Camcevi Etm Injection, Emulsion
FDA Label NDC 72851-100

CAMCEVI ETM is indicated for the treatment of adult patients with advanced prostate cancer.

The recommended dose of CAMCEVI ETM is 21 mg administered subcutaneously once every 3 months.

In patients treated with GnRH analogues for prostate cancer, treatment is usually continued upon development of metastatic castration-resistant prostate cancer.

CAMCEVI ETM must be administered by a healthcare provider.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Important: Read the instructions completely before you administer CAMCEVI ETM for the first time. Do NOT substitute any of the components from the kit for administration.

CAMCEVI ETM is packaged in a blister in the kit. Check to make sure the kit contains:

• One sterile, single-dose pre-filled syringe with plunger rod and backstop
• One sterile 18-gauge SurGuard^®3 safety needle, 5/8-inch needle
• Prescribing Information

Follow the detailed instructions to ensure correct preparation of CAMCEVI ETM prior to administration:

	STEP 1 Remove CAMCEVI ETM kit from refrigerator. Keep the contents in their original, sealed blister carton and allow to sit at room temperature for 30 minutes before use. Return to refrigerator after 30 minutes if not used.
Image1 (Camcevi Inj Image 1) Image2 (Camcevi Inj Image 2)	STEP 2 On a clean, dry surface, open carton and remove the contents. Examine all contents of the package. Do not use if any component is damaged. Check the expiration date on the syringe. Do not use if the expiration date has passed. The use of gloves is recommended during syringe assembly and administration.
Image3 (Camcevi Inj Image 3)	STEP 3 Remove pre-filled syringe (A) from the blister tray and open the safety needle (B) package by peeling back the paper tab. The safety needle (B) package is located beneath the blister tray. Visually inspect the syringe for particular matter prior to administration. The emulsion should appear off-white to pale yellow, viscous, and opalescent. Do not use if particulate matter is observed prior to administration.
Image4 (Camcevi Inj Image 4)	STEP 4 Remove the gray cap from the syringe (A). Attach the needle (B) to the end of the syringe (A) by gently screwing clockwise with approximately a three-quarter turn until the needle is secure. Do not overtighten, as the needle hub may become damaged resulting in leakage of the product during injection. The safety sheath may also be damaged if the needle is overtightened onto the syringe. See figure of assembled pre-filled syringe below. Image5 (Camcevi Inj Image 5)
Image6 (Camcevi Inj Image 6)	STEP 5 Choose an injection site on the upper- or mid-abdominal area with sufficient soft or loose subcutaneous tissue that has not recently been used. Clean the injection site with an alcohol swab. Do NOT inject in areas with brawny or fibrous subcutaneous tissue or locations that can be rubbed or compressed (i.e., with a belt or clothing waistband). In addition, avoid applying heat directly to the site of CAMCEVI ETM injection.
Image7 (Camcevi Inj Image 7)	STEP 6 (1) Move the safety sheath away from the needle and towards the syringe and (2) remove the clear needle cover immediately before injection. Note: Should the needle hub appear to be damaged, or leak, the product should NOT be used. The damaged needle should NOT be replaced and the product should NOT be injected. In the event of damage to the needle hub, use a new replacement CAMCEVI ETM kit.
Image8 (Camcevi Inj Image 8)	STEP 7 Use standard aseptic technique when performing the injection. Grab and bunch the skin around the injection site with one hand. Insert the needle at a 90° angle to the skin surface, and then release the bunched skin.
	STEP 8 Inject the full contents of the syringe with a slow and steady push on the plunger, and then withdraw the needle at the same 90° angle used for insertion.
Image Description (Camcevi Inj Image 9)	STEP 9 Immediately following the withdrawal of the needle, activate the safety sheath using a finger/thumb or flat surface and push until it completely covers the needle tip and locks into place. An audible and tactile “click” verifies a locked position. Check to confirm the safety sheath is fully engaged.
	STEP 10 After use, discard all components safely in a suitable sharps container. Dispose of the syringe and contaminated products according to local regulations/procedures.

Injectable emulsion: 21 mg leuprolide (equivalent to approximately 24 mg leuprolide mesylate) as a sterile, off-white to pale yellow, viscous, and opalescent emulsion in a single-dose, pre-filled syringe for subcutaneous injection.

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.

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 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.

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.

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 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.

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.

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)].

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)].

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)]

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.

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.

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

Risk Summary

Based on findings in animal studies and mechanism of action, CAMCEVI ETM can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. 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 (see data). Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

Data

Animal Data

Major fetal malformations were observed in developmental and reproductive toxicology studies in rabbits after a single administration of a monthly formulation of leuprolide administered on day 6 of pregnancy at test dosages of 0.00024, 0.0024, and 0.024 mg/kg (approximately 1/1500 to 1/15 the human dose based on body surface area using an estimated daily dose in animals and humans). Since a depot formulation was utilized in the study, a sustained exposure to leuprolide was expected throughout the period of organogenesis and to the end of gestation. Similar studies in rats did not demonstrate an increase in fetal malformations, however, there was increased fetal mortality and decreased fetal weights with the two higher doses of the monthly formulation of leuprolide in rabbits and with the highest dose in rats.

Risk Summary

The safety and efficacy of CAMCEVI ETM have not been established in females. There is no information regarding the presence of leuprolide in human milk, the effects on the breast-fed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Infertility

Males

Based on findings in animals and mechanism of action, CAMCEVI ETM may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

The safety and efficacy of CAMCEVI ETM in pediatric patients have not been established.

Of the 144 patients who received CAMCEVI ETM in the FP01C-17-001, 74% were 65 years of age or older, while 31% were 75 years of age or older. No overall differences in safety or effectiveness were observed between patients over the age of 65 and younger patients.

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.

Image10 (Camcevi Inj Structure)

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).

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.

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.

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 T_max 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.

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.

The efficacy of CAMCEVI ETM was evaluated in an open label, single arm, multinational study FP01C-17-001 (NCT03261999) in patients with advanced prostate carcinoma who have a screening morning serum testosterone level >150 ng/dL and Eastern Cooperative Oncology Group performance status ≤ 2. CAMCEVI ETM was administered subcutaneously at a dose of 21 mg initially on Day 0 and on Week 12.

The population (n = 144) had a median age of 70 years (range 51 to 89) and was 88% White, 11% Asian, and 1% Black. Disease stage was distributed as follows: 5% metastatic (M1), 41% locally advanced (T3/4 NX M0 or any T N1 M0), 30% localized (T1 or T2 N0 M0), and 24% not classifiable.

The major efficacy outcome measure was medical castration rate, defined as achieving and maintaining serum testosterone suppression to < 50 ng/dL by Week 4 through Week 24 of treatment. Following the first injection of CAMCEVI ETM, serum testosterone levels were suppressed to < 50 ng/dL by Week 4 (+/-1day) in 97.9% of the patients; and from Week 4 through Week 24 in 97.2% of patients (95% CI: 92.7- 98.9) estimated using the Kaplan-Meier method. The time course of change from baseline in testosterone suppression are shown in Figure 1. The percentage of patients with testosterone suppression to < 20 ng/dL was 70.8% on Day 28.

Figure 1 CAMCEVI ETM Mean (95% CI) Percentage Change from Baseline in Serum Testosterone Concentration Over Time

Image11 (Camcevi Inj Figure 1)

Note: 1 subject with baseline testosterone value < 0.05 ng/mL was excluded from analysis.

In the clinical trial, PSA levels were monitored and were lowered on average by 48% after 4 weeks after administration of CAMCEVI ETM, 88% after 3 months and remained suppressed throughout the 24 weeks of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline correlates with clinical benefit.

CAMCEVI ETM is a sterile, off-white to pale yellow, viscous, and opalescent injectable emulsion supplied in a kit as a single-dose, pre-filled syringe. CAMCEVI ETM is available as follows:

Store CAMCEVI ETM at 2°C to 8°C (36°F to 46°F). Protect CAMCEVI ETM from light by storing in the original package until time of use. Do not freeze or shake.

Excursions permitted to room temperature 25°C (77°F) for up to 6 days.

The rubber used in syringe tip cap and plunger stopper is not made of natural rubber latex.

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 treatment. 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 (5.2)].

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 (5.3)].

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 (5.4)].

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 (5.5)].

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 redness. 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