Triptorelin

TRIPTODUR is indicated for the treatment of pediatric patients 2 years of age and older with central precocious puberty (CPP). TRIPTODUR is a gonadotropin releasing hormone (GnRH) agonist indicated for the treatment of pediatric patients 2 years and older with central precocious puberty. ( 1 )

For extended-release injectable suspension: 22.5 mg of triptorelin as a lyophilized white to slightly yellow powder cake in a single-dose vial for reconstitution with the co-packaged 2 mL of diluent (Sterile Water) for Injection. For extended-release injectable suspension: 22.5 mg of triptorelin as a powder cake for reconstitution with the co-packaged 2 mL of diluent Sterile Water for Injection. ( 3 )

Hypersensitivity: TRIPTODUR is contraindicated in individuals with a known hypersensitivity to triptorelin, any other component of the product, or other GnRH agonists or GnRH [see Adverse Reactions (6.2) ] . Pregnancy: TRIPTODUR may cause fetal harm [see Use in Specific Populations (8.1) ] . Hypersensitivity reactions ( 4 ) Pregnancy ( 4 , 8.1 )

Initial Rise of Gonadotropins and Sex Steroid Levels: An increase in clinical signs and symptoms of puberty may be observed during the first 2-4 weeks of therapy since gonadotropins and sex steroids rise above baseline because of the initial stimulatory effect of the drug. ( 5.1 ) Psychiatric events: Have been reported in patients taking GnRH agonists. Events include emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms. ( 5.2 ) Convulsions: Have been observed in patients with or without a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and in patients on concomitant medications that have been associated with convulsions. ( 5.3 ) Severe Cutaneous Adverse Reactions (SCARs): Have been reported in patients receiving GnRH agonists, including triptorelin products. Interrupt TRIPTODUR if signs or symptoms of SCARs develop. Permanently discontinue TRIPTODUR if a SCAR is confirmed. ( 5.4 ) Pseudotumor Cerebri (Idiopathic Intracranial Hypertension): Have been reported in pediatric patients receiving GnRH agonists, including triptorelin. Monitor patients for headache, papilledema, and blurred vision. ( 5.5 )

5.1 Initial Rise of Gonadotropins and Sex Steroid Levels During the early phase of initial therapy or after subsequent doses, gonadotropins and sex steroids may rise above baseline because of a transient stimulatory effect of the drug [see Clinical Pharmacology (12.2) ] . Therefore, a transient increase in clinical signs and symptoms of puberty, including vaginal bleeding, may be observed during the first weeks of therapy or after subsequent doses.

5.2 Psychiatric Events Psychiatric events have been reported in patients taking GnRH agonists, including triptorelin. Post-marketing reports with this class of drugs include symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression. Monitor for development or worsening of psychiatric symptoms during treatment with TRIPTODUR [see Adverse Reactions (6) ] .

5.3 Convulsions Post-marketing reports of convulsions have been observed in patients receiving GnRH agonists, including triptorelin. These included patients with a history of seizures, epilepsy, cerebrovascular disorders, central nervous system anomalies or tumors, and patients on concomitant medications that have been associated with convulsions such as bupropion and SSRIs. Convulsions have also been reported in patients in the absence of any of the conditions mentioned above [ see Adverse Reactions (6) ].

5.4 Severe Cutaneous Adverse Reactions (SCARs) Severe cutaneous adverse reactions (SCARs) have been reported in patients receiving GnRH agonists, including triptorelin products [see Adverse Reactions ( 6.2 )] . These reactions include Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), including cases with visceral involvement and/or requiring skin grafts. Monitor patients for signs and symptoms of SCARs such as fever, flu-like symptoms, mucosal lesions, progressive skin rash or lymphadenopathy. Advise patients and caregivers of the signs and symptoms of SCARs. If a SCAR is suspected, interrupt TRIPTODUR. Consult a healthcare provider with expertise in the diagnosis and management of SCARS. If a diagnosis is confirmed permanently discontinue TRIPTODUR.

5.5 Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) Pseudotumor cerebri (idiopathic intracranial hypertension) has been reported in pediatric patients receiving GnRH agonists, including triptorelin. Monitor patients for signs and symptoms of pseudotumor cerebri, including headache, papilledema, blurred vision, diplopia, loss of vision, pain behind the eye or pain with eye movement, tinnitus, dizziness, and nausea.

The following serious adverse reactions are described here and elsewhere in the label: Initial Rise of Gonadotropins and Sex Steroid Levels [ see Warnings and Precautions ( 5.1 ) ] Psychiatric Events [ see Warnings and Precautions ( 5.2 ) ] Convulsions [ see Warnings and Precautions ( 5.3 ) ] Severe Cutaneous Adverse Reactions [ see Warnings and Precautions ( 5.4 ) ] Pseudotumor Cerebri (Idiopathic Intracranial Hypertension) [ see Warnings and Precautions ( 5.5 ) ] In clinical trials for TRIPTODUR, the most common adverse reactions (≥4.5%) are injection site reactions, menstrual (vaginal) bleeding, hot flush, headache, cough, and infections (bronchitis, gastroenteritis, influenza, nasopharyngitis, otitis externa, pharyngitis, sinusitis, and upper respiratory tract infection). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TRIPTODUR was evaluated in one uncontrolled, open-label single-arm clinical trial in which 44 children with central precocious puberty received two doses of TRIPTODUR and were observed for 12 months. The median age of the study population was 8 years (range 2-9 years) at treatment start; 88.6% of subjects were female, 59.1% were White, 27.3% were Black and 4.5% were Asian. Table 1 shows all the adverse reactions that occurred in at least 2 patients (≥4.5%) during the open-label single-arm trial. Table 1: Adverse Reactions1 Occurring in ≥ 2 Patients Treated with TRIPTODUR in an Open-Label Single-Arm Trial Adverse Reactions Number of Patients Reporting Event (%) (Total N=44) Infections & Infestations Bronchitis 2 (4.5) Gastroenteritis 3 (6.8) Influenza 2 (4.5) Nasopharyngitis 6 (13.6) Otitis externa 2 (4.5) Pharyngitis 2 (4.5) Sinusitis 2 (4.5) Upper respiratory tract infection 4 (9.1) Nervous System Disorders Headache 6 (13.6) Reproductive System & Breast Disorders Menstrual (Vaginal bleeding) 2 3 (7.7) Respiratory, Thoracic & Mediastinal Disorder Cough 3 (6.8) Vascular Disorders Hot flush 2 (4.5) 1 Injection site reactions are presented separately 2 Includes % of patients with vaginal bleeding or menstrual disorder (“menstrual cycle returned”) in 39 females out of N=44. Other Selected Adverse Reactions: Injection Site Reactions Injection site reactions occurring in patients immediately and/or 2 hours after injection include pain (45%), redness (14%), pruritus (2.3%) and swelling (2.3%). Psychiatric Disorders Anxiety (2.3%) and mood altered (2.3%)

6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of triptorelin or GnRH 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. Hypersensitivity Reactions: Anaphylactic shock, anaphylactoid reaction, angioedema, urticaria. Cardiovascular: Hypertension. Psychiatric: Emotional lability, such as crying, irritability, impatience, anger, and aggression . Depression, including rare reports of suicidal ideation and attempt. Many, but not all, of these patients had a history of psychiatric illness or other comorbidities with an increased risk of depression. Nervous System: Convulsions , pseudotumor cerebri (idiopathic intracranial hypertension) Vision Disorders: Visual impairment, visual disturbance Skin Reactions: erythema multiforme, bullous dermatitis, dermatitis exfoliative, drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome and toxic epidermal necrolysis, and acute generalized exanthematous pustulosis

7.1 Drug-Drug Interactions Results of in vitro studies show that drug-drug interactions with triptorelin are unlikely [see Clinical Pharmacology (12.3)] . However, in the absence of relevant data and as a precaution, hyperprolactinemic drugs should not be used concomitantly with triptorelin since hyperprolactinemia reduces the number of pituitary GnRH receptors.

7.2 Drug-Laboratory Test Interactions Administration of TRIPTODUR results in suppression of the pituitary-gonadal system. The effect of TRIPTODUR on pituitary and gonadal function is expected to disappear within six to twelve months after treatment discontinuation. Therefore, diagnostic tests of pituitary gonadotropic and gonadal functions conducted during treatment or after discontinuation of treatment may be affected.

8.1 Pregnancy Risk Summary TRIPTODUR is contraindicated in women who are pregnant [ see Contraindications ( 4 ) ] since expected hormonal changes that occur with TRIPTODUR treatment increase the risk for pregnancy loss. Available data with triptorelin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. Based on mechanism of action in humans and findings of increased pregnancy loss in animal studies, TRIPTODUR may cause fetal harm when administered to pregnant women. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% – 4% and 15% -20%, respectively. Data Animal Data In pregnant rats administered triptorelin at doses of 2, 10, and 100 mcg/kg/day during the period of organogenesis, maternal toxicity (decrease in body weight) and embryo-fetal toxicities (pre-implantation loss, increased resorption, and reduced number of viable fetuses) were observed at 100 mcg/kg, approximately 4 times the clinical dose based on body surface area. No embryonic and fetal developmental toxicities were observed in mice at doses up to 4 times the clinical dose. Teratogenic effects were not observed in viable fetuses in rats or mice.

8.2 Lactation Risk Summary There are no data on the presence of triptorelin in human milk, or the effects of the drug on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRIPTODUR and any potential adverse effects on the breastfed child from TRIPTODUR or from the underlying maternal condition

8.6 Renal Impairment TRIPTODUR has not been studied in children with renal impairment. Adult subjects with renal impairment had higher exposure than young healthy adult males [see Clinical Pharmacology (12.3) ].

8.4 Pediatric Use The safety and effectiveness of TRIPTODUR have been established in pediatric patients 2 years of age and older based on a single-arm open-label study of 44 children 2-9 years of age with CPP [see Clinical Studies (14) ] . The safety and effectiveness of TRIPTODUR have not been established in pediatric patients less than 2 years old.

8.7 Hepatic Impairment TRIPTODUR has not been studied in children with hepatic impairment. Adult subjects with hepatic impairment had higher exposure than young healthy adult males [see Clinical Pharmacology (12.3) ].

Triptorelin is a GnRH agonist.