SUPPRELIN LA: Package Insert and Label Information (Page 3 of 3)

12.3 Pharmacokinetics

Pharmacokinetics of histrelin after implantation of SUPPRELIN LA was evaluated in a total of 47 children with CPP (11 subjects in Study 1 and 36 subjects in Study 2). Patients were examined at 4 weeks after implant insertion and a few times throughout the treatment period. Median serum histrelin concentrations remained above the limit of quantification for the treatment period. Histrelin acetate levels were sustained throughout the study period for most subjects (Figure 3). The median of maximum serum histrelin concentrations over the study period was 0.43 ng/mL, which is expected to maintain gonadotropins at prepubertal levels. There was no apparent pharmacokinetic difference between naïve subjects to a LHRH agonist treatment and subjects who had previous treatment with a LHRH agonist (Figure 3).

Figure 3. Mean and Standard Deviation of Serum Histrelin Concentrations (ng/mL) Results at Each Visit

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in rats for 2 years at doses of 5, 25 or 150 mcg/kg/day (up to 11 times human exposures using body surface area comparisons, based on a 65 mcg/day dose in humans) and in mice for 18 months at doses of 20, 200, or 2000 mcg/kg/day (at less than therapeutic exposure to 70 times human exposure using body surface area comparisons, based on a 65 mcg/day dose in humans). As seen with other GnRH agonists, histrelin injection administration was associated with an increase in tumors of hormonally responsive tissues. There was a significant increase in pituitary adenomas in rats at mid and high doses (2-11 times human exposure based on body surface area comparisons with a 65 mcg/day human dose). There was an increase in pancreatic islet-cell adenomas in treated female rats and a non-dose-related increase in testicular Leydig-cell tumors (highest incidence in the low-dose group). In mice, there was significant increase in mammary-gland adenocarcinomas in all treated females. In addition, there were increases in stomach papillomas in male rats given high doses, and an increase in histiocytic sarcomas in female mice at the highest dose.

Mutagenicity studies have not been performed with histrelin acetate. Saline extracts of implants with and without histrelin acetate were negative in a battery of genotoxicity studies. Fertility studies have been conducted in rats and monkeys given subcutaneous daily doses of histrelin acetate up to 180 mcg/kg/day (up to 13 and 30 times human exposure, respectively using body surface area comparisons, based on a 65 mcg/day human dose) for 6 months and full reversibility of fertility suppression was demonstrated. The development and reproductive performance of offspring from parents treated with histrelin acetate has not been investigated.

14 CLINICAL STUDIES

The efficacy of SUPPRELIN LA in children with CPP has been evaluated in two single-arm, open label studies. Study 1 was conducted in 11 pretreated female patients, 3.7 to 11.0 years of age. Study 2 was conducted in 36 patients (33 females and 3 males), 4.5 to 11.6 years of age. Sixteen pretreated and 20 treatment-naïve patients were enrolled in Study 2. Baseline patient characteristics were typical of patients with CPP. Efficacy assessments were similar in both studies and included endpoints that measured the suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively) on treatment. Other assessments were clinical (evidence of stabilization or regression of signs of puberty) or gonadal steroid-dependent (bone age, linear growth). In Study 2, the primary measure of efficacy was LH suppression.

In Study 2, suppression of LH was induced in all treatment naïve subjects and maintained in all pretreated subjects at Month 1 after implantation and continued through Month 12 (suppression was defined as a peak LH < 4 mIU/mL following stimulation with the GnRH analog leuprolide acetate).

Secondary efficacy hormone assessments (FSH, estradiol and testosterone) and additional efficacy assessments (bone age advancement, linear growth, clinical progression of puberty) indicated stabilization of disease. Estradiol suppression was present in all 33 girls (100%) through Month 9 and 97% at Month 12. Testosterone suppression was maintained in the three pre-treated males participating in Study 2. The SUPPRELIN LA effect on efficacy endpoints in the Study 1 was consistent with that observed in Study 2.

16 HOW SUPPLIED/STORAGE AND HANDLING

SUPPRELIN LA (NDC 67979-002-01) is supplied in a corrugated shipping carton that contains 2 inner cartons: a small one for the vial containing the SUPPRELIN LA implant, which is shipped with a cold pack inside a polystyrene cooler that must be refrigerated upon arrival, and a larger one comprising the Implantation Kit, which must not be refrigerated, for use during insertion or removal of SUPPRELIN LA.

The SUPPRELIN LA implant contains 50 mg of histrelin acetate. The SUPPRELIN LA implant carton contains a cold pack for refrigerated shipment and a small carton containing an amber plastic pouch. Inside the pouch is a glass vial with a Teflon-coated stopper and an aluminum seal, containing the implant in 2 mL of sterile 1.8% sodium chloride solution. (Note: The 3.5 mL vial is not completely filled with saline).

Upon receipt, refrigerate the small carton containing the amber plastic pouch and glass vial (with the implant inside) until the day of insertion. The implant vial should not be opened until just before the time of insertion.

SUPPRELIN LA is stable when stored refrigerated, in its sealed vial, pouch, and carton, at 2-8 °C (36-46 °F) until the expiration date provided. Excursion permitted to 25 °C (77 °F) for 7 days. Do not freeze. Protect from light.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-Approved patient labeling (Medication Guide).

Initial Agonistic Action
Patients should be advised that a transient worsening of symptoms of puberty or onset of new symptoms may occur initially. However, within 4 weeks of histrelin therapy, complete suppression of gonadal steroids occurs and manifestations of puberty decrease [see Warnings and Precautions (5.1)].

Post-insertion Care
Patients should be instructed to refrain from getting the inserted arm wet for 24 hours and from strenuous exertion of the inserted arm for 7 days after implant insertion to allow the incision to fully close. The adhesive elastic bandage can be removed at that time. The patient should not remove the surgical strips; rather, the strips should be allowed to fall off on their own after several days.

Psychiatric Adverse 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 SUPPRELIN LA . Alert caregivers to the possibility of development or worsening of psychiatric symptoms, including depression, during treatment with SUPPRELIN LA [see Warnings and Precautions (5.3), Adverse Reactions (6.3)].

Convulsions
Inform caregivers that reports of convulsions have been observed in patients receiving GnRH agonists, including SUPPRELIN LA. 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 risk [see Warnings and Precautions (5.4) ].

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. Advise patients and caregivers to monitor for 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 (5.5) ].

Common Adverse Reactions
Patients should be advised to report to their physician any severe pain, redness, or swelling in and around the implant site. Infrequently, SUPPRELIN LA may be expelled from the body through the original incision site, rarely without the patient noticing. The patient should be instructed to monitor the incision site until it is healed. The patient should also return for routine checks of their condition and to ensure that SUPPRELIN LA is present and functioning in his/her body [see Adverse Reactions (6.1) ].

For more information, call 1-800-462-3636 or visit www.supprelinla.com.

Distributed by:
Endo Pharmaceuticals Inc.
Malvern, PA 19355 USA

SUPPRELIN® is a registered trademark of Endo Pharmaceuticals Inc. or one of its affiliates.

©2019 Endo Pharmaceuticals Inc. All rights reserved. Revised: 04/2022

Medication Guide SUPPRELIN® LA [Suh-Preh-Lin El-Ay] (histrelin acetate) subcutaneous implant

What is the most important information I should know about SUPPRELIN LA? In the first week of treatment, SUPPRELIN LA can cause an increase in some hormones. During this time you may notice more signs of puberty in your child, including light vaginal bleeding and breast enlargement in girls.Within 4 weeks of treatment, you should see signs in your child that puberty is stopping. Some people who had SUPPRELIN LA placed in their arm have had the implant come through the skin (extrusion). Call your child’s doctor right away if the SUPPRELIN LA implant comes through the skin. Some people taking GnRH agonists like SUPPRELIN LA have had new or worsening mental (psychiatric) problems. Mental (psychiatric) problems may include emotional symptoms such as: crying irritability restlessness (impatience) anger acting aggressive Call your child’s doctor right away if your child has any new or worsening mental symptoms or problems while taking SUPPRELIN LA. Some people taking GnRH agonists like SUPPRELIN LA have had seizures. The risk of seizures may be higher in people who: have a history of seizures have a history of epilepsy have a history of brain or brain vessel (cerebrovascular) problems or tumors are taking a medicine that has been connected to seizures such as bupropion or selective serotonin reuptake inhibitors (SSRIs) Seizures have also happened in people who have not had any of these problems.Call your child’s doctor right away if your child has a seizure while taking SUPPRELIN LA. Increased pressure in the fluid around the brain can happen in children taking GnRH agonist medicines including SUPPRELIN LA.Call your child’s doctor right away if your child has any of the following symptoms during treatment with SUPPRELIN LA: headache ringing in the ears eye problems, including blurred vision, double vision, and decreased eyesight dizziness nausea eye pain

What is SUPPRELIN LA? SUPPRELIN LA is an implanted gonadotropin releasing hormone (GnRH) medicine used for the treatment of children with central precocious puberty (CPP). It is not known if SUPPRELIN LA is safe and effective in children under 2 years of age.

SUPPRELIN LA should not be taken if your child is: allergic to gonadotropin releasing hormone (GnRH), GnRH agonist medicines, or any ingredients in the SUPPRELIN LA implant. See the end of this Medication Guide for a complete list of ingredients in SUPPRELIN LA. pregnant or becomes pregnant. SUPPRELIN LA can cause birth defects or loss of the baby.If your child becomes pregnant call your doctor.

Before your child receives SUPPRELIN LA, tell the doctor about all of your child’s medical conditions, including if they: have a history of mental (psychiatric) problems. have a history of seizures. have a history of epilepsy. have a history of brain or brain vessel (cerebrovascular) problems or tumors. are taking a medicine that has been connected to seizures such as bupropion or selective serotonin reuptake inhibitors (SSRIs). Tell your doctor about all the medicines your child takes , including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will your child receive SUPPRELIN LA? Your child’s doctor should do tests to make sure your child has CPP before treating with SUPPRELIN LA. SUPPRELIN LA lasts for 12 months. One implant will give the medicine for 12 months. After 12 months, the SUPPRELIN LA implant must be removed. The doctor may place a new SUPPRELIN LA implant at this time to continue treatment. SUPPRELIN LA is placed under the skin of the inside of the upper arm. The doctor will numb the arm of your child, make a small cut, and then place the SUPPRELIN LA implant under the skin. The cut may be closed with stitches or surgical strips and covered with a pressure bandage. Your child should keep the arm clean and dry and should not swim or bathe for 24 hours after receiving the SUPPRELIN LA implant. The bandage can be removed after 24 hours. Do not remove any surgical strips. Surgical strips will fall off on their own in a few days. Your child should avoid heavy play or exercise that uses the arm where the implant was placed for 7 days. After the cut has healed, your child can go back to his or her normal activities. The doctor will give you complete instructions. Keep all scheduled visits to the doctor. The doctor will do regular exams and blood tests to check for signs of puberty. Sometimes the doctor will have to do special tests, such as an ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI) if the SUPPRELIN LA implant is hard to find under your child’s skin.

What are the possible side effects of SUPPRELIN LA? SUPPRELIN LA may cause serious side effects. See “What is the most important information I should know about SUPPRELIN LA?” The most common side effect of SUPPRELIN LA includes skin reactions at the place where the implant is inserted. These reactions may include pain, redness, bruising, soreness, and swelling in and around the implant site. Call your child’s doctor if your child has bleeding, redness, or severe pain where the implant was inserted. These are not all the possible side effects of SUPPRELIN LA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What are the ingredients in SUPPRELIN LA? Active ingredient: histrelin acetate Inactive ingredients: stearic acid NF, hydrogel polymer reservoir composed of 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, trimethylolpropane trimethacrylate, benzoin methyl ether, Perkadox-16, and Triton X-100 Distributed by: Endo Pharmaceuticals Inc., Malvern, PA 19355, www.endo.com or call 1-800-462-3636.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rev: 04/2022

Package Label – Principle Display Panel – Vial Label

Package Label – Principle Display Panel – Carton Label

SUPPRELIN LA histrelin acetate implant

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67979-002 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HISTRELIN ACETATE (HISTRELIN) HISTRELIN ACETATE 50 mg

Inactive Ingredients Ingredient Name Strength STEARIC ACID 2-HYDROXYETHYL METHACRYLATE METHYL BENZOIN DI-(4-TERT-BUTYLCYCLOHEXYL)PEROXYDICARBONATE OCTOXYNOL 9

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:67979-002-01 1 VIAL, GLASS in 1 CARTON contains a VIAL, GLASS 1 1 IMPLANT in 1 VIAL, GLASS This package is contained within the CARTON (67979-002-01)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022058 05/31/2007

Labeler — Endo Pharmaceuticals Inc. (178074951)

Revised: 04/2022 Endo Pharmaceuticals Inc.