Leuprolide

CAMCEVI is indicated for the treatment of adult patients with advanced prostate cancer. CAMCEVI is a gonadotropin-releasing hormone (GnRH) agonist indicated for the treatment of adult patients with advanced prostate cancer.

Injectable emulsion: 42 mg leuprolide (equivalent to approximately 48 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. Injectable emulsion: 42 mg ( 3 )

CAMCEVI is contraindicated in patients known to be hypersensitive to GnRH, GnRH agonist analogs, or any of the excipients in CAMCEVI. Anaphylactic reactions to GnRH agonist analogs have been reported in the medical literature. Hypersensitivity to GnRH, GnRH agonist analogs, or any of the components of CAMCEVI. ( 4 )

Tumor Flare: Transient worsening of bone pain, uretral obstruction, spinal cord compression, or the occurrence of additional signs and symptoms of prostate cancer may develop during the first few weeks of treatment. Monitor patients closely and manage symptoms. ( 5.1 ) Hyperglycemia and Diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Monitor blood glucose levels and manage according to current clinical practice. ( 5.2 ) Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death, and stroke has been reported in men receiving GnRH agonists. Monitor for cardiovascular disease and manage according to current clinical practice. ( 5.3 ) QT/QTc Prolongation: Androgen deprivation therapy may prolong the QT interval. Consider periodic monitoring of electrocardiograms and electrolytes. ( 5.4 ) Convulsions: Manage convulsions according to the current clinical practice. ( 5.5 ) Severe Cutaneous Adverse Reactions: CAMCEVI can cause severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis. Interrupt CAMCEVI if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.6 ) Embryo-Fetal Toxicity: CAMCEVI may cause fetal harm. ( 5.8 , 8.1 )

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. 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 Severe Cutaneous Adverse Reactions CAMCEVI 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 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 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.

5.7 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 )].

5.8 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 )].

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) ] The most common (≥5%) adverse reactions were hot flushes, hypertension, injection site reactions, fatigue, upper respiratory tract infections, musculoskeletal pain, pain in extremity, arthralgia, micturition urgency, nocturia, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord BioPharma Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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. FP01C-13-001 The safety of CAMCEVI was evaluated in an open-label, single-arm, international clinical trial (FP01C-13-001) in patients with advanced prostate cancer. Patients 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. Table 1. Adverse Reactions Occurring in ≥5% of CAMCEVI in Advanced Prostate Cancer Patients – FP01C-13-001 Adverse Reaction CAMCEVI N = 137 All Grades (%) Grade 3-4 (%) Vascular disorders Hot flushes a 50 0 Hypertension b 15 0 General disorders and administration site conditions Injection site reactions c 11 0 Fatigue d 10 0 Infections and infestations Upper respiratory tract infection e 11 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain f 11 0 Pain in extremity 10 0 Arthralgia 7 0 Renal and urinary disorders Micturition urgency g 6 0 Nocturia 6 0 Nervous system disorders Dizziness h 5 0.7 a includes hot flush and flushing b includes hypertension, essential hypertension, and blood pressure increased c includes injection site pain, injection site erythema, injection site hemorrhage, injection site nodule, injection site paraesthesia, injection site pruritus, and injection site warmth d includes fatigue and asthenia e includes upper respiratory tract infection, sinusitis, and nasopharyngitis f includes musculoskeletal pain, back pain, and bone pain g includes micturition urgency and dysuria h includes dizziness, dizziness postural, vertigo, and vertigo positional.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of CAMCEVI or 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: hypersensitivity reactions including anaphylaxis, 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: leukopenia 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 induration or swelling, SJS/TEN, DRESS, AGEP, dermatitis exfoliative, bullous dermatitis, and erythema multiforme Urogenital System: prostate pain

Females and males of reproductive potential: CAMCEVI may impair fertility. ( 8.3 ) Safety and effectiveness in pediatric patients have not been established. ( 8.4 )

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.

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.