Camcevi (Accord Healthcare, 42 mg) Product Monograph

RECENT MAJOR LABEL CHANGES

Not Applicable.

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ........................................................................................... 2

TABLE OF CONTENTS ............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .............................................................................................................. 4

1.1 Pediatrics (< 18 years of age) .................................................................................. 4

1.2 Geriatrics (> 65 years of age) .................................................................................. 4

2 CONTRAINDICATIONS ................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ............................................................ 4

4 DOSAGE AND ADMINISTRATION ................................................................................. 5

4.1 Dosing Considerations ............................................................................................ 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 5

4.4 Administration ........................................................................................................ 5

4.5 Missed Dose ............................................................................................................ 9

5 OVERDOSAGE ............................................................................................................. 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 9

7 WARNINGS AND PRECAUTIONS ................................................................................ 10

7.1 Special Populations ............................................................................................... 14

7.1.1 Pregnant Women .............................................................................................. 14

7.1.2 Breast-feeding ................................................................................................... 15

7.1.3 Pediatrics (< 18 years of age) ............................................................................ 15

7.1.4 Geriatrics (> 65 years of age) ............................................................................ 15

8 ADVERSE REACTIONS................................................................................................ 15

8.1 Adverse Reaction Overview .................................................................................. 15

8.2 Clinical Trial Adverse Reactions ............................................................................ 15

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 18

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other ....... 19

Quantitative Data .............................................................................................................. 19

8.5 Post-Market Adverse Reactions ............................................................................ 19

9 DRUG INTERACTIONS ............................................................................................... 20

9.2 Drug Interactions Overview .................................................................................. 20

9.4 Drug-Drug Interactions ......................................................................................... 20

9.5 Drug-Food Interactions ......................................................................................... 21

9.6 Drug-Herb Interactions ......................................................................................... 21

9.7 Drug-Laboratory Test Interactions........................................................................ 21

10 CLINICAL PHARMACOLOGY ....................................................................................... 21

10.1 Mechanism of Action ............................................................................................ 21

10.2 Pharmacodynamics ............................................................................................... 21

10.3 Pharmacokinetics .................................................................................................. 22

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 23

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................... 23

PART II: SCIENTIFIC INFORMATION ...................................................................................... 24

13 PHARMACEUTICAL INFORMATION ........................................................................... 24

14 CLINICAL TRIALS ....................................................................................................... 25

14.1 Clinical Trials by Indication........................................................................................ 25

15 MICROBIOLOGY ....................................................................................................... 27

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 27

PATIENT MEDICATION INFORMATION ................................................................................. 30

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

CAMCEVI (leuprolide mesylate) is indicated for:

• treatment of adult patients with advanced prostate cancer.

1.1 Pediatrics (< 18 years of age)

• No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics (> 65 years of age)

• The mean age of the male patients studied in the clinical trials was 71 years (range 51–88 years). The safety and efficacy of CAMCEVI was established in this population (see 14 CLINICAL TRIALS).

2 CONTRAINDICATIONS

CAMCEVI is contraindicated in:

• patients with hypersensitivity to gonadotropin releasing hormone (GnRH) analogues, or any of the components of CAMCEVI. Anaphylactic reactions including anaphylactic shock to synthetic GnRH or GnRH analogues have been reported in post-marketing surveillance. For a complete listing, see the section 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• women and paediatric patients.
• women who are or may become pregnant.
• women who are nursing.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• CAMCEVI should be administered by a healthcare professional.
• CAMCEVI, 42 mg administered subcutaneously is designed to provide continuous extended release of leuprolide for 6 months.

4.2 Recommended Dose and Dosage Adjustment

• CAMCEVI 42 mg (6-Month)

  The recommended dose of CAMCEVI is 42 mg administered every six months as a single subcutaneous injection (see 4.4 ADMINISTRATION).

4.4 Administration

CAMCEVI is administered by subcutaneous injection, whereupon it forms a solid drug delivery depot releasing leuprolide mesylate over 6 months. The injectable emulsion contains approximately 42 mg of leuprolide base (equivalent to approximately 48 mg leuprolide mesylate). The recommended dosing is 1 subcutaneous injection every 24 weeks.

As with other drugs administered by subcutaneous injection, the injection site should vary periodically. The specific injection location chosen should be an area with sufficient soft or loose subcutaneous tissue. In clinical trials, the injection was administered in the upper- or mid-abdominal area. Areas with brawny or fibrous subcutaneous tissue or locations that can be rubbed or compressed (i.e., with a belt or clothing waistband) should be avoided.

Administration Procedure

IMPORTANT: Allow the product to reach room temperature before using. The use of gloves is recommended during administration [Occupational Health and Safety (OH&S)].

Do NOT substitute any of the components from the kit for administration

Follow the instructions as directed to ensure proper preparation of CAMCEVI prior to administration:

CAMCEVI 42 mg kit contains:

• One sterile pre-filled plastic syringe closed with elastomeric grey tip cap, plunger and finger grip
• One sterile 18-gauge SurGuard®3 safety needle, 5/8 inch needle

Syringe Assembly

1. 1.

   Keep contents in their original, sealed blister container and allow pre-filled syringe to sit at room temperature for 30 minutes prior to subcutaneous injection.

   Return to refrigerator after 30 minutes if not used.

2. 2.

   On a clean, dry surface, remove pre-filled CAMCEVI 42 mg syringe (A) and needle cartridge (B) from the blister container. Visually inspect the contents prior to use.

   Check the expiration date on the syringe. Do not use if the expiration date has passed.

   Visually inspect the syringe for particulate 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.

3. 3. Remove pre-filled syringe (A) from blister tray and open the safety needle (B) package by peeling back the paper tab.

1. 4. Remove the gray cap from syringe (A).
2. 5. 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.

Administration Procedure

Prepare the Injection Site	Expose Needle	Administer Treatment	Activate Safety Sheath and Discard Needle
			Using finger/thumb: 1. 2. OR Using flat surface: 1. 2.

1. 1.

   Choose an injection site on the upper- or mid-abdominal area 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).

   (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 kit.

2. 2. Pull the blue cover off the needle. Use standard sharps safety techniques to avoid needle sticks.
3. 3. Grab and bunch the skin around the injection site with one hand. Insert the needle at a 90° angle, then release the bunched skin.
4. 4. Inject the full contents of the syringe with a slow and steady push, then withdraw the needle at the same 90° angle used for insertion.

1. 5. Intra-arterial or intravenous injection has to be strictly avoided
2. 6. 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.
3. 7. After use, place the used syringe with needle protected in a suitable sharps container. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

4.5 Missed Dose

Maintaining testosterone suppression is important in treating the symptoms of hormone- dependent prostate cancer. Missing an appointment by a few days should not disrupt the benefits of treatment, but keeping a consistent schedule of leuprolide injections is an important part of treatment. Call your healthcare professional for instructions if you miss a dose.

5 OVERDOSAGE

There is no clinical experience with the effects of an acute overdose. There is no known antidote for CAMCEVI overdose. In the event of an overdose, stop CAMCEVI, undertake general supportive measures until clinical toxicity has been diminished or resolved.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

CAMCEVI is available as follows:

• CAMCEVI is a sterile, off-white to pale yellow, viscous and opalescent injectable emulsion.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

CAMCEVI, like other GnRH analogues, causes a transient increase in serum concentration of testosterone during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or ureteral or bladder outlet obstruction. Cases of spinal cord compression, which may contribute to paralysis with or without fatal complications, have been reported with GnRH analogues. If spinal cord compression or renal impairment due to ureteral obstruction develops, standard treatment of these complications should be instituted.

Patients with metastatic vertebral lesions and/or with urinary tract obstruction should begin leuprolide therapy under close supervision.

Administration procedure should be followed, as lack of clinical efficacy may occur due to incorrect administration of the product (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests and 4.4 Administration, Administration Procedure).

Carcinogenesis and Mutagenesis

No carcinogenicity studies or genotoxicity studies have been conducted specifically with CAMCEVI.

Two-year carcinogenicity studies conducted with leuprolide in rats found increased incidences of pituitary hyperplasia and adenomas, pancreatic islet-cell adenomas, and testicular interstitial cell adenomas (see 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity).

Genotoxicity studies performed with leuprolide using bacterial and mammalian systems found no evidence of genotoxic potential (see 16 NON-CLINICAL TOXICOLOGY, Genotoxicity).

Cardiovascular

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH analogues in men. The risk appears low based on the reported odds ratios, and should be evaluated carefully along with cardiovascular risk factors. Reports of events related to cardiovascular ischemia including myocardial infarction, stroke and cardiovascular-related deaths have been reported in patients treated with GnRH analogues.

Physicians should consider whether the benefits of androgen deprivation therapy outweigh the potential cardiovascular risk.

Patients receiving GnRH analogues should be monitored for symptoms and signs suggestive of development of cardiovascular disease, and management according to current clinical practice and guidelines should be considered (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

Effect on QT/QTc interval

Androgen deprivation therapy may prolong the QT/QTc interval. In patients with a history of or risk factors for QT prolongation including congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure, and/or in patients receiving concomitant medicinal products that might prolong the QT interval, physicians should assess whether the benefits of androgen deprivation therapy outweigh the potential risks including the potential for Torsade de pointes prior to initiating CAMCEVI.

Driving and Operating Machinery

Fatigue and dizziness have been reported in patients taking CAMCEVI.

Therefore, exercise caution when driving or operating a vehicle or potentially dangerous machinery.

Endocrine and Metabolism

Pituitary apoplexy

During post-marketing surveillance, serious cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of GnRH analogues, with a majority occurring within 2 weeks of the first dose, and some within the first hour. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention is required. Pre-existing gonadotropin-secreting pituitary adenoma was diagnosed in a majority of patients. If the presence of macroadenomas is evidenced by imaging and biochemical assessments, this should be surgically removed prior to start of GnRH analogues including CAMCEVI treatment.

Hypogonadism

Long-term administration of leuprolide will cause suppression of pituitary gonadotropins and gonadal hormone production with clinical symptoms of hypogonadism. These changes have been observed to reverse on discontinuation of therapy. However, whether the clinical symptoms of induced hypogonadism will reverse in all patients has not yet been established.

Hyperglycemia and Diabetes

Hyperglycaemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogues. Hyperglycaemia may represent development of diabetes mellitus or worsening of glycaemic control in patients with diabetes. Monitor blood glucose and/or glycosylated haemoglobin (HbA1c) periodically in patients receiving a GnRH analogue and manage with current practice for treatment of hyperglycaemia or diabetes.

Fatty liver disease

Metabolic changes affecting the liver (fatty liver) may be experienced.

Hematologic

Anemia is a known physiologic consequence of testosterone suppression. Assessment of anemia risk and management according to local clinical practice and guidelines should be considered.

Immune

Acute Hypersensitivity Reactions

Acute hypersensitivity reactions, including anaphylaxis, have been reported with leuprolide-containing therapy. Leuprolide is contraindicated in patients with a history of hypersensitivity to gonadotropin-releasing hormone (GnRH) or GnRH agonist analogs.

Delayed Hypersensitivity Reactions

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 in association with leuprorelin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for severe skin reactions. If signs and symptoms suggestive of these reactions appear, leuprorelin should be withdrawn immediately and an alternative treatment considered (as appropriate).

Monitoring and Laboratory Tests

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

Monitor response to leuprolide by periodically measuring serum concentrations of testosterone and prostate specific antigen. Results of testosterone determinations are dependent on assay methodology. It is advisable to be aware of the type and precision of the assay methodology to make appropriate clinical and therapeutic decisions.

Testosterone levels should also be evaluated in the case of suspected or known handling errors, as lack of efficacy may result from incorrect preparation or administration. Baseline risk factors of cardiovascular diseases should be assessed. Patients receiving leuprolide should be monitored periodically for risk factors, signs and symptoms of cardiovascular diseases. In addition, baseline ECG recording and serum potassium, calcium, and magnesium levels are recommended. Monitoring of ECG and serum electrolyte levels during treatment should also be considered for those at risk for electrolyte abnormality and QTc prolongation.

Lipids, blood glucose levels and/or glycosylated hemoglobin (HbA1c) should be checked periodically in patients treated with GnRH analogues and more frequently in diabetic patients (see 7 WARNINGS AND PRECAUTIONS, Endocrine and Metabolism).

The effects of leuprolide on bone lesions may be monitored by bone scans, while its effects on prostatic lesions may be monitored by ultrasonography, and/or CT scan in addition to digital rectal examination. Intravenous pyelogram, ultrasonography, or CT scan may also be utilized to diagnose or assess the status of obstructive uropathy.

Musculoskeletal

Decreased bone mineral density can be anticipated with long term use of a GnRH analogue. Androgen deprivation therapy is associated with increased risks of osteoporosis and skeletal bone fractures. The risk of skeletal bone fracture increases with the duration of androgen deprivation therapy. Assessment of osteoporosis risk and management according to clinical practice and guidelines should be considered.

In patients with significant risk factors for decreased bone mineral content and/or bone mass such as chronic alcohol and/or tobacco use, presumed or strong family history of osteoporosis, or chronic use of drugs that can reduce bone mass such as anticonvulsants or corticosteroids, CAMCEVI may pose an additional risk. In these patients, risk versus benefit must be weighed carefully before therapy with CAMCEVI is initiated.

Neurologic

Convulsions have been reported in patients on leuprolide with or without a history of predisposing factors in the post-market setting. Convulsions are to be managed according to the current clinical practice.

Idiopathic Intracranial Hypertension (pseudotumor cerebri)

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in adult and pediatric patients receiving GnRH agonists. Monitor patients for signs and symptoms of idiopathic intracranial hypertension, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with the eye movement, tinnitus, dizziness, and nausea. Refer the patient to an ophthalmologist to confirm the presence of papilledema. Treatment should be discontinued immediately if the patient develops any signs or symptoms suggestive of idiopathic intracranial hypertension.

Tumor Flare

CAMCEVI, like other GnRH analogues, 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 occasionally develop during the first few weeks of CAMCEVI treatment. A small number of patients may experience a temporary increase in bone pain, which can be managed symptomatically.

As with other GnRH analogues, isolated cases of ureteral obstruction and spinal cord compression have been observed, which may contribute to paralysis with or without fatal complications. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted.

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

Reproductive Health: Female and Male Potential

• Fertility

Based on findings in animals and mechanism of action, CAMCEVI may impair fertility in males of reproductive potential (see 10 CLINICAL PHARMACOLOGY, 16 NON-CLINICAL TOXICOLOGY).

Continuous daily administration of leuprolide results in decreased levels of luteinizing hormone (LH), follicle stimulating hormone (FSH) and reduction of testosterone to castrate levels.

• Teratogenic Risk

CAMCEVI is contraindicated in women who are or may become pregnant (see 2 CONTRAINDICATIONS). Based on findings in animals, CAMCEVI may cause fetal harm if administered to pregnant women (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

Respiratory

There have been post-marketing reports of interstitial pneumonitis associated with leuprolide use. Treatment should be discontinued immediately if the patient develops any signs or symptoms suggestive of interstitial lung disease.

7.1 Special Populations

7.1.1 Pregnant Women

Leuprolide is contraindicated in women who are or may become pregnant (see 2 CONTRAINDICATIONS). Studies in animals have shown leuprolide can result in embryotoxicity and lethality (see 16 NON-CLINICAL TOXICOLOGY). CAMCEVI is not indicated for use in women as safety and efficacy have not been established in this group of patients.

7.1.2 Breast-feeding

CAMCEVI is contraindicated for use in nursing women as safety and efficacy have not been established in this group of patients.

7.1.3 Pediatrics (< 18 years of age)

CAMCEVI is contraindicated for use in children as safety and efficacy have not been established in this group of patients.

7.1.4 Geriatrics (> 65 years of age)

The mean age of the male patients studied in the clinical trials was 71 years (range 51–88 years). The safety and efficacy of CAMCEVI was established in this population. (See 14 CLINICAL TRIALS).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety of CAMCEVI was evaluated in a clinical trial involving patients with advanced prostate cancer who received at least one dose of CAMCEVI. CAMCEVI, like other GnRH analogues, caused a transient increase in serum testosterone concentrations during the first week of treatment, declining thereafter to baseline levels or below by the end of the second week of treatment. Therefore, potential exacerbations in signs and symptoms of the disease during the first weeks of treatment are of concern in patients with vertebral metastases and/or urinary obstruction or hematuria which, if aggravated, may lead to neurological problems (such as weakness and/or paresthesia of the lower limbs) or increase the obstruction (see 7 WARNINGS AND PRECAUTIONS).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials therefore may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful for identifying and approximating rates of adverse drug reactions in real-world use.

In an open-label, non-comparative clinical trial (FP01C13-001), 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. The median follow-up duration was 336 days.

The most common adverse reactions (incidence ≥ 10%) were hot flush, hypertension, injection site reactions, upper respiratory infections, musculoskeletal pain, fatigue, and pain in extremity.

Serious Adverse Events (SAE) occurred in 15% of patients treated with CAMCEVI. The most common (≥1%) SAE observed was subdural haematoma (1.5%).

Fatal adverse reactions occurred in 2% of patients including one due to cerebrovascular accident (0.7%), one due to pulmonary embolism (0.7%), and one due to metastatic prostate cancer to lungs (0.7%) and acute kidney injury.

Discontinuation occurred in 11% of subjects. The most common reason for discontinuation was due to adverse events in 4% of patients including acute kidney injury, atrial fibrillation, cerebrovascular accident, death, hormone refractory prostate cancer and metastatic prostate cancer.

The following adverse events (all grades) occurred in the clinical trial of CAMCEVI and were reported in ≥5% of patients (Table 2).

Table 2 Summary of Adverse Events Reported in ≥ 5% of Patients Treated with CAMCEVI

• ^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.

8.3 Less Common Clinical Trial Adverse Reactions

The following are selected clinically significant adverse reactions reported in less than 5% of patients receiving CAMCEVI in study FP01C-13-001:

The safety profile of CAMCEVI was further examined and followed in the open-label, single-arm safety extension study (FP01C-13-001-EX) with 30 subjects enrolled. No new safety signals were identified in the safety extension study.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other

Quantitative Data

Laboratory abnormalities were observed, but it was difficult to assess relationship to the drug treatment as most occurred in <3% of patients and most in 1 subject each. The following laboratory abnormalities occurred in the clinical trial for CAMCEVI and were reported in > 1% of patients (

Table 3).

Note: *Two patients had clinically significant PSA increase in CAMCEVI trial, but only one of them had the increased PSA judged with severe clinical significance.

The following grade 1–2 laboratory abnormalities occurred in 1 subject each (0.7%): blood creatinine increased, blood lactic acid increased, decreased hemoglobin, eosinophil count increased, erythrocytes decreased, fasting blood glucose increased, gastric acid increased, hematocrit decreased, lymphocyte percentage decreased, neutrophil count increased/neutrophil percentage increased (1 subject each), potassium increased, urine red blood cells increased, and white blood cell increased.

8.5 Post-Market Adverse Reactions

During post-marketing surveillance of other leuprolide dosage forms and other patient populations, the following adverse events were reported.

Cardiovascular System: Hypotension;

Endocrine and Metabolism: Pituitary apoplexy, Fatty liver disease;

Eye disorders: Photosensitivity reactions;

Gastrointestinal System: Hepatic dysfunction;

General disorders and administration site conditions: Localized reactions including induration and abscess, fibromyalgia (e.g., joint and muscle pain, headaches, sleep disorders, gastrointestinal distress, and shortness of breath);

Hemic and Lymphatic System: Decreased white blood cells;

Integumentary System: Hair growth;

Central/Peripheral Nervous System: Convulsion, spinal fracture/paralysis, hearing disorder;

Miscellaneous: Hard nodule in throat, weight gain, increased uric acid;

Musculoskeletal System: Tenosynovitis-like symptoms, decreased bone density;

Respiratory System: Respiratory disorders; interstitial lung disease, anaphylactoid or asthmatic process

Skin and subcutaneous tissue disorders:

Erythema multiforme, toxic skin eruption, and severe cutaneous adverse reactions (SCARs) including Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

No formal drug interaction studies have been conducted with leuprolide.

No data is available on the interaction with alcohol.

9.4 Drug-Drug Interactions

No pharmacokinetic drug interactions were conducted with CAMCEVI.

Interactions with drugs have not been established.

Since androgen deprivation treatment may prolong the QTc interval, the concomitant use of leuprolide with medicinal products known to prolong the QTc interval or medicinal products able to induce torsades de pointes should be carefully evaluated. Such medicinal products include but are not limited to the examples that follow: Class IA (e.g. quinidine, disopyramide), Class III (e.g. amiodarone, sotalol, dofetilide, ibutilide, dronedarone), or Class IC (e.g. flecainide, propafenone) antiarrhythmic medicinal products, antipsychotics (e.g. chlorpromazine), antidepressants (e.g. amitriptyline, nortriptyline), opioids (e.g. methadone), macrolide antibiotics and analogues (e.g. erythromycin, clarithromycin, azithromycin), quinolone antibiotics (e.g. moxifloxacin), antimalarials (e.g. quinine), azole antifungals, 5- hydroxytryptamine (5-HT3) receptor antagonists (e.g. ondansetron), and beta-2 adrenoceptor agonists (e.g. salbutamol).

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Therapy with leuprolide results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after leuprolide therapy may be affected.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Leuprolide, a GnRH analogue, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. 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, and estrone and estradiol in pre-menopausal females). However, long term administration of leuprolide results in decreased levels of LH and FSH. In males, testosterone is reduced to levels associated with castration (≤50ng/dL in serum). In pre-menopausal females, estrogens are reduced to post-menopausal levels.

10.2 Pharmacodynamics

Following the first dose of CAMCEVI, mean serum testosterone concentrations transiently increased, then fell to below castrate threshold levels (≤ 50 ng/dL) within 3 weeks and remained below castrate levels with continued treatment.

A post hoc analysis of ECG and serum concentration was performed because some subjects had high QTcF and dQTcF values during the study period. This analysis showed an increase in QTcF related to leuprolide treatment. The maximum observed dQTcF during treatment (12.4 msec [90% CI 8.44, 16.40 msec]) occurred on Day 168. Similar increases were noted on Days 28 and 336. Central tendency analysis and concentration-effect modeling indicate that the increase in QTcF was not related to leuprolide levels, but instead correlated with the reduced testosterone serum concentration induced by leuprolide. The mean increase in dQTcF exceeded 10 msec at the four ECG sampling time points from Day 28 through Day 336, and the upper boundary of the confidence interval in the concentration-effect model exceeded 10 msec at testosterone levels below 35 ng/dl.

Overall, nine subjects had outlier QTcF responses: QTcF ≥ 500 msec, or QTcF ≥ 480 msec with dQTcF ≥ 60 msec, or both.

The post hoc analysis did not detect a clinically relevant effect of leuprolide on heart rate, PR interval, or QRS interval.

10.3 Pharmacokinetics

Table 4 PK Parameters of Camcevi 42 mg in PK population

^a not reportable for 2 subjects

Absorption

The pharmacokinetics were observed during injections of CAMCEVI administered initially (n = 31 patients) and at 24 weeks (n = 29 patients). Following the first and the second doses of CAMCEVI, mean serum leuprolide concentrations rose rapidly to reach the C_max of 94.5 and 99.0 ng/mL at 3.23 and 2.08 hours (median T_max), respectively. Following the initial rapid increase, leuprolide concentrations declined gradually over the remaining duration of the dosing interval (Day 3 to Day 168). The mean serum concentrations during this "plateau" phase were mostly maintained at 0.497–2.57 (after Day 3 to Day 168) and 0.507–2.39 ng/ml (after Day 171 to Day 336) post the first and the second dose, respectively.

Distribution

The mean steady state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.

Metabolism

Leuprolide is a peptide that is primarily metabolized by peptidases and not by CYP enzymes.

The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M I concentrations were approximately 20% of mean leuprolide concentrations.

Elimination

In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half life of approximately 3 hours based on a 2-compartment model.

No drug excretion study was conducted specifically with CAMCEVI.

Special Populations and Conditions

The pharmacokinetics of the drug have not been determined in patients with hepatic or renal impairment.

• Pediatrics: CAMCEVI is contraindicated in pediatric patients (see 2 CONTRAINDICATIONS).

• Geriatrics: The mean age of the male patients studied in the clinical trials was 71 years (range 51–88 years). The safety and efficacy of CAMCEVI was established in this population. (See 14 CLINICAL TRIALS).

  • Sex: Only male patients were included in studies with CAMCEVI.
  • No clinically meaningful differences in systemic exposure of leuprolide were observed based on age, race, or body weight.

11 STORAGE, STABILITY AND DISPOSAL

Store CAMCEVI at a refrigerated temperature of 2°C to 8°C (35.6 ºF and 46.4 ºF). Protect CAMCEVI from light by storing in the original package until time of use. Do not freeze or shake.

12 SPECIAL HANDLING INSTRUCTIONS

CAMCEVI should be handled following Occupational Health and Safety (OH&S) safety guidelines. The use of gloves is recommended.

Keep contents in their original, sealed blister container and allow pre-filled syringe to sit at room temperature for 30 minutes prior to subcutaneous injection.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Leuprolide mesylate

Chemical name: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide mesylate

Molecular formula and molecular mass: C₅₉H₈₄N₁₆O₁₂ ∙ (CH₄O₃S)n, n = 1.5–1.8 ; 1209.41 Daltons (free base)

Structural formula:

Physicochemical properties: Leuprolide mesylate is a white to off-white powder, freely soluble in water, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP); insoluble in acetone and acetonitrile; and the pKa is 6.1.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Indication 1: Treatment of Adult Patients with Advanced Prostate Cancer

Table 5 Summary of patient demographics for clinical trials in prostate cancer

The efficacy of CAMCEVI was evaluated in an open-label, single arm, multi-center, multinational phase 3 study in adult patients with histologically confirmed advanced prostate carcinoma (baseline morning serum testosterone level 150 ng/dL; Eastern Cooperative Oncology Group [ECOG] ≤ 2). A total of 137 subjects were enrolled and received at least one dose of the study drug (intent-to-treat [ITT] population), and 124 subjects completed the study without major protocol violations affecting the primary efficacy endpoint (per-protocol [PP] population). Of 137 subjects enrolled, 128 subjects received both doses of CAMCEVI (compliance of 93.4%).

The median age of the patients in the study was 71 years and all were male. The population was 90% white, 6% black, 4% Asian and 0.7% unknown. The mean and median duration with diagnosed prostate cancer was 4.9 and 2.0 years, respectively. With regard to disease stage, 23.4% (32/137) subjects had prostate carcinoma stage IV, 27.0% (37/137) subjects had prostate carcinoma stage III, 22.6% (31/137) subject had prostate carcinoma stage II, 2.9% (4/137) subjects had prostate carcinoma stage I, and 23.4% (32/137) subjects had unknown prostate carcinoma stage at baseline. There were 83.2% (114/137) subjects with Grade 0, 16.1% (22/137) subjects with Grade 1, and 0.7% (1/137) subject with Grade 2 in ECOG performance status at baseline. The median testosterone concentration at baseline was 440 ng/dL.

The primary endpoints of the study was to determine the percentage of subjects achieving serum testosterone suppression (<50 ng/dL) by week 4 (day 28), and maintaining that suppression from week 4 through week 48 (day 336) of treatment. To demonstrate clinical efficacy, the lower bound of the 95% confidence interval for the primary endpoint estimate was prespecified to be greater than 90%. Insufficient suppression of testosterone was defined as suppression that did not occur by Day 28 or the occurrence of a testosterone level > 50 ng/dL between Day 28 and Day 336. The secondary endpoints consisted of post suppression excursions, percentage of patients that achieved and maintained testosterone suppression below 20ng/dL and serum PSA levels.

Study Results

In the ITT population serum testosterone levels were suppressed to castrate levels (≤ 50 ng/dL) by Day 28 following the first injection of CAMCEVI in 98.5% of the patients (135/137). The percentage of patients with testosterone suppression (≤ 50 ng/dL) from week 4 through week 48 was 97.0% in the ITT population (Table 6). The percentage of patients with testosterone suppression (≤ 20 ng/dL) was 69.3% (95/137) on Day 28, and 85.4% (117/137) on Day 336 in the ITT population. In the PP population, the percentage of patients with testosterone suppression (≤ 20 ng/dL) was 69.4% (86/124) on Day 28, and 92.7% (115/124) on Day 336.

Table 6 Primary Endpoint Results for Study FP01C-13-001

Two of 137 subjects (1.5%) did not reach castrate levels on Day 28. One subject had a baseline level of 498 ng/dL, and his testosterone level was suppressed to 61.4 ng/dL on Day 28, and then reached castrate levels at the next measurement (Day 56) of 9.2 ng/dL. This subject stayed below 50 ng/dL for the duration of the study. The second subject had a baseline value of 297 ng/dL, and his testosterone level was suppressed to 53.4 ng/dL on Day 28 and 59.8 ng/dL on Day 56 before rebounding to 257 ng/dL on Day 84 with accompanying increasing Prostate Specific Antigen (PSA) levels, at which time he was discontinued due to lack of efficacy. Following the second injection of CAMCEVI, an additional 2 subjects (2/137; 1.5%) each exhibited 1 episode of transient post-suppression breakthrough (serum testosterone > 50 ng/dL). One subject showed 54.7 ng/dL on Day 170, while the other showed 61.4 ng/dL on Day 170 and 59.7 ng/dL on Day 171. Both subject’s serum testosterone levels returned to castrate levels and stayed below through the remainder of the study.

Serum PSA levels were substantially reduced after the first injection, and this effect remained until the end of the study. In the ITT population, the PSA levels were lowered on average by 51% after 4 weeks (Day 28) after administration of CAMCEVI and lowered by 79% at the end of study (Day 336). Similar decreases in PSA levels were observed in the PP population.

PSA based results should always be interpreted with caution as they are not validated surrogate endpoints of clinical benefit in individual patients

15 MICROBIOLOGY

Not applicable.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Published studies on a sustained release formulation of leuprolide demonstrated that the product has a low order of acute toxicity in mice and rats, with LD50's above 5000 mg/kg (greater than 400 mg/kg of leuprolide) for oral, subcutaneous and intraperitoneal routes of administration, and above 2000 mg/kg (greater than 160 mg/kg as leuprolide) for intramuscular injection. The only clinical signs observed were related to local effects at the site of injection.

3-Month Single Dose Subcutaneous Toxicity Study in Male Sprague-Dawley Rats

Leuprolide mesylate (6.8, 20.3 and 33.8 mg/body) was administered to 7-week-old male rats via single subcutaneous injection that resulted in sustained release of leuprolide over a 91-day period. Serum testosterone was suppressed to castrate level (≤50 ng/dL) throughout the study, with a fluctuation above castrate level at one timepoint observed in the low-dose group. No mortality or moribundity were noted in any of the leuprolide mesylate-treated groups or a reference leuprolide-treated group. A shortening of prothrombin time and decreases in the weight of the testis, epididymis, prostate, and seminal vesicles were observed in all leuprolide-treated groups. Pituitary hyperplasia was noted in all leuprolide-treated groups; compressed adjacent tissues were noted in one animal from the low-dose leuprolide mesylate group, and focal (nodular) hyperplasia with atypia was noted in one animal from the reference group. The no observed adverse effect level (NOAEL) of leuprolide mesylate was below 6.8 mg/body (approximately 20.4–25.8 mg/kg, or 4-5 times the recommended human dose based on body surface area), since pituitary hyperplasia noted at this level and higher was considered adverse.

6-Month Single Dose Subcutaneous Toxicity Study in Male Sprague-Dawley Rats

Leuprolide mesylate (6.8, 20.3 and 33.8 mg/body) was administered to 9-week-old male rats via single subcutaneous injection that resulted in sustained release of leuprolide over 182 days. Serum testosterone was suppressed to castrate levels (≤50 ng/dL) throughout the study, with fluctuations above castrate level at three timepoints observed in the low-dose group and one timepoint in the high-dose group. Focal hyperplasia and adenoma in the pituitary that contributed to pituitary enlargement, nodules or masses was observed in all leuprolide mesylate-treated groups and a reference leuprolide-treated group. One animal from the low-dose leuprolide mesylate group was terminated 2 days before end of study due to declined clinical condition primarily caused by such pituitary changes. Other leuprolide related changes observed included reductions in the weight of male sex organs, heart, liver and kidney, food consumption, body weight, red blood cell counts and prothrombin time. Notable changes in serum biochemistry included reduced alkaline phosphatase and increased cholesterol. The NOAEL was below 6.8 mg/body (approximately 16.0-22.0 mg/kg) since the pituitary changes of hyperplasia and adenoma noted at this level and higher were considered to be adverse. At the dose of 6.8 mg/body, systemic exposure (AUC) was approximately 4 times the human exposure at the recommended dose. Local tolerance of leuprolide mesylate was also assessed in this study, and injection site inflammation was observed in some animals at the highest dose.

No studies with repeat administration were conducted. CAMCEVI is an extended-release formulation. Effects of continuous release were observed for a 6-month period.

Single Dose Subcutaneous Toxicity Studies in Dogs

A single SC injection (60 mg in 0.5 mL) of sustained release leuprolide or a supporting formulation in dogs showed no overt toxicities, no body weight abnormalities, and no remarkable observations at the injection sites during the study. In another study, dogs received a single SC injection (45 mg in 0.375 mL) of leuprolide or a supporting formulation. There were no body weight abnormalities during the study. Overt toxicity not related to the test article was observed in two dogs (i.e., seizures and otitis externa). Three dogs demonstrated minimal edema at the injection site on Day 1, and one dog had slight edema at the injection site on Day 14.

Carcinogenicity

No carcinogenicity studies have been conducted specifically with CAMCEVI.

Two-year carcinogenicity studies with leuprolide were conducted 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.

Genotoxicity

No mutagenicity, clastogenicity or aneugenicity studies have been conducted specifically with CAMCEVI.

A sustained release formulation of leuprolide was not genotoxic in either an in vitro cytogenetics assay using Chinese hamster lung cells, an in vivo micronucleus assay in mice, or the Ames test with five strains of Salmonella typhimurium.

Reproductive and Developmental Toxicology

No reproductive and developmental toxicology studies have been conducted specifically with CAMCEVI.

Reproduction and teratology studies conducted with a sustained release formulation indicate all effects observed are related to consequences of repeated administration of this pharmacologic agent. Fertility studies, where male rats were dosed once every four weeks for three doses prior to mating, showed that the drug produced reversible atrophy of the testes or accessory sex organs at doses as low as 0.024 mg/kg (as leuprolide), and a decrease in LH, FSH and testosterone levels. A reversible decrease in copulation and implantation sites was also observed at the high dose of 2.4 mg/kg. No effects on the fetuses were observed.

Female rats dosed at 2.4 mg leuprolide acetate/kg once, four weeks prior to mating, caused an interruption in the estrus cycle and decreased vaginal size. Weights of the ovaries and uterus were decreased. Following mating, corpora lutea and the number of implantation sites were decreased at 0.24 mg/kg and above; the number of live fetuses was reduced at 2.4 mg/kg and above. No abnormal development was noted in the fetuses.

In the perinatal study, the administration of the sustained release formulation of leuprolide in rats prior to delivery at up to 8 mg/kg showed effects on sex organ weights, but no adverse effects on the fetuses, including weights of their sex organs.

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. Increased fetal mortality and decreased fetal weights with the two higher doses were observed.