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histrelin acetate implant
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Supprelin LA (histrelin acetate) subcutaneous implant is indicated for the treatment of children with central precocious puberty (CPP).
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
The recommended dose of Supprelin LA is one implant every 12 months. Each implant contains 50 mg histrelin acetate. The implant is inserted subcutaneously in the inner aspect of the upper arm and provides continuous release of histrelin (65 mcg/day) for 12 months of hormonal therapy. Supprelin LA should be removed after 12 months of therapy (the implant has been designed to allow for a few additional weeks of histrelin acetate release, in order to allow flexibility of medical appointments). At the time an implant is removed, another implant may be inserted to continue therapy. Discontinuation of Supprelin LA should be considered at the discretion of the physician and at the appropriate time point for the onset of puberty (approximately 11 years for females and 12 years for males).
2.2 Recommended Procedure
This procedure section is intended to provide guidance for the insertion and removal of Supprelin LA. The actual procedure used, however, is at the discretion of the qualified healthcare provider performing the procedure.
Suggested Insertion Procedure
Setting up the Sterile Field
The implant vial should not be opened until just before the time of insertion. Open the vial by removing the metal band and carefully pour the sterile contents (implant and sterile saline) onto the Sterile Field drape. The implant can then be handled with sterile gloves or with the sterile mosquito clamp provided.
Preparing the Patient and the Insertion Site
If local anesthesia is selected: a vial of sterile local anesthetic (note that the exterior of the vial is not sterile) has been provided along with a sterile hypodermic needle for injection. After determining the absence of known allergies to the anesthetic agent, inject anesthetic into the subcutaneous tissue, starting at the planned incision site, then infiltrating along the intended subcutaneous insertion path, up to the length of the implant (a little more than one inch). Local anesthesia may also be supplemented by the use of distraction techniques.
The following sections describe the suggested procedure for insertion of the implant using the Insertion Tool provided. The method of insertion used, however, is at the discretion of the healthcare provider performing the procedure.
Loading the Insertion Tool
When first grasping the sterile Insertion Tool, confirm that the cannula is fully extended. Verify this by inspecting the position of the green retraction button. The button should be locked in position all the way forward, towards the cannula, farthest from the handle.
The implant can be picked up using sterile gloves or with the sterile mosquito clamp provided. Avoid bending or pinching the implant. Note that the implant may come out of its vial slightly curved after refrigerated storage. To help make the implant more symmetrical prior to loading into the Tool, you can roll the implant a few times (while wearing a sterile glove) between the fingers and thumb.
Insert the implant into the cannula of the Insertion Tool manually or using the mosquito clamp. When inserting the implant into the cannula, DO NOT FORCE the implant. If resistance is felt, the implant should be removed and manually manipulated or rolled as needed, and re-inserted into the cannula.
When fully inserted, the implant rests inside the cannula so that just the tip of the implant is visible at the beveled end of the cannula.
Making the Incision
Inserting the Implant
Be sure to VISIBLY RAISE THE SKIN (known as tenting) at all times during the pocket-making and insertion procedures to ensure correct subcutaneous placement (“just under the skin”) of the implant. Note that the cannula of the Insertion Tool, or whatever tool is being used to create the pocket, SHOULD NOT ENTER MUSCLE TISSUE. Deep insertion of the implant will not affect the performance of Supprelin LA, but may cause difficulty in the later removal of the implant.
If using the cannula of the loaded Insertion Tool to create the pocket, carefully insert the tip of the cannula into the incision and advance through the subcutaneous tissue, while visibly raising the skin along the length of the cannula up to, but no farther than, the inscribed black line on the cannula. DO NOT DEPRESS THE GREEN RETRACTION BUTTON ON THE TOOL WHILE INSERTING OR ADVANCING THE TOOL INTO THE INCISION.
Pull the Tool back, almost to the beveled tip of the cannula, and advance the Tool forward again, so that the cannula re-enters the pocket completely, but no farther than the inscribed black line. Be sure to keep the insertion path just immediately subcutaneous.
If another tool was used to create the pocket, now insert the loaded cannula of the Insertion Tool containing the implant through the incision, up to the inscribed black line.
Hold the Insertion Tool in place with the base against the patient’s arm (if possible) as you carefully move your thumb to the green retraction button. Depress the button to release the locking mechanism, then slide the button back toward the handle until it stops, all the while holding the body of the Insertion Tool in place.
Retracting the button causes the cannula to withdraw from the incision, leaving the implant in the subcutaneous tissue. DO NOT FURTHER ADVANCE THE CANNULA ONCE THE RETRACTION PROCESS HAS STARTED. Likewise, do not withdraw the Insertion Tool until the button is fully retracted or the implant may be pulled partially out of the incision. Once the retraction is complete, the Tool can be fully withdrawn.
NOTE: It may be helpful during the process of retraction and withdrawal of the cannula to apply pressure to the skin over the implant, to help ensure that the implant remains in the subcutaneous pocket.
Placement of the implant should be confirmed by palpation. Note that the tip of a properly placed implant may not be visible through the incision.
After implantation, briefly cover the site with a sterile gauze pad and apply pressure to ensure hemostasis.
Closing the Incision
Once closed, cover the incision site with sterile gauze pads and secure the dressing with the bandage provided.
Please provide the patient’s parent or guardian with a Patient Information Leaflet, which includes information about the implant and instructions on proper care of the insertion site.
Suggested Removal Procedure
Removal of the Supprelin LA implant is a surgical procedure. Sterile gloves and aseptic technique must be used to minimize any chance of infection.
Setting up the Sterile Field
Preparing the Patient and the Site
The implant to be removed should first be located by palpating the inner aspect of the upper arm, near the incision from the prior year.
Generally, the previous implant is readily palpated. In the event the implant is difficult to locate, ultrasound may be used. If ultrasound fails to locate the implant, other imaging techniques such as CT or MRI may be used to locate it (plain films are not recommended as the implant is not radiopaque).
Making the Incision and Removing the Implant
Generally, the tip of the implant will be visible through the incision, possibly covered by a pseudocapsule of tissue. In order to facilitate the removal of the implant, it may be necessary to palpate the head of the implant through the incision using your smallest finger, especially if the head of the implant is not readily visible. In addition, you may need to push down on the distal end of the implant and “massage it forward” towards the incision.
Carefully nick the pseudocapsule to reveal the polymer tip of the implant. It may be beneficial to insert the sterile mosquito clamp provided into the hole created in the pseudocapsule and expand by opening the clamp. Widening the opening of the pseudocapsule may ease the extraction of the implant.
Gently but securely grasp the implant with the sterile mosquito clamp and extract the implant.
Dispose of the implant in a proper manner, treating it like any other bio-waste.
If inserting a new implant, see the Suggested Insertion Procedure instructions provided above. Note that you can insert the new implant into the same “pocket” as the removed implant, or make a new incision at a different site in the same arm or in the contralateral arm.
If a new implant is not to be inserted, proceed to close the incision.
Closing the Incision
Once closed, cover the incision site with sterile gauze pads and secure the dressing with the bandage provided.
3 DOSAGE FORMS AND STRENGTHS
Supprelin LA is a sterile, nonbiodegradable, diffusion-controlled, MedLaunch™ polymer (also known as “hydrogel”) reservoir drug delivery system designed to deliver histrelin acetate continuously for 12 months after subcutaneous implantation. The sterile implant contains 50 mg histrelin acetate and delivers approximately 65 mcg histrelin acetate per day over 12 months.
Supprelin LA is contraindicated in patients who are hypersensitive to gonadotropin releasing hormone (GnRH) or GnRH agonist analogs.
Supprelin LA is contraindicated in females who are or may become pregnant while receiving the drug. Supprelin LA may cause fetal harm when administered to pregnant patients. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. The possibility exists that spontaneous abortion may occur [see USE IN SPECIFIC POPULATIONS (8.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Initial Agonistic Action
Supprelin LA, like other GnRH agonists, initially causes a transient increase in serum concentrations of estradiol in females and testosterone in both sexes during the first week of treatment. Patients may experience worsening of symptoms or onset of new symptoms during this period. However, within 4 weeks of histrelin therapy, suppression of gonadal steroids occurs and manifestations of puberty decrease.
5.2 Implant Insertion/Removal Procedure
Implant insertion is a surgical procedure and it is important that the insertion instructions are followed to avoid potential complications. The insertion and removal of the implant should be done aseptically. Proper surgical technique is critical in minimizing adverse events related to the insertion and the removal of the histrelin implant. On occasion, localizing and/or removal of implant products have been difficult and imaging techniques were used, including ultrasound, CT, or MRI (note: the histrelin implant is not radiopaque). Rare events of spontaneous extrusion of the implant have been observed in clinical trials. During Supprelin LA treatment, patients should be evaluated for evidence of clinical and biochemical suppression of CPP manifestations (see Section 5.3, Monitoring and Laboratory tests). Detailed instructions on the insertion and removal procedures of the implant are provided above [see DOSAGE AND ADMINISTRATION (2.2)].
6 ADVERSE REACTIONS
6.1 Overall Adverse Reaction Profile
The most common adverse reactions with Supprelin LA involved the implant site. Local reactions after implant insertion include bruising, pain, soreness, erythema and swelling. During the early phase of therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug. Therefore, an increase in clinical signs and symptoms may be observed [see WARNINGS AND PRECAUTIONS (5.1)].
6.2 Adverse Reactions in Clinical Trials
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 Supprelin LA in children with CPP was evaluated in two single-arm clinical trials conducted in a total of 47 patients (44 females and 3 males) over a period of time ranging from 9 to 18 months. The most commonly reported adverse reaction was implant site reaction, which was reported by 24 of 47 (51.1%) patients. Implant site reaction includes discomfort, bruising, soreness, pain, tingling, itching, implant area protrusion and swelling. Two subjects experienced a serious adverse reaction: 1 subject who coincidentally had Stargardt’s Disease experienced amblyopia and 1 subject had a benign pituitary tumor (pituitary adenoma). One subject discontinued the study due to an adverse reaction of infection at the implant site. There were no clinically meaningful findings in standard clinical hematology and chemistry tests and/or in vital signs. The incidence of implantation adverse events reported by more than 2 patients are summarized in Table 1.
The following adverse reactions were reported as possibly related or related in 1 patient each: wound infection, breast tenderness, dysmenorrhea, epistaxis, erythema, feeling cold, gynecomastia, headache, menorrhagia, migraine, mood swings, pituitary tumor benign, pruritus, weight increased, disease progression and influenza-like illness. The adverse reaction metrorrhagia was reported as possibly related or related in 2 patients.
7 DRUG INTERACTIONS
Overview: No formal drug-drug, drug-food, or drug-herb interaction studies were performed with Supprelin LA.
8 USE IN SPECIFIC POPULATIONS
Pregnancy category X [see CONTRAINDICATIONS (4)].
Animal Data: Major fetal abnormalities were observed in rabbits at 3 times human therapeutic exposure but not in rats after administration of histrelin acetate throughout gestation. There was dose-related increased fetal mortality during organogenesis in both rats given 1, 3, 5 or 15 mcg/kg/day (at less than therapeutic exposures using body surface area comparisons, based on a 65 mcg per day human dose) and in rabbits at 20, 50 or 80 mcg/kg/day (at 3 times human exposure using body surface area comparisons, based on a 65 mcg/day dose in humans).
There have been no reports of overdose in Supprelin LA clinical trials. High doses of histrelin acetate injection in animal studies were generally associated only with effects attributed to the expected pharmacology. The method of drug delivery makes accidental or intentional overdosage unlikely.
Supprelin LA is a sterile, non-biodegradable, diffusion-controlled, MedLaunch™ polymer reservoir containing histrelin acetate, a synthetic nonapeptide analog of the naturally occurring gonadotropin releasing hormone (GnRH) possessing a greater potency than the natural sequence hormone. Supprelin LA is designed to deliver approximately 65 mcg histrelin acetate per day over 12 months.
The Supprelin LA implant looks like a small thin flexible tube and consists of a 50-mg histrelin acetate drug core inside a 3.5 cm by 3 mm, cylindrical, MedLaunch™ polymer reservoir (Figure 1).
Figure 1. Supprelin LA Implant Diagram (not to scale)
The chemical name of histrelin acetate is: L-Pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-N-benzyl-D-histidyl-L-leucyl-L-arginyl-L-proline N-ethylamide, acetate salt. The molecular formula for histrelin acetate is C66H86N18O12 x 2 CH3COOH and its molecular weight is 1443.70 (or 1323.52 as free base). Histrelin is also chemically described as 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-Nt-benzyl-Dhistidyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide diacetate. The chemical structure of the free base (histrelin) is represented below in Figure 2.
Figure 2. Structure of Histrelin
The drug core also contains the inactive ingredient stearic acid NF. The MedLaunch™ polymer reservoir is a hydrophilic cartridge composed of 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, trimethylolpropane trimethacrylate, benzoin methyl ether, Perkadox-16, and Triton X-100. Each implant is packaged hydrated in a glass vial containing 2 mL of sterile 1.8% sodium chloride solution, so that it is primed for immediate release of the drug upon insertion.
A single use, sterile, Insertion Tool is provided along with the implant that can be used for the placement of the Supprelin LA implant into the subcutaneous tissue of the inner aspect of the upper arm. The Insertion Tool is enclosed in a sterile bag and is provided separately from the implant in the Implantation Kit [see RECOMMENDED PROCEDURE (2.2)].
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Supprelin LA is a GnRH agonist and an inhibitor of gonadotropin secretion when given continuously. It delivers approximately 65 mcg histrelin acetate per day. Both animal and human studies indicate that following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn causes a reduction in ovarian and testicular steroidogenesis.
In humans, administration of histrelin acetate results in an initial increase in circulating levels of LH and FSH, leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of histrelin acetate causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH.
Long-term treatment with histrelin acetate suppresses the LH response to GnRH causing LH levels to decrease to prepubertal levels within 1 month of treatment. As a result, serum concentrations of sex steroids (estrogen or testosterone) also decrease. Consequently, secondary sexual development ceases to progress in most patients. Additionally, linear growth velocity is slowed which improves the chance of attaining predicted adult height.
Pharmacokinetics of histrelin acetate 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 or150 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 carton contains an opaque amber plastic pouch. Inside the pouch is a 3.5 mL clear glass vial with a Teflon-coated stopper and an aluminum seal, containing the hydrated implant immersed in 2 mL of sterile 1.8% sodium chloride solution.
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
[See FDA-Approved Patient Labeling (17.4)]
17.1 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)].
17.2 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.
17.3 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 WARNINGS AND PRECAUTIONS (5.2)].
Supprelin® LA [Suh-Preh-Lin El-Ay]
Read the Patient Information that comes with Supprelin LA before your child begins treatment. This information does not take the place of talking with your child’s doctor about their medical condition or treatment.
What is Supprelin LA?
CPP makes puberty come early in girls (before 8 years of age) and in boys (before 9 years of age). Signs of early puberty include breast enlargement in girls and the appearance of hair in the genital area in boys and girls. Supprelin LA works by reducing the amount of sex hormones in the blood to delay early puberty.
Who should not use Supprelin LA?
How is Supprelin LA used?
What are the possible side effects of Supprelin LA?
These may not be all the side effects of Supprelin LA. Ask your child’s doctor for more information.
General information about Supprelin LA
For more information, call 1-800-462-3636 or visit www.supprelinla.com
MedLaunch™ is a Trademark of Endo Pharmaceuticals.
Supprelin® LA is a Registered Trademark of Endo Pharmaceuticals.
©2011, Endo Pharmaceuticals
PK000033 Rev. 05 March 2011
Package Label - Principal Display Panel - Vial Label
Supprelin® LA (histrelin acetate) Subcutaneous implant
Contains one sterile implant.
PK000032 Rev. 02
Package Label - Principal Display Panel - Vial Carton
Panels 1 and 3:
Supprelin® LA (histrelin acetate) Subcutaneous implant
The sterile Supprelin® LA implant consists of a 50-mg histrelin acetate drug core inside a non-
The HYDRON® polymer reservoir is composed of 2-hydroxyethyl methacrylate, 2-hydroxyropyl
Each implant is packaged in a glass vial containing 2 mL of 1.8% sodium chloride, sterile. Each vial is
Do not use if the seal on the glass vial is broken.
Supprelin® LA and HYDRON® are registered trademarks of Endo Pharmaceuticals
Panel 3: Endo logo
Panels 2 and 4:
Supprelin® LA (histrelin acetate) Subcutaneous implant
Sterile for Subcutaneous Use
Must be refrigerated. Do not freeze.
Store at 2°-8°C (36°-46°F). Protect from light.
Keep out of the reach of children.
Panel 4: Bar Code – N3 67979 00201 6
Revised: 03/2011 Endo Pharmaceuticals Solution Inc
Reproduced with permission of U.S. National Library of Medicine
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