Triptorelin Pamoate

TRELSTAR is indicated for the treatment of advanced prostate cancer [ see Clinical Studies (14) ]. TRELSTAR is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of advanced prostate cancer. ( 1 )

For injectable suspension: 3.75 mg, 11.25 mg, 22.5 mg of slightly yellow lyophilized microgranules in a single-dose vial for reconstitution with an injection kit containing one syringe filled with sterile water for injection, a vial adapter to help with reconstitution, and one needle (see figure in section 2.2). For injectable suspension: 3.75 mg, 11.25 mg, 22.5 mg. ( 3 )

Known hypersensitivity to triptorelin or any other component of the product, or other GnRH agonists or GnRH. ( 4 )

4.1 Hypersensitivity TRELSTAR is contraindicated in individuals with a known hypersensitivity to triptorelin or any other component of the product, or other GnRH agonists or GnRH [ see Warnings and Precautions (5.1) ].

Hypersensitivity: Anaphylactic shock, hypersensitivity, and angioedema have been reported. In the event of a reaction, discontinue TRELSTAR and initiate appropriate medical management. ( 5.1 ) Tumor Flare: Transient increase in serum testosterone levels can occur within the first few weeks of treatment. This may worsen prostate cancer and result in spinal cord compression and urinary tract obstruction. Monitor patients at risk and manage as appropriate. ( 5.2 ) Metabolic Syndrome: The use of GnRH agonists may lead to an increased risk of metabolic changes such as hyperglycemia, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease. Monitor for signs and symptoms of metabolic syndrome including lipids, blood glucose level and/or HbA1c and manage according to institutional guidelines. ( 5.3 ) Cardiovascular Diseases: Increased risk of myocardial infarction, sudden cardiac death and stroke has been reported in men. Monitor for cardiovascular disease and manage according to current clinical practice. ( 5.4 ) Convulsions: Convulsions have occurred in patients treated with GnRH analogs (including TRELSTAR) with or without a history of predisposing factors. Manage patients who experience convulsions according to institutional guidelines. ( 5.5 ) Severe Cutaneous Adverse Reactions (SCARs): SCARs have been reported in patients receiving GnRH agonists, including triptorelin products. Interrupt TRELSTAR if signs or symptoms of SCARs develop. Permanently discontinue TRELSTAR if SCARs are confirmed. ( 5.6 ) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. ( 5.7 ) Embryo-Fetal Toxicity: TRELSTAR may cause fetal harm. ( 5.10 , 8.1 )

5.1 Hypersensitivity Reactions Anaphylactic shock, hypersensitivity, and angioedema related to TRELSTAR administration have been reported. In the event of a hypersensitivity reaction, discontinue TRELSTAR immediately and administer the appropriate supportive and symptomatic care.

5.2 Tumor Flare Initially, triptorelin (TRELSTAR), like other GnRH agonists, causes a transient increase in serum testosterone levels [ see Clinical Pharmacology (12.2) ]. As a result, worsening signs and symptoms of prostate cancer during the first weeks of treatment have been reported with GnRH agonists. Patients may experience worsening of symptoms or onset of new symptoms, including bone pain, neuropathy, hematuria, or urethral or bladder outlet obstruction. Closely monitor patients with metastatic vertebral lesions and/or with urinary tract obstruction during the first few weeks of therapy.

5.3 Metabolic Syndrome The use of GnRH agonists (including TRELSTAR) may lead to metabolic changes such as hyperglycemia, diabetes mellitus, and hyperlipidemia. Non-alcoholic fatty liver disease, including cirrhosis, occurred in the post-marketing setting. Hyperglycemia may represent new-onset of diabetes mellitus or worsening of glycemic control in patients with pre-existing diabetes. Monitor for changes in serum lipids, blood glucose and/or glycosylated hemoglobin (HbA1c) periodically in patients receiving TRELSTAR and manage according to institutional guidelines.

5.4 Cardiovascular Diseases Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with the use of GnRH agonists (including TRELSTAR) 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. Monitor patients receiving TRELSTAR for symptoms and signs suggestive of development of cardiovascular disease and manage according to current institutional guidelines.

5.5 Convulsions Convulsions have occurred in patients treated with GnRH analog (including TRELSTAR). These events included patients with risk factors for seizures such as a history of epilepsy, intracranial tumors or co-medication with other drugs known to present a risk of seizure reactions. Convulsions have also been reported in patients in the absence of known risk factors. Manage patients receiving TRELSTAR who experience convulsion according to institutional guidelines.

5.6 Severe Cutaneous Adverse Reactions TRELSTAR 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 TRELSTAR 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 TRELSTAR 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 TRELSTAR.

5.7 Effect on QT/QTc Interval Androgen deprivation therapy with TRELSTAR 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.

5.8 Laboratory Tests Monitor serum levels of testosterone following injection of TRELSTAR. In the majority of patients, testosterone levels increased above baseline, and then declined thereafter to castrate levels (< 50 ng/dL) within four weeks [see Clinical Studies ( 14 ) and Adverse Reactions ( 6 )] .

5.9 Laboratory Test Interactions Chronic or continuous administration of TRELSTAR in therapeutic doses results in suppression of pituitary-gonadal axis. Diagnostic tests of the pituitary-gonadal function conducted during treatment and after cessation of therapy may therefore be misleading.

5.10 Embryo-Fetal Toxicity Based on findings from animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman [ Clinical Pharmacology (12.1) ] . In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1) ] .

The following is discussed in more detail in other sections of the labeling: Hypersensitivity Reactions [ see Warnings and Precautions ( 5.1 ) ] Tumor Flare [ see Warnings and Precautions ( 5.2 ) ]. Metabolic Syndrome [ see Warnings and Precautions ( 5.3 ) ] Cardiovascular Diseases [ see Warnings and Precautions ( 5.4 ) ]. Convulsions [ see Warnings and Precautions ( 5.5 ) ]. Severe Cutaneous Adverse Reactions [ see Warnings and Precautions ( 5.6 ) ]. Effect of QT/QTc Interval [ see Warnings and Precautions ( 5.7 ) ]. 3.75 mg: The most common adverse reactions (≥ 5%) during TRELSTAR 3.75 mg therapy included hot flushes, skeletal pain, impotence, and headache. ( 6.1 ) 11.25 mg: The most common adverse reactions (≥ 5%) during TRELSTAR 11.25 mg therapy included hot flushes, skeletal pain, headache, edema in legs, and leg pain. ( 6.1 ) 22.5 mg: The most common adverse reactions (≥ 5%) during TRELSTAR 22.5 mg therapy included hot flushes, erectile dysfunction, and testicular atrophy. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Verity Pharma at 1-844-837-4891 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of the three TRELSTAR formulations was evaluated in clinical trials involving patients with advanced prostate cancer. Mean testosterone levels increased above baseline during the first week following the initial injection, declining thereafter to baseline levels or below by the end of the second week of treatment. The transient increase in testosterone levels may be associated with temporary worsening of disease signs and symptoms, including bone pain, neuropathy, hematuria, and urethral or bladder outlet obstruction. Spinal cord compression with weakness or paralysis of the lower extremities have occurred [ see Warnings and Precautions (5.2) ]. Adverse reactions reported for each of the three TRELSTAR formulations in the clinical trials, are presented in Table 2, Table 3, and Table 4. The majority of adverse reactions related to TRELSTAR are a result of its pharmacological action, i.e., the induced variation in serum testosterone levels, either an increase in testosterone at the initiation of treatment, or a decrease in testosterone once castration is achieved. Local reactions at the injection site or allergic reactions may occur. The following adverse reactions were reported to have a possible or probable relationship to therapy as described by the treating physician in at least 1% of patients receiving TRELSTAR 3.75 mg. Table 2. TRELSTAR 3.75 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reaction s * TRELSTAR 3.75 mg N = 140 N % Application Site Disorders Injection site pain 5

3.6 Body as a Whole Hot flush 82

58.6 Pain 3

2.1 Leg pain 3

2.1 Fatigue 3

2.1 Cardiovascular Disorders Hypertension 5

3.6 Central and Peripheral Nervous System Disorders Headache 7

5.0 Dizziness 2

1.4 Gastrointestinal Disorders Diarrhea 2

1.4 Vomiting 3

2.1 Musculoskeletal System Disorders Skeletal pain 17

12.1 Psychiatric Disorders Insomnia 3

2.1 Impotence 10

7.1 Emotional lability 2

1.4 Red Blood Cell Disorders Anemia 2

1.4 Skin and Appendages Disorders Pruritus 2

1.4 Urinary System Disorders Urinary tract infection 2

1.4 Urinary retention 2 1.4 * Adverse reactions for TRELSTAR 3.75 mg are coded using the WHO Adverse Reactions Terminology (WHOART) The following adverse reactions were reported to have a possible or probable relationship to therapy as described by the treating physician in at least 1% of patients receiving TRELSTAR 11.25 mg. Table 3. TRELSTAR 11.25 mg: Treatment-Related Adverse Reactions Reported by 1% or More of Patients During Treatment Adverse Reactions * TRELSTAR 11.25 mg N = 174 N % Application Site Injection site pain 7

4.0 Body as a Whole Hot flush 127

73.0 Leg pain 9

5.2 Pain 6

3.4 Back pain 5

2.9 Fatigue 4

2.3 Chest pain 3

1.7 Asthenia 2

1.1 Peripheral edema 2

1.1 Cardiovascular Disorders Hypertension 7

4.0 Dependent edema 4

2.3 Central and Peripheral Nervous System Disorders Headache 12

6.9 Dizziness 5

2.9 Leg cramps 3

1.7 Endocrine Breast pain 4

2.3 Gynecomastia 3

1.7 Gastrointestinal Disorders Nausea 5

2.9 Constipation 3

1.7 Dyspepsia 3

1.7 Diarrhea 2

1.1 Abdominal pain 2

1.1 Liver and Biliary System Abnormal hepatic function 2

1.1 Metabolic and Nutritional Disorders Edema in legs 11

6.3 Increased alkaline phosphatase 3

1.7 Musculoskeletal System Disorders Skeletal pain 23

13.2 Arthralgia 4

2.3 Myalgia 2

1.1 Psychiatric Disorders Decreased libido 4

2.3 Impotence 4

2.3 Insomnia 3

1.7 Anorexia 3

1.7 Respiratory System Disorders Coughing 3

1.7 Dyspnea 2

1.1 Pharyngitis 2

1.1 Skin and Appendages Rash 3

1.7 Urinary System Disorders Dysuria 8

4.6 Urinary retention 2

1.1 Vision Disorders Eye pain 2

1.1 Conjunctivitis 2 1.1 * Adverse reactions for TRELSTAR 11.25 mg are coded using the WHO Adverse Reactions Terminology (WHOART) The following adverse reactions occurred in at least 5% of patients receiving TRELSTAR 22.5 mg. The table includes all reactions whether or not they were ascribed to TRELSTAR by the treating physician. The table also includes the incidence of these adverse reactions that were considered by the treating physician to have a reasonable causal relationship or for which the relationship could not be assessed. Table 4. TRELSTAR 22.5 mg: Adverse Reactions Reported by 5% or More of Patients During Treatment Adverse Reactions * TRELSTAR 22.5 mg N = 120 Treatment-Emergent Treatment-Related N % N % General Disorders and Administration Site Conditions Edema peripheral 6 5.0 0 0 Infections and Infestations Influenza 19 15.8 0 0 Bronchitis 6 5.0 0 0 Endocrine Diabetes Mellitus/Hyperglycemia 6 5.0 0 0 Musculoskeletal and Connective Tissue Disorders Back pain 13 10.8 1

0.8 Arthralgia 9 7.5 1

0.8 Pain in extremity 9 7.5 1

0.8 Nervous System Disorders Headache 9 7.5 2

1.7 Psychiatric Disorders Insomnia 6 5.0 1

0.8 Renal and Urinary Disorders Urinary tract infection 14 11.6 0 0 Urinary retention 6 5.0 0 0 Reproductive System and Breast Disorders Erectile dysfunction 12 10.0 12

10.0 Testicular atrophy 9 7.5 9

7.5 Vascular Disorders Hot flush 87 72.5 86

71.7 Hypertension 17 14.2 1 0.8 * Adverse reactions for TRELSTAR 22.5 mg are coded using the Medical Dictionary for Regulatory Activities (MedDRA) Changes in Laboratory Values During Treatment The following abnormalities in laboratory values not present at baseline were observed in 10% or more of patients: TRELSTAR 3.75 mg : There were no clinically meaningful changes in laboratory values detected during therapy. TRELSTAR 11.25 mg : Decreased hemoglobin and RBC count and increased glucose, BUN, SGOT, SGPT, and alkaline phosphatase at the Day 253 visit. TRELSTAR 22.5 mg : Decreased hemoglobin and increased glucose and hepatic transaminases were detected during the study. The majority of the changes were mild to moderate.

6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of gonadotropin releasing hormone agonists. 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. Pituitary Apoplexy – During post-marketing surveillance, rare cases of pituitary apoplexy (a clinical syndrome secondary to infarction of the pituitary gland) have been reported after the administration of gonadotropin-releasing hormone agonists. In majority of these cases, a pituitary adenoma was diagnosed with a majority of pituitary apoplexy cases occurring within 2 weeks of the first dose, and some within the first hour. […]

No drug-drug interaction studies involving TRELSTAR have been conducted. Human pharmacokinetic data with triptorelin suggest that C-terminal fragments produced by tissue degradation are either degraded completely within tissues, are rapidly degraded further in plasma, or cleared by the kidneys. Therefore, hepatic microsomal enzymes are unlikely to be involved in triptorelin metabolism. However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with TRELSTAR since hyperprolactinemia reduces the number of pituitary GnRH receptors.

Females and males of reproductive potential: TRELSTAR may impair fertility. ( 8.3 )

8.1 Pregnancy Risk Summary Based on findings in animal studies and mechanism of action, TRELSTAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . Expected hormonal changes that occur with TRELSTAR treatment increase the risk for pregnancy loss. In animal developmental and reproductive toxicology studies, daily administration of triptorelin to pregnant rats during the period of organogenesis caused maternal toxicity and embryo-fetal toxicities, including loss of pregnancy, at doses as low as 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus. Data Animal Data Studies in pregnant rats administered triptorelin at doses of 2, 10, and 100 mcg/kg/day (approximately equivalent to 0.2, 0.8, and 8 times the estimated human daily dose based on body surface area) during the period of organogenesis demonstrated maternal toxicity and embryo-fetal toxicities. Embryo-fetal toxicities consisted of pre-implantation loss, increased resorption, and reduced mean number of viable fetuses at the high dose. Teratogenic effects were not observed in viable fetuses in rats or mice. Doses administered to mice were 2, 20, and 200 mcg/kg/day (approximately equivalent to 0.1, 0.7, and 7 times the estimated human daily dose based on body surface area).

8.2 Lactation The safety and efficacy of TRELSTAR have not been established in females. There are no data on the presence of triptorelin in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child. Because of the potential for serious adverse reactions in a breastfed child from TRELSTAR, a decision should be made to either 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 mechanism of action, TRELSTAR may impair fertility in males of reproductive potential [see Clinical Pharmacology ( 12.1 )] .

8.4 Pediatric Use The safety and effectiveness of TRELSTAR in pediatric patients have not been established.

8.5 Geriatric Use Prostate cancer occurs primarily in an older population. Clinical studies with TRELSTAR have been conducted primarily in patients ≥ 65 years [ see Clinical Pharmacology (12.3) and Clinical Studies (14) ].

8.6 Renal Impairment Subjects with renal impairment had higher exposure than young healthy males [ see Clinical Pharmacology (12.3) ].

8.7 Hepatic Impairment Subjects with hepatic impairment had higher exposure than young healthy males [ see Clinical Pharmacology (12.3) ].

Triptorelin is a synthetic decapeptide agonist analog of gonadotropin releasing hormone (GnRH). Comparative in vitro studies showed that triptorelin was 100-fold more active than native GnRH in stimulating luteinizing hormone release from monolayers of dispersed rat pituitary cells in culture and 20-fold more active than native GnRH in displacing 125 I-GnRH from pituitary receptor sites. In animal studies, triptorelin pamoate was found to have 13‑fold higher luteinizing hormone-releasing activity and 21-fold higher follicle-stimulating hormone-releasing activity compared to the native GnRH.