Camcevi ETM

Description for Camcevi ETM

CAMCEVI ETM is a sterile formulation of leuprolide mesylate for subcutaneous injection. CAMCEVI ETM is designed to deliver approximately 21 mg of leuprolide over 3 months.

Leuprolide mesylate is a synthetic nonapeptide analog of naturally occurring GnRH and is a GnRH agonist. The analog possesses greater potency than the natural hormone. The chemical name is 5-oxo-L- prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide mesylate (salt) with the following structural formula. The pH of 50 mg/mL solution of leuprolide mesylate in water is approximately 5.7.

CAMCEVI ETM is supplied as a kit with a pre-filled, single-dose, sterile syringe for subcutaneous injection. Each pre-filled syringe delivers 21 mg leuprolide (equivalent to approximately 24 mg leuprolide mesylate), poly (D, L-lactide-co-Glycolide) (160 mg) polymer and N-methyl-2-pyrrolidone (116 mg).

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Tumor Flare [see Warnings and Precautions (5.1)]
• Hyperglycemia and Diabetes [see Warnings and Precautions (5.2)]
• Cardiovascular Diseases [see Warnings and Precautions (5.3)]
• QT/QTc Prolongation [see Warnings and Precautions (5.4)]
• Convulsions [see Warnings and Precautions (5.5)]
• Severe Cutaneous Adverse Reactions [See Warnings and Precautions (5.6)]

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of CAMCEVI ETM was evaluated in an open-label, single arm, clinical trial (FP01C-17- 001), patients with advanced prostate cancer received CAMCEVI ETM administered subcutaneously at a dose of 21 mg on Day 0 and Day 84 [see Clinical Studies (14)]. Of 144 patients enrolled, 132 (92%) received both doses of CAMCEVI ETM.

Serious adverse reactions occurred in 6% of patients who received CAMCEVI ETM. Serious adverse reactions included acute myocardial infarction, cerebrovascular accident, drug induced liver injury, and pancreatitis (each 0.7%).

Permanent discontinuation of CAMCEVI ETM due to an adverse reaction occurred in 0.7% of patients (stroke).

The most common (≥5%) adverse reactions, including laboratory abnormalities, were increased triglycerides, increased alanine aminotransferase, hot flush, hypertension, decreased hemoglobin, increased sodium, increased aspartate aminotransferase, injection site reaction, weight increase, increased potassium, decreased neutrophils, and decreased white blood cells.

Table 1 summarizes the most common (≥5%) adverse reactions in FP01C-17-001.

Table 1: Adverse Reactions Occurring in ≥5% of Patients - FP01C-17-001

Adverse Reaction	All Grades N = 144 (%)	Grade 3-4a N = 144 (%)
Hot flush	24	0
Hypertensiona	15	0.7
Injection site reactionb	10	0
Weight increase	8	0
a Only includes a grade 3 adverse reaction. Hypertension includes blood pressure increased, essential hypertension, and hypertension. b Injection site reaction includes injection site erythema, hemorrhage, induration, nodule, localized edema; and injection site pain.

Clinically relevant adverse reactions in < 5% of patients who received CAMCEVI ETM included insomnia, acute myocardial infarction, cerebrovascular accident, diabetes mellitus, decreased libido, and electrocardiogram QT prolonged.

Table 2 summarizes laboratory abnormalities in FP01C-17-001.

Table 2: Laboratory Abnormalities Occurring in ≥5% of Patients - FP01C-17-001

Laboratory Abnormality	All Grades N = 144 (%)	Grade 3-4 a N = 144 (%)
Chemistry
Increased triglycerides	44	1.4
Increased alanine aminotransferase	28	0.7
Increased sodium	13	0
Increased aspartate aminotransferase	13	0
Increased potassium	7	0
Hematology
Decreased hemoglobin	15	0
Decreased neutrophils	6	0
Decreased white blood cells	6	0
a Only includes a grade 3 adverse reaction.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of leuprolide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

During postmarketing surveillance, which includes other dosage forms and other patient populations, the following adverse reactions were reported.

Allergic Conditions: anaphylactoid or asthmatic process, rash, urticaria, and photosensitivity reactions

Cardiovascular System: hypotension, myocardial infarction, pulmonary embolism

Central/Peripheral Nervous System: convulsion, peripheral neuropathy, spinal fracture/paralysis

Endocrine System: pituitary apoplexy, diabetes

Hepato-biliary disorder: drug-induced liver injury

Hematologic: white blood cells decreased

Psychiatric: mood swings, including depression, suicidal ideation and attempt

Respiratory, thoracic and mediastinal disorder: interstitial lung disease

Musculoskeletal System: decreased bone density, tenosynovitis-like symptoms, fibromyalgia

Skin and Subcutaneous: injection site reactions, SJS/TEN, DRESS, AGEP, dermatitis exfoliative, bullous dermatitis, and erythema multiforme

Urogenital System: prostate pain

Drug Interactions for Camcevi ETM

No information provided.

Warnings for Camcevi ETM

Included as part of the PRECAUTIONS section.

Precautions for Camcevi ETM

Tumor Flare

CAMCEVI ETM, like other GnRH agonists, causes a transient increase in serum levels of testosterone during the first week of treatment, declining thereafter to baseline levels or below by the end of the second week of treatment. Transient worsening of symptoms, or the occurrence of additional signs and symptoms of prostate cancer, may develop during the first few weeks of CAMCEVI ETM treatment. Patients treated with CAMCEVI ETM may experience a temporary increase in bone pain, which can be managed symptomatically.

Cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications.

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should be closely observed during the first few weeks of therapy.

Hyperglycemia and Diabetes

Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent the development of diabetes mellitus or worsening of glycemic control in patients with diabetes. Monitor blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving a GnRH agonist and manage with current practice for treatment of hyperglycemia or diabetes.

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 a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.

QT/QTc Prolongation

Androgen deprivation therapy may prolong the QT/QTc 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 drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

Convulsions

Convulsions have been reported in patients receiving GnRH agonists, like CAMCEVI ETM [see Adverse Reactions (6.2)]. Manage patients receiving a GnRH agonist who experience convulsions according to current clinical practice.

Severe Cutaneous Adverse Reactions

CAMCEVI ETM can cause severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). SCARs, including SJS/TEN, DRESS, and AGEP, occurred in patients receiving CAMCEVI ETM or other GnRH agonists; including cases with visceral involvement and/or requiring skin grafts [see Adverse Reactions (6.2)].

Monitor patients for the development of SCARs.

If a SCAR is suspected, interrupt CAMCEVI ETM until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other Grade 4 skin reactions, permanently discontinue CAMCEVI ETM.

Laboratory Tests

Monitor serum levels of testosterone following injection of CAMCEVI ETM. In the majority of patients treated with CAMCEVI ETM, testosterone levels increased above baseline during the first week, and then declined thereafter to castration levels (<50 ng/dL) within 4 weeks [see Clinical Studies (14) and Adverse Reactions (6)].

Embryo-Fetal Toxicity

Based on findings in animal studies and mechanism of action, CAMCEVI ETM can cause fetal harm when administered to a pregnant woman. In animal developmental and reproductive toxicology studies, administration of a monthly formulation of leuprolide on day 6 of pregnancy (sustained

exposure was expected throughout the period of organogenesis) caused adverse embryo-fetal toxicity in animals at doses less than the human dose based on body surface area using an

estimated daily dose. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Population (8.1), Clinical Pharmacology (12.1)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted with leuprolide in rats and mice. In rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group). In mice, no pituitary abnormalities were observed at a dose as high as 60 mg/kg for 2 years. Patients have been treated with leuprolide for up to 3 years with doses as high as 10 mg/day and for 2 years with doses as high as 20 mg/day without demonstrable pituitary abnormalities.

Mutagenicity studies have been performed with leuprolide using bacterial and mammalian systems. These studies provided no evidence of mutagenic potential.

Leuprolide may reduce male and female fertility. Administration of leuprolide to male and female rats at doses of 0.024, 0.24, and 2.4 mg/kg as monthly depot formulation for up to 3 months (approximately as low as 1/30 of the human dose based on body surface area using an estimated daily dose in animals and humans) caused atrophy of the reproductive organs, and suppression of reproductive function. These changes were reversible upon cessation of treatment.

OVERDOSES

No information provided.

Contraindications for Camcevi ETM

CAMCEVI ETM is contraindicated in patients known to be hypersensitive to GnRH, GnRH agonist analogs, or any of the excipients in CAMCEVI ETM. Anaphylactic reactions to GnRH agonist analogs have been reported in medical literature.

+

Clinical Pharmacology for Camcevi ETM

Mechanism Of Action

Leuprolide, a GnRH agonist, acts as an inhibitor of gonadotropin secretion. Animal and human studies indicate that following an initial stimulation of gonadotropins, chronic administration of leuprolide results in suppression of ovarian and testicular steroidogenesis. This effect is reversible upon discontinuation of drug therapy.

Pharmacodynamics

Mean serum testosterone concentrations transiently increased, then fell to below castrate threshold levels (< 50 ng/dL) within 4 weeks following administration of the dose of leuprolide, and generally remained below castrate thresholds levels throughout treatment.

In humans, subcutaneous administration of single daily doses of leuprolide result in an initial increase in circulating levels of LH and FSH, leading to a transient increase in levels of the gonadal steroids (testosterone and dihydrotestosterone in males). However, continuous daily administration of leuprolide results in decreased levels of LH and FSH. In males, testosterone is reduced to below castration levels. These decreases generally occur within 2 to 4 weeks after initiation of treatment, and castration levels of testosterone in prostatic cancer patients have been demonstrated for periods of up to 5 years.

Pharmacokinetics

Leuprolide concentration is variable, exhibiting an initial rapid increase followed by a rapid decline over the first 3 days before reaching steady concentrations for the duration of the dosing interval. The mean serum leuprolide C_max was 34.8 ng/mL following the first dose and 32.6 ng/mL following the second dose of CAMCEVI ETM. The mean serum leuprolide concentration was maintained at 0.32 – 1.91 ng/mL after Day 3 following the first dose and maintained at 0.23 – 2.02 ng/mL after Day 3 following the second dose. The mean AUC_{0-3 mon} was 80.1 day.ng/mL following the first dose and 92.9 day.ng/mL following the second dose of CAMCEVI ETM.

Absorption

The median Tmax of leuprolide was 4 hours following the first and second doses of CAMCEVI ETM.

Distribution

The mean steady-state volume of distribution of leuprolide was 27 L following an intravenous bolus in healthy male volunteers. Protein binding of leuprolide ranged from 43% to 49% in vitro.

Elimination

The mean systemic clearance was 7.6 L/h and terminal elimination half-life of approximately 3 hours following an intravenous bolus of leuprolide in healthy male volunteers.

Metabolism

Administration of radiolabeled leuprolide was metabolized to smaller inactive peptides which may then be further catabolized.

Excretion

Excretion of leuprolide has not been evaluated with CAMCEVI ETM.

Specific Populations

No clinically significant differences in the systemic exposure of leuprolide were observed based on age (51 to 89 years), race (White, Asian), or body weight (54 to 119 kg). The effect of renal or hepatic impairment on the pharmacokinetics of leuprolide has not been evaluated.

Patient Information for Camcevi ETM

Hypersensitivity

• Inform patients that if they have experienced hypersensitivity with other GnRH agonist drugs like CAMCEVI ETM, CAMCEVI ETM is contraindicated [see Contraindications (4)].

Tumor Flare

• Inform patients that CAMCEVI ETM can cause tumor flare during the first weeks of Inform patients that the increase in testosterone can cause an increase in urinary symptoms or pain. Advise patients to contact their healthcare provider if uretral obstruction, spinal cord compression, paralysis, or new or worsened symptoms occur after beginning CAMCEVI ETM treatment [see Warnings and Precautions (5.1)].

Hyperglycemia and Diabetes

• Advise patients that there is an increased risk of hyperglycemia and diabetes with CAMCEVI ETM therapy. Inform patients that periodic monitoring for hyperglycemia and diabetes is required when being treated with CAMCEVI ETM [see Warnings and Precautions (2)].

Cardiovascular Diseases

• Inform patients that there is an increased risk of myocardial infarction, sudden cardiac death, and stroke with CAMCEVI ETM treatment. Advise patients to immediately report signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (3)].

QT/QTc Prolongation

• Inform patients that CAMCEVI ETM can cause QT/QTc prolongation. Advise patients to immediately contact their healthcare provider in the event of syncope, presyncopal symptoms, or cardiac palpitations [see Warnings and Precautions (4)].

Convulsions

• Inform patients that there is an increased risk of convulsions with CAMCEVI ETM treatment. Advise patients to immediately contact their healthcare provider if they experience convulsions [see Warnings and Precautions (5)].

Severe Cutaneous Adverse Reactions

• Inform patients that severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which may be life threatening or fatal, may occur during treatment with CAMCEVI ETM. Advise patients to contact their healthcare provider or seek medical attention right away if they experience signs or symptoms of SCARs, e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy [see Warnings and Precautions (5.6)].

Injection Site Reactions

• Inform patients that injection site related adverse reactions may occur such as transient burning/stinging, pain, bruising, and Advise patients to contact their healthcare provider if they experience rash or severe injection site reactions [see Adverse Reactions (6.1)].

Urogenital Disorders

• Advise patients that CAMCEVI ETM may cause impotence.

Infertility

• Inform patients that CAMCEVI ETM may cause infertility [see Use In Specific Populations (8.3)]. 

Manufactured for:
Foresee Pharmaceuticals Co., Ltd.
Taipei City 115, Taiwan (R.O.C.) 

By:
Fareva Pau
Fareva Pau, Avenue du Bearn, IDRON, 64320, France