CAMCEVI Prolonged-release suspension for injection Ref.[50038] Active ingredients: Leuprorelin

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 leuprorelin. Periodic monitoring of electrocardiograms and electrolytes should be considered.

Cardiovascular diseases

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors when determining a treatment for patients with prostate cancer. Patients receiving GnRH agonists should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.

Transient testosterone flare

Leuprorelin, like other GnRH agonists, 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 symptoms, including bone pain, neuropathy, haematuria, or ureteral or bladder outlet obstruction (see section 4.8). These symptoms usually subside on continuation of therapy.

Additional administration of an appropriate antiandrogen should be considered beginning 3 days prior to leuprorelin 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.

Following surgical castration, leuprorelin does not lead to a further decrease in serum testosterone levels in male patients.

Bone density

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with GnRH agonists (see section 4.8).

Antiandrogen therapy significantly increases the risk for fractures owing to osteoporosis. Only limited data is available on this issue. Fractures owing to osteoporosis were observed in 5% of patients following 22 months of pharmacological androgen deprivation therapy and in 4% of patients following 5 to 10 years of treatment. The risk for fractures owing to osteoporosis is generally higher than the risk for pathological fractures.

Apart from long lasting testosterone deficiency, increased age, smoking and consumption of alcoholic beverages, obesity and insufficient exercise may have an influence on the development of osteoporosis.

Pituitary apoplexy

During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of GnRH agonists, with a majority occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy was presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention is required.

Hyperglycaemia and diabetes

Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Blood glucose and/or glycosylated haemoglobin (HbA1c) should be monitored periodically in patients receiving a GnRH agonist and patients should be managed with current practice for treatment of hyperglycemia or diabetes.

Convulsions

Post-marketing reports of convulsions have been observed in patients on leuprorelin with or without a history of predisposing factors (see section 4.8). Convulsions are to be managed according to the current clinical practice.

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.

Other events

Cases of ureteral obstruction and spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.

Patients with vertebral and/or brain metastases as well as patients with urinary tract obstruction should be closely monitored during the first few weeks of therapy.

No interaction studies have been performed. There have been no reports of any interactions of leuprorelin with other medicinal products.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use of leuprorelin 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).

CAMCEVI is contraindicated in women.

Based on findings in animals and mechanism of action, leuprorelin may impair fertility in males of reproductive potential (see section 5.3).

Leuprorelin-containing medicinal products have minor influence on the ability to drive and use machines. The administration of this medicinal product can cause fatigue, dizziness and visual disturbances (see sections 4.8). Patients should be advised not to drive or operate machinery if these adverse reactions occur.

Summary of the safety profile

Adverse reactions seen with leuprorelin-containing medicinal products are mainly subject to the specific pharmacological action of leuprorelin, namely increases and decreases in certain hormone levels. The most commonly reported adverse reactions are hot flushes, nausea, malaise and fatigue and transient local irritation at the site of injection. Mild or moderate hot flushes occur in approximately 58% of patients.

Tabulated list of adverse reactions

The following undesirable effects were reported during clinical studies with leuprorelincontaining medicinal products for injection in patients with advanced prostate carcinoma. Undesirable effects are classified, by frequency, as very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000) and very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1. Undesirable effects reported for leuprorelin-containing medicinal products for injection:

Description of selected adverse reactions

Other undesirable effects which have been reported in general to occur with leuprorelin 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 medicinal products in this class. Infarction of pre-existing pituitary adenoma has been reported rarely after administration of both short and long acting GnRH agonists. There have been rare reports of thrombocytopenia and leucopenia. Changes in glucose tolerance have been reported.

Convulsions have been reported after GnRH agonist analogue administration (see section 4.4).

Local adverse reactions reported after injection of leuprorelin-containing medicinal products are similar to the local adverse reactions associated with similar subcutaneously injected medicinal products. Generally, these localised adverse reactions following subcutaneous injection are mild and described as being of brief duration.

Anaphylactic/anaphylactoid reactions have been reported rarely after GnRH agonist analogue administration.

Changes in bone density

Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with GnRH analogues. It can be anticipated that long periods of treatment with leuprorelin may show increasing signs of osteoporosis. Regarding the increased risk for fractures owing to osteoporosis,see section 4.4.

Exacerbation of signs and symptoms of the disease

Treatment with leuprorelin can cause exacerbations of signs and symptoms of the disease during the first few weeks. If conditions such as vertebral metastases and/or urinary obstruction or haematuria are aggravated, neurological problems, such as weakness and/or paraesthesia of the lower limbs or worsening of urinary symptoms may occur.

Clinical experience on local skin tolerability with CAMCEVI

Local skin tolerability of CAMCEVI was assessed in the main study FP01C-13-001 per four aspects: itchiness, erythema, burning, and stinging sensation. Of the 137 subjects receiving subcutaneous injections of CAMCEVI, most subjects showed no to mild skin irritation after the injection. Generally, the reported localised events were mild to moderate and resolved.

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 national reporting system listed in Appendix V.

Not applicable.