2.1 Recommended Dosage

CAMCEVI must be administered by a healthcare provider.
The recommended dose of CAMCEVI is 42 mg administered subcutaneously once every 6 months.

2.2 Preparation and Administration

Syringe Assembly

1. Remove CAMCEVI kit from refrigerator. Open carton and remove blister.
2. Allow prefilled syringe to sit at room temperature for 30 minutes prior to subcutaneous injection.
3. Examine all contents of the package. Do not use if any component is damaged.
4. Check the expiration date on the syringe.  Do not use if the expiration date has passed.
5. The use of gloves is recommended during syringe assembly and administration. 
6. On a clean, dry surface, remove pre-filled syringe (A) and needle cartridge (B) from the blister carton. Visually inspect the contents prior to use.
7. Remove the gray cap from the syringe (A).
8. Twist the clear cap off the bottom of the needle cartridge (B).
9. Attach the needle (B) to the end of the syringe (A) by pushing and turning the needle until firmly connected to the syringe. Do not over twist the needle and strip the threading.

Remove contents	Syringe Assembly	Assembled Pre-Filled Syringe

Administration Procedure

1. 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 injection.
2. Pull the blue cover off the needle (B). Use standard sharps safety techniques to avoid needle sticks.
3. 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.
4. 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.

Prepare the Injection Site	Administer Treatment

Needle Protection

1. Do not remove the needle from the syringe.  Use the enclosed Point-Lok® device to prevent needle sticks.
2. Retrieve the Point-Lok® needle protection device from the Camcevi kit and place it on a secured, flat surface with its largest surface base touching the surface as shown in the diagram below.
3. Immediately after use of the needle, gently insert the exposed needle into the Point-Lok® device opening at the top of the Point-Lok® device. (see Figure 1 below)
4. Push the needle into the top opening until it is fully inserted into the Point-Lok® device. This action will seal the needle tip and lock the needle firmly into the Point-Lok® device. (see Figure 2 below)

5. After use, place the used syringe with needle protected in a suitable sharps container. Dispose of contaminated product in a safe manner according to Centers for Disease Control and Prevention, USA and Federal/State/Local regulations (EPA,OSHA) and health care facility guidelines or local equivalent.

5.1 Tumor Flare

CAMCEVI, 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 treatment. Patients treated with CAMCEVI may experience a temporary increase in bone pain, which can be managed symptomatically.

As with other GnRH agonists, 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.

5.2 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.

5.3 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.

5.4 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.

5.5 Convulsions

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

5.6 Laboratory Tests

Monitor serum levels of testosterone following injection of CAMCEVI. In the majority of patients treated with CAMCEVI, 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)].

5.7 Embryo-Fetal Toxicity

Based on findings in animal studies and mechanism of action, CAMCEVI 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)].

6.1 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. In an open-label, non-comparative clinical trial (FP01C-13-001), patients with advanced prostate cancer received CAMCEVI administered subcutaneously at a dose of 42 mg on Day 0 and Day 168.  Of 137 patients enrolled, 93% received both doses of CAMCEVI. 

Serious adverse reactions occurred in 15% of patients who received CAMCEVI, including 1% of patients who experienced subdural hematoma. Fatal adverse reactions occurred in 2% of patients, including cerebrovascular accident (0.7%) and pulmonary embolism (0.7%).

The most common adverse reactions (>10%) occurring during a median follow-up duration of 336 days were hot flush, hypertension, injection site reactions, upper respiratory tract infections, musculoskeletal pain, fatigue, and pain in extremity.

Table 1 summarizes the adverse reactions in FP01C-13-001.

6.2 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

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 

Urogenital System: prostate pain

8.1 Pregnancy

Risk Summary

Based on findings in animal studies and mechanism of action, CAMCEVI 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.

8.2 Lactation

Risk Summary

The safety and efficacy of CAMCEVI have not been established in females. There is no information regarding the presence of leuprolide in human milk, the effects on the breastfed 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.

8.3 Females and Males of Reproductive Potential

Infertility

Males

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

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 137 patients who received CAMCEVI in the FP01C-13-001 study, 74% were 65 years of age or older, while 37% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

12.1 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.

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.

12.2 Pharmacodynamics

Mean serum testosterone concentrations transiently increased, then fell to below castrate threshold levels (≤ 50 ng/dL) within 3 weeks following administration of the dose of leuprolide, and generally remained below castrate thresholds levels throughout treatment.

12.3 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 Cmax was 94.5 and 99 ng/mL following the first and second doses of CAMCEVI, respectively. The mean serum concentration was maintained at 0.497–2.57 and 0.507–2.39 ng/ml after Day 3 post the first and second doses, respectively. The mean AUC0-6 mon was 224 and 268 day.ng/mL following the first and second doses of CAMCEVI, respectively.

13.1 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.

PRINCIPAL DISPLAY PANEL- Syringe Label

NDC 72851-042-01

Rx Only

CAMCEVITM

(leuprolide) injectable emulsion

42 mg single-dose prefilled syringe

For Subcutaneous Injection Only

PRINCIPAL DISPLAY PANEL- Outer Label

NDC 72851-042-01

Rx Only

CAMCEVITM

(leuprolide) injectable emulsion

42 mg single-dose prefilled syringe

This bilster carton contans:

• One sterile 42 mg pre-filled syringe
• One sterile 18-gauge needle

Single Dose Administration Kit with prefilled syringe

For Subcutaneous Injection Only once Every 6 Months