CAMCEVI 42mg long-release injection suspension medication leaflet

CAMCEVI 42 mg prolonged-release suspension for injection

Each pre-filled syringe with prolonged-release suspension for injection contains leuprorelinmesilate equivalent to 42 mg leuprorelin.

For the full list of excipients, see section 6.1.

Prolonged-release suspension for injection.

Pre-filled syringe with off-white to pale yellow viscous and opalescent suspension.

CAMCEVI is indicated for the treatment of hormone dependent advanced prostate cancer andfor the treatment of high-risk localised and locally advanced hormone dependent prostate cancerin combination with radiotherapy.

CAMCEVI should be administered under the direction of a healthcare professional havingavailable the appropriate expertise for monitoring the response to treatment.

CAMCEVI 42 mg is administered as a single subcutaneous injection every six months. Theinjected suspension forms a solid medicinal product delivery depot and provides continuousrelease of leuprorelin over a six-month period.

As a rule, therapy of advanced prostate cancer with leuprorelin entails long-term treatment andtherapy should not be discontinued when remission or improvement occurs.

Leuprorelin may be used as neoadjuvant or adjuvant therapy in combination with radiotherapyin high-risk localised and locally advanced prostate cancer.

Response to leuprorelin should be monitored by clinical parameters and by measuring prostatespecific antigen (PSA) serum levels. Clinical studies have shown that testosterone levelsincreased during the first 3 days of treatment in the majority of non-orchiectomised patients andthen decreased to below medical castration levels within 3 to 4 weeks. Once attained, castratelevels were maintained as long as leuprorelin therapy continued (<1% testosteronebreakthroughs). In case the patient’s response appears to be sub-optimal, it should be confirmedthat serum testosterone levels have reached or are remaining at castrate levels.

In patients with metastatic castration resistant prostate cancer not surgically castrated receivinga gonadotropin-releasing hormone (GnRH) agonist, such as leuprorelin, and eligible fortreatment with androgen biosynthesis inhibitors or androgen receptor inhibitors, treatment witha GnRH agonist may be continued.

No clinical studies were performed in patients having either renal or hepatic impairment.

The safety and efficacy of leuprorelin in children aged 0 to 18 years have not been established(see also section 4.3). No data are available.

CAMCEVI should be administered subcutaneously only by healthcare professionals who arefamiliar with these procedures. For instructions on administration of the medicinal product, seesection 6.6.

Intra-arterial or intravenous injection, respectively, has to be strictly avoided.

As with other medicinal products administered by subcutaneous injection, the injection siteshould be varied periodically.

CAMCEVI is contraindicated in women and paediatric patients.

Hypersensitivity to the active substance, to other GnRH agonists or to any of the excipientslisted in section 6.1.

Patients who previously underwent orchiectomy (as with other GnRH agonists, leuprorelin doesnot 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 spinalmetastases (see also section 4.4).

In patients with a history of or risk factors for QT prolongation and in patients receivingconcomitant medicinal products that might prolong the QT interval (see section 4.5) physiciansshould assess the benefit/risk ratio including the potential for Torsade de pointes prior toinitiating leuprorelin. Periodic monitoring of electrocardiograms and electrolytes should beconsidered.

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

Leuprorelin, like other GnRH agonists, causes a transient increase in serum concentrations oftestosterone, dihydrotestosterone and acid phosphatase during the first week of treatment.

Patients may experience worsening of symptoms or onset of new symptoms, including bonepain, neuropathy, haematuria, or ureteral or bladder outlet obstruction (see section 4.8). Thesesymptoms usually subside on continuation of therapy.

Additional administration of an appropriate antiandrogen should be considered beginning 3 daysprior to leuprorelin therapy and continuing for the first two to three weeks of treatment. This hasbeen reported to prevent the sequelae of an initial rise in serum testosterone.

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

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

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

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

During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndromesecondary 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 thefirst hour. In these cases, pituitary apoplexy was presented as sudden headache, vomiting, visualchanges, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse.

Immediate medical attention is required.

Metabolic changes

Hyperglycemia and an increased risk of developing diabetes have been reported in menreceiving GnRH agonists. Hyperglycemia may represent development of diabetes mellitus orworsening of glycemic control in patients with diabetes. Blood glucose and/or glycosylatedhaemoglobin (HbA1c) should be monitored periodically in patients receiving a GnRH agonistand patients should be managed with current practice for treatment of hyperglycemia ordiabetes. Metabolic changes associated with GnRH agonist may also include fatty liver disease.

Post-marketing reports of convulsions have been observed in patients on leuprorelin with orwithout a history of predisposing factors (see section 4.8). Convulsions are to be managedaccording to the current clinical practice.

Idiopathic intracranial hypertension:

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patientsreceiving leuprorelin. Patients should be warned for signs and symptoms of idiopathicintracranial hypertension, including severe or recurrent headache, vision disturbances andtinnitus. If idiopathic intracranial hypertension occurs, discontinuation of leuprorelin should beconsidered.

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 inassociation with leuprorelin treatment. At the time of prescription patients should be advised ofthe signs and symptoms and monitored closely for severe skin reactions. If signs and symptomssuggestive of these reactions appear, leuprorelin should be withdrawn immediately and analternative treatment considered (as appropriate).

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

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

No pharmacokinetic drug-drug interaction studies have been performed. There have been noreports of any interactions of leuprorelin with other medicinal products.

Since androgen deprivation treatment may prolong the QT interval, the concomitant use ofleuprorelin with medicinal products known to prolong the QT interval or medicinal productsable 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 malesof reproductive potential (see section 5.3).

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

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

The following undesirable effects were reported during clinical studies with leuprorelin-containing 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 forinjection

Infections and infestationscommon nasopharyngitisuncommon urinary tract infection, local skin infection

Blood and lymphatic systemdisorderscommon haematology changes, anaemia

Metabolism and nutritiondisordersuncommon aggravated diabetes mellitus

Psychiatric disordersuncommon abnormal dreams, depression, decreased libido

Nervous system disordersuncommon dizziness, headache, hypoaesthesia, insomnia, tastedisturbance, smell disturbance, vertigorare abnormal involuntary movementsnot known idiopathic intracranial hypertension (pseudotumor cerebri) (seesection 4.4)

Cardiac disordersuncommon QT prolongation (see sections 4.4 and 4.5), myocardialinfarction (see section 4.4)

Vascular disordersvery common hot flashesuncommon hypertension, hypotensionrare syncope, collapse

Respiratory, thoracic andmediastinal disordersuncommon rhinorrhoea, dyspnoeanot known interstitial lung disease

Gastrointestinal disorderscommon nausea, diarrhoea, gastroenteritis/colitisuncommon constipation, dry mouth, dyspepsia, vomitingrare flatulence, eructation

Skin and subcutaneous tissuedisordersvery common ecchymoses, erythemacommon pruritus, night sweatsuncommon clamminess, increased sweatingrare alopecia, skin eruption

Not known Stevens-Johnson syndrome/Toxic Epidermal Necrolysis(SJS/TEN) (see section 4.4)

Toxic Skin Eruption

Erythema Multiforme

Musculoskeletal andconnective tissues disorderscommon arthralgia, limb pain, myalgia, rigors, weaknessuncommon back pain, muscle cramps

Renal and urinary disorderscommon urinary infrequency, difficulty in micturation, dysuria,nocturia, oliguriauncommon bladder spasm, haematuria, aggravated urinaryfrequency, urinary retention

Reproductive system andbreast disorderscommon breast tenderness, testicular atrophy, testicular pain,infertility, breast hypertrophy, erectile dysfunction,reduced penis sizeuncommon gynaecomastia, impotence, testicular disorderrare breast pain

General disorders andadministration site conditionsvery common fatigue, injection site burning, injection site paraesthesiacommon malaise, injection site pain, injection site bruising, injection sitestinginguncommon injection site pruritus, injection site induration, lethargy, pain,pyrexiarare injection site ulcerationvery rare injection site necrosis

Investigationscommon increased blood creatinine phosphokinase, prolongedcoagulation timeuncommon increased alanine aminotransferase, increased bloodtriglycerides, prolonged prothrombin time, increased weight

Other undesirable effects which have been reported in general to occur with leuprorelintreatment include peripheral oedema, pulmonary embolism, palpitations, myalgia, an alterationin the skin sensation, muscle weakness, chills, rash, amnesia, and visual disturbances. Muscularatrophy has been observed with long-term use of medicinal products in this class. Infarction ofpre-existing pituitary adenoma has been reported rarely after administration of both short andlong 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 aresimilar to the local adverse reactions associated with similar subcutaneously injected medicinalproducts. Generally, these localised adverse reactions following subcutaneous injection are mildand described as being of brief duration.

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

Decreased bone density has been reported in the medical literature in men who have hadorchiectomy or who have been treated with a GnRH analogue. It can be anticipated that longperiods of treatment with leuprorelin may show increasing signs of osteoporosis. Regarding theincreased risk for fractures owing to osteoporosis (see section 4.4).

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

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

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. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reportingsystem listed in Appendix V.

Leuprorelin does not have the potential for abuse, and deliberate overdose is unlikely. There areno reports of abuse or overdose having occurred in clinical practice with leuprorelin, but in theevent that excessive exposure becomes a reality, observation and symptomatic supportivetreatment are recommended.

Pharmacotherapeutic group: Endocrine therapy, gonadotropin releasing hormone analogues;

ATC code: L02AE02

Leuprorelin mesilate is a synthetic nonapeptide agonist of naturally occurring GnRH that, whengiven continuously, inhibits pituitary gonadotropin secretion and suppresses testicularsteroidogenesis in males. This effect is reversible upon discontinuation of medicinal producttherapy. However, the agonist possesses greater potency than the natural hormone and the timeto recovery of testosterone levels may vary between patients.

Administration of leuprorelin results in an initial increase in circulating levels of luteinisinghormone (LH) and follicle stimulating hormone (FSH), leading to a transient increase in levelsof the gonadal steroids, testosterone and dihydrotestosterone in males. Continuousadministration of leuprorelin results in decreased levels of LH and FSH. In males, testosteroneis reduced to below castrate threshold (≤ 50 ng/dL).

Following the first dose of leuprorelin, mean serum testosterone concentrations transiently increased,then fell to below castrate threshold levels (≤ 50 ng/dL) within 3-4 weeks, and were maintained belowcastrate threshold with 6-monthly administration of the medicinal product (Figure 1 below).

Long-term studies on leuprorelin have shown that continuation of therapy maintainstestosterone below the castrate level for up to seven years, and presumably indefinitely.

Tumour size was not measured directly during the clinical trial programme, but there was anindirect beneficial tumour response as shown by a 97% reduction in mean PSA for leuprorelin.

In a phase III randomised clinical study including 970 patients with locally advanced prostatecancer (mainly T2c-T4 with some T1c to T2b patients with pathological regional nodal disease)of whom 483 were assigned to short-term androgen suppression (6 months) in combination withradiation therapy and 487 to long-term therapy (3 years), a non-inferiority analysis comparedthe short-term to long- term concomitant and adjuvant hormonal treatment with GnRH agonist(triptorelin or goserelin). The 5-year overall mortality was 19.0% and 15.2%, in the short-termand long-term groups, respectively. The observed hazard ratio (HR) of 1.42 with an upper one-sided 95.71% CI of 1.79 or two-sided 95.71% CI of 1.09; 1.85 (p=0.65 for non-inferiority),demonstrate that the combination of radiotherapy plus 6 months of androgen deprivationtherapy provides inferior survival as compared with radiotherapy plus 3 years of androgendeprivation therapy. Overall survival at 5 years of long-term treatment and short-term treatmentshows 84.8% and 81.0% survival, respectively. Overall quality of life using QLQ -C30 did notdiffer significantly between the two groups (p=0.37). Results are dominated by the populationof patients with locally advanced tumours.

Evidence for the indication of high-risk localised prostate cancer is based on published studiesof radiotherapy combined with GnRH analogues, including leuprorelin. Clinical data from fivepublished studies were analysed (EORTC 22863, RTOG 85-31, RTOG 92-02, RTOG 8610, and

D’Amico et al., JAMA, 2004), which all demonstrate a benefit for the combination of GnRHanalogue with radiotherapy. Clear differentiation of the respective study populations for theindications locally advanced prostate cancer and high-risk localised prostate cancer was notpossible in the published studies.

Clinical data have shown that radiotherapy followed by 3 years of androgen deprivation therapyis preferable to radiotherapy followed by 6 months of androgen deprivation therapy.

The recommended duration of androgen deprivation therapy in medical guidelines for T3-T4patients receiving radiotherapy is 2-3 years.

The multicentre, single-arm, open-label, 48-week phase 3 study of leuprorelin included137 male patients with high-risk localised and locally advanced prostate cancer in need forandrogen deprivation therapy. The efficacy of the medicinal product (two doses administered24 weeks apart) was evaluated by the percentage of subjects with serum testosteroneconcentrations suppressed to castrate threshold levels, the effect on serum LH levels as measurefor testosterone level control, and the effect on serum PSA levels.

The percentage of patients with serum testosterone levels below the castrate threshold(≤ 50 ng/dL) by day 28 was 98.5% (135 out of 137 patients; intent-to-treat) and 99.2% (123 outof 124 subjects; per protocol), respectively (Figure 1).

Figure 1: Mean serum testosterone concentration over time with CAMCEVI (n=124; perprotocol population)

Dotted line indicates the castrate level (50 ng/dL) of serum testosterone.

Mean serum LH levels were significantly reduced after the first injection, and this effectremained until the end of the study (decrease versus baseline by 98% [day 336]).

Tumour size was not directly measured in this study, but an indirect beneficial tumour responsecan be presumed for leuprorelin as shown by a significant reduction in mean PSA levels overtime after injection of the medicinal product (mean of 70 ng/mL at baseline decreased to a meanminimum of 2.6 ng/mL [per-protocol population] at Day 168.

The European Medicines Agency has waived the obligation to submit the results of studies withthe reference medicinal product containing leuprorelin in all subsets of the paediatric populationin prostate carcinoma (see section 4.2 for information on paediatric use).

Following the first and the second doses of leuprorelin, an initial rapid increase of serumleuprorelin concentration was observed, followed by a rapid decline over the first 3 days post-dose: after an initial “burst” phase characterised by mean serum leuprorelin concentrations of99.7 and 93.7 ng/mL after approximately 3.7 and 3.8 hours post dosing, respectively, meanserum leuprorelin levels maintained relatively constant over each 24-week dosing interval, withleuprorelin being continuously released by the third day after dosing with steady serumconcentrations ('plateau' phase) through the 24-week (approximately 6-month) dosing interval(mean concentration: 0.37 to 2.97 ng/mL). There is no indication of significant accumulationwith repeated leuprorelin dosing at 24-week intervals.

The initial acute increase of leuprorelin concentrations after CAMCEVI are followed by a rapiddecline to a steady state levels.

The pharmacokinetics/pharmacodynamics (as per serum testosterone level) profiles ofleuprorelin versus serum testosterone level observed after initial injection of CAMCEVI (firstdose) and at 24 weeks (second dose) is shown in Figure 2 (study FP01C-13-001; Part II).

Figure 2: Pharmacokinetic/pharmacodynamic response to CAMCEVI

The mean steady-state volume of distribution of leuprorelin following intravenous bolusadministration to healthy male volunteers was 27 litres. In-vitro binding to human plasmaproteins ranged from 43% to 49%.

No metabolism study was conducted with leuprorelin.

In healthy male volunteers, a 1 mg bolus of leuprorelin administered intravenously revealed thatthe mean systemic clearance was 8.34 L/h, with a terminal elimination half- life ofapproximately 3 hours based on a two-compartment model.

No excretion studies have been conducted with leuprorelin.

Preclinical studies with leuprorelin revealed in both sexes effects on the reproductive system,which were expected from the known pharmacological properties. These effects were shown tobe reversible after discontinuation of the treatment and an appropriate period of regeneration.

Leuprorelin did not show teratogenicity. Embryotoxicity/lethality was observed in rabbits, inline with the pharmacological effects of leuprorelin on the reproductive system.

Consistent with the GnRH agonistic effects of leuprorelin hyperplasia and adenoma wereobserved in the anterior pituitary of rats.

Carcinogenicity studies were performed in rats and mice over 24 months. In rats, a dose-relatedincrease in pituitary apoplexy was observed after subcutaneous administration at doses of 0.6 to4 mg/kg/day. No such effect was observed in mice.

Leuprorelin was not mutagenic in a set of in-vitro and in-vivo assays.

Poly(D,L-lactide)

N-methylpyrrolidone

Not applicable.

2 years.

Store in a refrigerator (2°C - 8°C).

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

One pack contains:1 pre-filled syringe (cyclic olefin copolymer, closed with bromobutyl elastomeric grey tip cap,plunger and finger grip), 1 sterile safety needle (18 gauge, 5/8 inch).

Follow the instructions as directed to ensure proper preparation of CAMCEVI prior toadministration.

Important: Prior to use allow CAMCEVI to reach room temperature (15 °C to 25 °C). The useof gloves is recommended during administration.

CAMCEVI contains:

* One blister containing one sterile pre-filled syringe;

* One sterile safety needle.

Assembled pre-filled syringe:

Step 1 - Prepare the medicinal product:

Allow to reach room temperature and inspectcontents

- Remove CAMCEVI from refrigerator.

- Prior to use allow CAMCEVI to reach roomtemperature (15 °C to 25 °C). This takesapproximately 15 to 20 minutes.

- On a flat, clean and dry surface open cartonand remove the blister container and thesachet. Remove the pre-filled CAMCEVIsyringe (A) from the blister container.

Remove the safety needle (B) from thesachet. Examine all contents of the package.

Do not use if any component is damaged.

- Check the expiry date on the syringe. Do notuse if the expiry date has passed.

- Visually inspect the medicine prior to use.

The pre-filled syringe should contain off-white to pale yellow viscous and opalescentsuspension. Do not use if foreign particles arenoticed inside the syringe barrel.

Step 2 - Syringe assembly:

Attach the needle - Remove the grey cap from the syringe (A).

- Attach the needle (B) to the end of thesyringe (A) by pushing and turningclockwise with approximately a three-quarter turn until the needle is secure. Donot overtighten. Discard pre-filled

CAMCEVI syringe if over-twist causessyringe breakage.

Step 3 - Administration procedure:

Prepare the injection site - Choose an injection site on the upper- ormid-abdominal area with sufficient soft orloose subcutaneous tissue that has notrecently been used. The injection siteshould be varied periodically.

- Clean the injection site with an alcoholswab. Do NOT inject in areas with brawnyor fibrous subcutaneous tissue or locationsthat can be rubbed or compressed (i.e., witha belt or clothing waistband).

- Pull the needle cap from the needle (B).

Grab and bunch the skin around theinjection site with one hand. Insert the

Administer treatment needle at a 90° angle, then release thebunched skin.

- Inject the full contents of the syringe with aslow and steady push, then withdraw theneedle at the same 90° angle used forinsertion.

Intra-arterial or intravenous injection have to be strictlyavoided.

Step 4 - Discard needle and pre-filled syringe

Needle Protection - Immediately following the withdrawal of the needle,activate the safety shield using a finger/thumb or flat

Thumb Surface surface and push until it completely covers the needleactivation activation tip and locks into place.

- An audible and tactile “click” verifies a lockedposition. Check to confirm the safety sheath is fullyengaged. After use, place the used syringe with needleprotected in a suitable sharps container.

Any unused medicinal product or waste materialshould be disposed of in accordance with localrequirements.

Accord Healthcare S.L.U.

World Trade Center,

Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039, Barcelona,

Spain

EU/1/22/1647/001

Date of first authorisation: 24 May 2022

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu.