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warnings and cautions
5 WARNINGS AND PRECAUTIONS 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 and 5.3 ) Effect on QT/QTc Interval: Androgen deprivation therapy may prolong the QT interval. Consider risks and benefits. ( 5.4 ) Hyperglycemia and Diabetes: Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH analogs. Monitor blood glucose level and manage according to current clinical practice. ( 5.5 ) 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. ( 5.6 ) 5.1 Hypersensitivity Reactions Anaphylactic shock, hypersensitivity, and angioedema related to triptorelin administration have been reported. In the event of a hypersensitivity reaction, therapy with TRELSTAR should be discontinued immediately and the appropriate supportive and symptomatic care should be administered. 5.2 Transient Increase in Serum Testosterone Initially, triptorelin, like other GnRH agonists, causes a transient increase in serum testosterone levels. As a result, isolated cases of worsening of 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 [ see Clinical Pharmacology (12.2) ]. 5.3 Metastatic Vertebral Lesions and Urinary Tract Obstruction Cases of spinal cord compression, which may contribute to weakness or paralysis with or without fatal complications, have been reported with GnRH agonists. If spinal cord compression or renal impairment develops, standard treatment of these complications should be instituted, and in extreme cases an immediate orchiectomy considered. Patients with metastatic vertebral lesions and/or with upper or lower urinary tract obstruction should be closely observed during the first few weeks of therapy. 5.4 Effect on QT/QTc Interval 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 Hyperglycemia and Diabetes Hyperglycemia and an increased risk of developing diabetes have been reported in men receiving GnRH agonists. Hyperglycemia may represent 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. 5.6 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. 5.7 Laboratory Tests Response to TRELSTAR should be monitored by measuring serum levels of testosterone periodically or as indicated. 5.8 Laboratory Test Interactions Chronic or continuous administration of triptorelin 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.
6 ADVERSE REACTIONS 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 Actavis at 1-800-272-5525 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. Isolated cases of spinal cord compression with weakness or paralysis of the lower extremities have occurred [ see Warnings and Precautions (5.3) ]. Adverse reactions reported for each of the three TRELSTAR formulations in the clinical trials, are presented in Table 2, Table 3, and Table 4. Often, causality is difficult to assess in patients with metastatic prostate cancer. The majority of adverse reactions related to triptorelin 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 ascribed 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 ascribed 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 Postmarketing 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. During postmarketing 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 a 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. In these cases, pituitary apoplexy has presented as sudden headache, vomiting, visual changes, ophthalmoplegia, altered mental status, and sometimes cardiovascular collapse. Immediate medical attention has been required. During postmarketing experience, convulsions, and thromboembolic events including, but not limited to, pulmonary emboli, cerebrovascular accident, myocardial infarction, deep venous thrombosis, transient ischemic attack, and thrombophlebitis have been reported.