2.1 Dosing Information

TRIPTODUR must only be administered by a healthcare provider.

The dosage of TRIPTODUR is 22.5 mg reconstituted with accompanying diluent (Sterile Water) 2 mL, and administered as a single intramuscular injection once every 24 weeks.

TRIPTODUR treatment should be discontinued at the appropriate age of onset of puberty at the discretion of the physician.

2.2 Monitoring

Monitor response to TRIPTODUR with LH levels after a GnRH or GnRH agonist stimulation test, basal LH, or serum concentration of sex steroid levels beginning 1 to 2 months following initiation of therapy, during therapy as necessary to confirm maintenance of efficacy, and with each subsequent dose.

Measure height (for calculation of growth rate) every 3-6 months and monitor bone age periodically.

Noncompliance with drug regimen or inadequate dosing may result in inadequate control of the pubertal process with gonadotropins and/or sex steroids increasing above prepubertal levels. If the dose of TRIPTODUR is not adequate switching to an alternative GnRH agonist for the treatment of CPP with the ability for dose adjustment may be necessary.

2.3 Reconstitution and Administration Instructions

Read these instructions completely before you begin.

• Triptodur suspension will sediment very quickly and should be injected immediately after reconstitution in accordance with the detailed instructions below.

• If the sequence of steps to prepare the suspension is interrupted and/or the vial is put aside, the suspension will start to separate into diluent and microgranules.

• To minimize the risk of needle blockage during the injection, ensure that the preparation of the injection is not interrupted and/or the mixed suspension syringe is not put aside because the suspension will sediment quickly.

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1. Use appropriate aseptic technique for preparation and administration.
2. Screw the plunger rod into the barrel end of the prefilled sterile water diluent syringe.

3. To remove the cap, twist counterclockwise to separate from the Luer lock on the syringe barrel.
4. Firmly attach one of the 21-gauge sterile safety needles onto the prefilled sterile
water diluent syringe with a push and clockwise twist. This 21-gauge needle will only be used for reconstitution of the product.

a. Remove the plastic Flip-off from the vial. Disinfect the visible part of the stopper
b. Pull back on the safety cover towards the syringe and away from the 21-gauge needle. Then pull the clear needle shield off.

5. Insert the 21-gauge needle through the stopper. Inject the Sterile Water diluent into the vial, ensuring the diluent rinses the sides of the vial. Do not release the plunger rod.

6. If the syringe plunger is not maintained in position, it will naturally withdraw product into the syringe. Thoroughly mix the vial with agitation for 30 to 60 seconds, ensuring the diluent rinses the sides of the vial.

7. Before moving on to the next step, check visually that the suspension appears milky and homogeneous without any visible aggregates or precipitates.
a. If the suspension DOES NOT appear milky and homogeneous without any visible aggregates or precipitates, continue with the agitation. An up and down agitation can also be used to help eliminate aggregates or precipitates. The complete and homogeneous (milky) suspension of the product may require up to 60 seconds of agitation.
Important: Once mixed, proceed to the next steps and administer without delay.
8. The suspension will sediment very quickly so it is imperative to withdraw the suspension into the syringe directly after suspending the product in the vial.
9. Invert the vial and move back the syringe in order to position the end of the 21-gauge needle very near the level of the stopper, making sure the needle lumen is still completely in the vial.
10. Pull back the plunger rod slowly to withdraw the reconstituted product into the syringe, withdrawing as much of the reconstituted product into the syringe as possible. Move the tip of the needle at the level of the stopper so as to be able to withdraw a maximum amount of suspension.

11. Withdraw the needle from the vial and push the safety cover forward toward the needle until you hear and/or feel it lock. Then remove the first 21-gauge needle by grasping the needle hub to disconnect the needle from the syringe and discard it. This (first) 21-gauge needle will no longer be used.

12. Firmly attach the second sterile needle onto the syringe with a push and clockwise twist and pull back the safety cover towards the syringe. This 21-gauge needle will be used for administration. Triptodur must only be administered with a thin-wall 21 -gauge needle.

13. Do not prime the needle. Inspect the suspension visually for particulate matter and discoloration.

a. If the suspension does not appear milky and homogeneous, continue with an up and down agitation.
b. If the suspension appears milky and homogeneous without visible aggregates or precipitates, administer the suspension immediately.
14. Inject the patient intramuscularly, preferably in either buttock or thigh using the entire contents of the syringe. The injection of the suspension should be performed rapidly and in a steady and uninterrupted manner in order to avoid any potential blockage of the needle.

15. After administering the injection, immediately activate the safety cover:
a. Center your thumb or forefinger on the textured finger pad area of the safety cover and push it forward over the needle until you hear or feel it lock.
b. Use the one-handed technique and activate the mechanism away from yourself and others.
c. Immediately discard the syringe assembly into a suitable sharps container.

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 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.

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.

6.2 Post-marketing Experience

The following adverse reactions have been identified during post-approval use of triptorelin. 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

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

8.2 Lactation

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.

8.6 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)].

8.7 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)].

12.1 Mechanism of Action

Triptorelin is a GnRH agonist.

12.2 Pharmacodynamics

Following the first administration, there is a transient surge in circulating levels of LH, FSH, testosterone, and estradiol [see Warnings and Precautions (5.2)] . After chronic and continuous administration, by 4 weeks after initiation of therapy, a sustained decrease in LH and FSH secretion and marked reduction in sex steroids are observed.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis was evaluated in an 18-month study in mice and a 24-month study in rats. In rats, triptorelin doses of 120, 600, and 3000 mcg/kg given every 28 days (approximately 0.2, 0.8, and 4 times the estimated human monthly dose based on body surface area) resulted in increased mortality with a drug treatment period of 13 to 19 months. The incidences of benign and malignant pituitary tumors and histosarcomas were increased in a dose-related manner. There were no treatment-related tumors in mice at exposure up to 4-fold higher than the estimated human monthly dose based on body surface area.

Mutagenicity studies performed with triptorelin using bacterial and mammalian systems ( in vitroAmes test and chromosomal aberration test in CHO cells and an in vivomouse micronucleus test) provided no evidence of mutagenic potential.

After 60 days of subcutaneous treatment followed by a minimum of four estrus cycles prior to mating, triptorelin at doses of 2, 20, and 200 mcg/kg (approximately 0.07, 0.7, and 7 times the estimated human daily dose based on body surface area) or two monthly injections as slow release microspheres (~20 mcg/kg/day) had no effect on the fertility or general reproductive function of female rats.

No studies were conducted to assess the effect of triptorelin on male fertility.

Store at 20 to 25°C (68 to 77°F) excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze.

Hypersensitivity Reactions

Inform caregivers that anaphylactic shock, hypersensitivity, and angioedema have been reported with triptorelin use and to immediately seek medical attention if any hypersensitivity reaction occurs.

Symptoms after Initial TRIPTODUR Administration

Inform caregivers that during the first weeks after the first TRIPTODUR injection, signs of puberty may occur such as vaginal bleeding [see Warnings and Precautions (5.1)and Adverse Reactions (6.1)] . Caregivers should notify the physician if these symptoms continue beyond the second month after TRIPTODUR administration.

Psychiatric Events

Inform caregivers that symptoms of emotional lability, such as crying, irritability, impatience, anger, and aggression have been observed in patients receiving GnRH agonists, including triptorelin. Alert caregivers to the possibility of development or worsening of psychiatric symptoms, including depression, during treatment with TRIPTODUR [see Warnings and Precautions (5.2)and Adverse Reactions (6.2)].

Convulsions

Inform caregivers that reports of convulsions have been observed in patients receiving GnRH agonists, including triptorelin. 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 may be at increased risk [see Warnings and Precautions (5.3)].

Pseudotumor Cerebri (Idiopathic Intracranial Hypertension)

Inform patients and caregivers that reports of pseudotumor cerebri (idiopathic intracranial hypertension) have been observed in pediatric patients receiving GnRH agonists, including triptorelin. Monitor patients for signs and symptoms of pseudotumor cerebri, including headache, and vision issues such as blurred vision, double vision, loss of vision, pain behind the eye or pain with eye movement, ringing in the ears, dizziness, and nausea. Advise patients and caregivers to contact their healthcare provider if the patient develops any of these symptoms. [see Warnings and Precautions (5.4)] .

Pregnancy is Contraindicated

TRIPTODUR is contraindicated in pregnancy. If the patient becomes pregnant while taking the drug, the patient should be informed of the potential risk to fetus [see Use in Specific Populations (8.1)].

Compliance with the Dosing Schedule

Inform caregivers about the importance of adherence to the TRIPTODUR dosing schedule of one injection every 24 weeks. Patients should not miss or delay a scheduled dose.