

In addition, the following related systemic adverse events were reported by < 2 % of patients treated with ELIGARD:

• General disorders: Sweating, insomnia, syncope, rigors, weakness, lethargy.
• Gastrointestinal disorders: Flatulence, constipation, dyspepsia.
• Haematologic disorders: Decreased red blood cell count, haematocrit and haemaglobin.
• Metabolic disorders: Weight gain.
• Musculoskeletal disorder: Tremor, backache, joint pain, muscle atrophy, limb pain.
• Nervous system disorders: Disturbance of smell and taste, depression, vertigo.
• Reproductive/Urogenital disorders: Testicular soreness, impotence*, decreased libido*, gynaecomastia*, breast soreness/ tenderness*, testicular atrophy*, erectile dysfunction, penile disorder*, reduced penis size.
• Skin disorders: Alopecia, clamminess, night sweats*, increased sweating*.
• Vascular disorders: Hypertension, hypotension.

*Expected pharmacological consequences of testosterone suppression.

Tabulated list of additional adverse reactions

Body System Undesirable effect Very Common Common Uncommon Rare Very Rare Not known Infections and Infestations: nasopharyngitis urinary tract infection, local skin infection Metabolism and nutrition disorders: aggravated diabetes mellitus Psychiatric disorders: abnormal dreams Nervous system disorders: headache, hypoaesthesia abnormal involuntary movements idiopathic intracranial hypertension (pseudotumor cerebri) (see section 4.4) Cardiac disorders: QT prolongation (see sections 4.4 and 4.5) Vascular disorders: Collapse Respiratory, thoracic and mediastinal disorders: rhinorrhoea, dyspnoea interstitial lung disease Gastrointestinal disorders: diarrhoea, dry mouth, vomiting, eructation Skin and subcutaneous tissue disorders: ecchymoses, skin eruption, Stevens-Johnson syndrome/ Toxic Epidermal Necrolysis (SJS/TEN) (see section 4.4), Toxic Skin Eruption, Erythema Multiforme Musculoskeletal, connective tissue and bone disorders: muscle cramps Renal and urinary disorders: urinary infrequency, difficulty in micturation, dysuria, bladder spasm, haematuria, aggravated urinary frequency, urinary retention Reproductive system and breast disorders: infertility General disorders and administrative site conditions: injection site paraesthesia, pyrexia, injection site necrosis Investigations: increased blood creatinine phosphokinase, prolonged coagulation time, increased alanine aminotransferase, increased blood triglycerides, prolonged prothrombin time.

Description of selected adverse reactions

• Other adverse events which have been reported in general to occur with ELIGARD treatment include peripheral oedema, pulmonary embolism, palpitations, myalgia, an alteration in the skin sensation, muscle weakness, chills, rash, amnesia and visual disturbances.
• Muscular atrophy has been observed with long-term use of medicines in this class. Infarction of pre-existing pituitary apoplexy has been reported rarely after administration of both short and long-acting GnRH agonists such as ELIGARD.
• There have been rare reports of thrombocytopenia and leucopenia.
• Changes in glucose tolerance have been reported.
• Anaphylactic/anaphylactoid reactions have been reported rarely after ELIGARD (GnRH agonist analogue) administration.
• Changes in Bone Density: Decreased bone density has been reported in the medical literature in men who had orchiectomy or who have been treated with an LH-RH agonist analogue, such as ELIGARD. It can be anticipated that long periods of medical castration in men will have effects on bone density.
• Post-marketing experience: Cases of pituitary apoplexy have been reported. In the majority of cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status and sometimes cardiovascular collapse. Immediate medical attention has been required.
• Convulsions have been reported after GnRH agonist analogue administration, such as ELIGARD.
• Interstitial lung disease has been reported with an unknown frequency, in post marketing experience.

In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8). Treatment should be symptomatic and supportive.