Supprelin LA (histrelin acetate) subcutaneous implant contains a synthetic nonapeptide analog of the naturally occurring gonadotropin releasing hormone (GnRH) that possesses a greater potency than the natural sequence hormone. 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 Nethylamide, 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-Lseryl- L-tyrosyl-Nt-benzyl-D-histidyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide diacetate. The chemical structure of the free base (histrelin) is represented below in Figure 1.

Figure 1. Structure of histrelin

The Supprelin LA implant looks like a small thin flexible tube. The sterile implant consists of a 50-mg histrelin acetate drug core inside a non-biodegradable, 3.5 cm by 3 mm, cylindrical hydrogel reservoir (Figure 2).

Figure 2. Histrelin Implant diagram (not to scale)

The drug core also contains the inactive ingredient stearic acid NF. The hydrogel reservoir is a cartridge composed of 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, trimethylolpropane trimethacrylate, benzoin methyl ether, Perkadox-16, and Triton X-100. Each hydrated implant is packaged in a glass vial containing 2 mL of 1.8% sodium chloride, sterile solution, so that it is primed for immediate release of the drug upon insertion. The 3.5 mL Type I clear glass vial with the implant is closed with a pre-treated grey Teflon coated stopper and sealed with an aluminum crimp seal.

A single use sterile insertion tool (Trocar) is to be used with Supprelin LA. The insertion tool is enclosed in a sterile bag as part of the implantation kit.

Last updated on RxList: 8/5/2008

Supprelin LA (histrelin acetate) subcutaneous implant is indicated for the treatment of children with central precocious puberty (CPP).

Children with CPP (neurogenic or idiopathic) have an early onset of secondary sexual characteristics (earlier than 8 years of age in females and 9 years of age in males). They also show a significantly advanced bone age that can result in diminished adult height attainment.

Prior to initiation of treatment a clinical diagnosis of CPP should be confirmed by measurement of blood concentrations of total sex steroids, luteinizing hormone (LH) and follicle stimulating hormone (FSH) following stimulation with a GnRH analog, and assessment of bone age versus chronological age. Baseline evaluations should include height and weight measurements, diagnostic imaging of the brain (to rule out intracranial tumor), pelvic/testicular/adrenal ultrasound (to rule out steroid secreting tumors), human chorionic gonadotropin levels (to rule out a chorionic gonadotropin secreting tumor), and adrenal steroids to exclude congenital adrenal hyperplasia.

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 acetate (65 mcg per day) for 12 months of hormonal therapy. Supprelin LA must 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).

Insertion Procedure

The implant should be kept refrigerated (2-8°C) until the day of part of the implantation kit, does not require refrigeration. All other supplies necessary to insert and/or remove the implant will be provided in the implantation kit.

It is important to use aseptic techniques to minimize any chance of infection. Sterile gloves are required for the insertion procedure and subsequent removal of the implant.

The implant is inserted using the procedure outlined below:

Identifying the Insertion Site

The patient should be on his/her back, with the arm least used (e.g., left arm for a right-handed person) flexed so the physician has ready access to the inner aspect of the upper arm. Prop the arm with pillows so the patient can easily hold that position. The optimum site for insertion is approximately half way between the shoulder and the elbow and in the crease between the bicep and triceps.

Loading the Insertion Tool

Load the insertion tool prior to prepping the insertion field and insertion site. Remove the insertion tool from its sterile bag. The tool is shipped with the cannula fully extended. Verify this by inspecting the position of the green retraction button. The button should be all the way forward, towards the cannula, away from the handle. Remove the metal band from the vial, remove the rubber stopper, and use a mosquito clamp to grasp either tip of the implant. Avoid grabbing or clamping the middle of the implant to prevent distortion of the implant.

Insert the implant into the cannula of the insertion tool. The implant will rest in the cannula so that just the tip is visible at the bottom of the bevel.

Inserting the Implant

1. Swab the insertion area with povidone-iodine swabs, then lay a fenestrated drape over the insertion site (for clarity of illustration, the accompanying photos do not show the drape).

Anesthetic

2. Anesthetic (i.e., local, conscious sedation or general) utilized should be determined at the discretion of the physician and/or surgeon performing the procedure. After determining the absence of known allergies to the anesthetic agent, a topical lidocaine or lidocaine/epinephrine cream can be used to anesthetize the area prior to injection of local anesthetic. Inject a few milliliters of the anesthetic, starting at the planned incision site, then infiltrating up to the length of the implant, 32 mm, in a fan-like fashion.

Incision

3. Using a scalpel, make a 2-3 mm incision immediately subcutaneous and perpendicular to the shoulder.

Insertion

4. Grasp the insertion tool by its handle, as shown.

5. Insert the tip of the insertion tool into the incision with the bevel up and advance the tool subcutaneously along the path of the anesthetic, up to the inscribed line on the cannula. Pull back the tool about an inch, almost to the tip, while keeping the insertion path just immediately subcutaneous. Keep the insertion tool extended and locked while pulling back the insertion tool. Push the tool back into the arm, up to the black line. This will create a “pocket” for the implant. To ensure subcutaneous placement, the insertion tool should visibly raise the skin at all times during insertion. Be sure that the insertion tool doesn't

6. Hold the insertion tool in place as you move your thumb to the green retraction button. Press the button down to release the locking mechanism, then draw the button back to the back stop, all the while holding the tool in place. The cannula will withdraw from the incision, leaving the implant in the dermis. Withdraw the insertion tool from the incision. Release of the implant can be checked by palpation.

NOTE: Do not try to push the tool in deeper once the retraction process has started to avoid severing the implant. If you wish to re-start the process, withdraw the tool, grasp the implant by the tip to extract it, reset the retraction button to its most forward position, reload the implant, and start again.

Alternatively, the implant can be inserted manually by creating a pocket with the mosquito clamp large enough to allow insertion of the implant. Procedures for incision and closure are the same as instructed above.

After placement, sterile gauze may be used to apply pressure briefly to the insertion site to ensure hemostasis.

Closing the Incision

7. To close the incision, use one or two sutures (optional), knots facing inside the incision. Apply a light coating of antibiotic ointment directly onto the incision. The incision can also be closed with two surgical strips. Apply one or two of the gauze pads over the incision and secure with an adhesive elastic bandage.

Removal Procedure and New Implant Insertion

Supprelin LA must be removed after 12 months of therapy. The techniques and instruments required are the same as for implantation. Assemble all the necessary implements prior to the procedure.

Locating the Implant

The implant may be located by palpating the area near the incision from the prior year. Generally, the implant is readily palpated. Press the distal end of the implant to determine the proximal tip's location relative to the old incision.

In the event the implant is difficult to locate, ultrasound can 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).

Preparing the Site

1. Patient position and site preparation are the same as for the initial insertion. Swab the area above and around the implant with the povidone-iodine swabs. Drape the area with a fenestrated drape.

Anesthetic

2. After determining the absence of known allergies to the anesthetic agent, press down on the implant tip furthest from the old incision to determine the location of the tip closest to the incision. Inject a small amount of lidocaine/epinephrine at the tip near the incision, then advance the needle along the length, but beneath the implant, steadily injecting a small amount of anesthetic along the way. The anesthetic will raise the implant up within the dermis. If you are inserting a new implant, you have the option of either placing the new one in the same “pocket” as the removed one, or using the same incision; insert the new implant in the opposite direction. If placing the new implant in the opposite direction, inject a few milliliters of the anesthetic, starting at the planned incision site, then infiltrating up to the length of the location of the new implant, 32 mm, in a fan-like fashion. Apply anesthetic prior to removal of the old implant.

Incision/Implant Removal

3. Using a scalpel, make a 2-3 mm incision near the tip and about 1-2 mm deep. Generally, the tip of the implant will be visible through a pseudocapsule of tissue. If not, push down on the distal tip of the implant and massage it forward towards the incision. Carefully nick the pseudocapsule to reveal the polymer tip. Insert the mosquito clamp into the hole created in the pseudocapsule and expand by opening the clamp. Widening the opening of the pseudocapsule helps ease the extraction of the old implant.

4. Grasp the tip with the mosquito clamp and extract the implant.

5. Dispose of the implant in a proper manner, treating it like any other bio-waste.

If inserting a new implant - proceed according to “Loading the Insertion Tool”, “Insertion”, and “Closing the Incision” sections above.

The new implant may be placed through the same incision site. Alternatively, the contralateral arm may be used.

6. Provide the patient with the Patient Labeling material.

Dosage Forms And Strengths

Supprelin LA is a sterile, nonbiodegradable, diffusion-controlled reservoir drug delivery system designed to deliver histrelin acetate continuously for 12 months after subcutaneous implantation. The sterile histrelin acetate implant contains 50 mg histrelin acetate and delivers approximately 65 mcg histrelin acetate per day over 12 months.

Storage And Handling

Supprelin LA (NDC 67979-002-01) is supplied in a carton containing 2 inner cartons: a small one for the vial containing the Supprelin LA implant, which is shipped with a cold pack in a polystyrene cooler and must be refrigerated upon arrival, and one for the implantation kit for use with Supprelin LA.

The Supprelin LA implant carton contains an amber plastic pouch. Inside the pouch is a glass vial with a Tefloncoated stopper and an aluminum seal, containing the implant immersed in 2 mL of 1.8% sterile sodium chloride. The sterile insertion tool is part of the implantation kit.

Supprelin LA is stable when refrigerated under the recommended storage conditions (2-8ºC) for up to 2 years. Excursion permitted to 25°C (77°F) for 7 days. Do not freeze. Protect from light. The implantation kit should be stored at room temperature.

FDA revision date: 07/02/08. Manufacturer information: n/a

Last updated on RxList: 8/5/2008

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].

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.

Table 1: Incidence of implantation adverse reactions reported by ≥ 2 patients treated with Supprelin LA in both clinical trials

Adverse Reactions	N=47 N (%)
Implant site reaction	24 (51.1)
Keloid scar	3 (6.4)
Scar	3 (6.4)
Suture related complication	3 (6.4)
Application site pain	2 (4.3)
Post procedural pain	2 (4.3)

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.

Overview: No formal drug-drug, drug-food, or drug-herb interaction studies were performed with Supprelin LA.

Drug-Laboratory Interactions: Therapy with Supprelin LA results in suppression of the pituitary-gonadal system. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after Supprelin LA therapy may be affected. Supprelin LA decreased mean serum insulin-like growth factor-1 (IGF-1) levels by approximately 11% in one study (Study 1). Supprelin LA increased the serum concentration of dehydroepiandrosterone (DHEA) in 8 of 36 patients in another study (Study 2).

Last updated on RxList: 8/5/2008

Included as part of the PRECAUTIONS section.

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.

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 Monitoring and Laboratory tests). Detailed instructions on the insertion and removal procedures of the implant are provided above [see DOSAGE AND ADMINISTRATION].

Monitoring and Laboratory Tests

LH, FSH and estradiol or testosterone should be monitored at 1 month post implantation then every 6 months thereafter. Additionally, height (for calculation of height velocity) and bone age should be assessed every 6-12 months.

Patient Counseling Information

[See FDA-Approved Patient Labeling]

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].

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.

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].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies were conducted in rats for 2 years at doses of 5, 25 or 150 mcg/kg per day (up to 11 times human exposures using body surface area comparisons, based on a 65 mcg per day dose in humans) and in mice for 18 months at doses of 20, 200, or 2000 mcg/kg per day (at less than therapeutic exposure to 70 times human exposure using body surface area comparisons, based on a 65 mcg per 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 per 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 per day (up to 13 and 30 times human exposure, respectively using body surface area comparisons, based on a 65 mcg per 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.

Use In Specific Populations

Pregnancy

Pregnancy category X [see CONTRAINDICATIONS].

Supprelin LA is contraindicated in females who are, or may become, pregnant while receiving the drug. Supprelin LA can cause fetal harm when administered to a pregnant patient. The possibility exists that spontaneous abortion may occur.

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 per kg per 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 per kg per day (at 3 times human exposure using body surface area comparisons, based on a 65 mcg per day dose in humans).

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. The use of Supprelin LA in children under 2 years is not recommended.

Last updated on RxList: 8/5/2008

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 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].

Last updated on RxList: 8/5/2008

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.

Pharmacodynamics

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

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

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.

Last updated on RxList: 8/5/2008

FDA-Approved Patient Labeling

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

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?

Supprelin LA is an under-the-skin (subcutaneous) implant that contains the medicine histrelin, a gonadotropin releasing hormone (GnRH). Supprelin LA is used for treatment of children with central precocious puberty (CPP).

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 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?

Your child should not use Supprelin LA if he/she is allergic to gonadotropin releasing hormone (GnRH), GnRH agonist medicines, or anything in the Supprelin LA implant.

Supprelin LA should not be used in:

• children under 2 years of age
• women who are or may become pregnant (Supprelin LA can cause birth defects or loss of the baby).

How is Supprelin LA used?

• Your child's doctor should do tests to make sure your child has CPP before treating your child with Supprelin LA.
• Supprelin LA lasts for 12 months. One implant provides the medicine for 12 months. After 12 months, Supprelin LA must be removed. The doctor may insert a new Supprelin LA at this time to continue treatment.
• Supprelin LA is placed under the skin of the inside of the upper arm. The doctor will temporarily numb the arm of your child, make a small cut, and then place Supprelin LA 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. The bandage can be removed after 24 hours. Do not remove any surgical strips. They will fall off on their own in several days.
• Your child should avoid heavy play or exercise that uses the implanted arm 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. Your child's doctor will do regular exams and blood tests to check for signs of puberty. Sometimes the doctor will have to do special examinations, such as ultrasound or MRI, if the Supprelin LA implant is difficult to find under your child's skin.

What are the possible side effects of Supprelin LA?

In the first few weeks of treatment, Supprelin LA can cause a brief increase in some hormones, and 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.

• The most common side effects of Supprelin LA are skin reactions at the place where the implant is inserted. Such reactions may include bruising, soreness, pain, tingling, itching, and swelling. They usually go away without treatment within 2 weeks. Call your child's doctor if your child has bleeding, redness or pain at the insertion site.
• Serious and life-threatening allergic reactions have happened with GnRH medicines (the type of medicine in 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

This patient labeling summarizes the most important information about Supprelin LA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Supprelin LA that is written for health professionals. You can also visit www.indevus.com on the internet.

Last updated on RxList: 8/5/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

HISTRELIN - IMPLANT

(HISS-treh-lin)

COMMON BRAND NAME(S): Supprelin LA, Vantas

USES: Histrelin is used in men to treat advanced prostate cancer. It is not a cure. Most types of prostate cancer need the male hormone testosterone to grow and spread. Histrelin works by reducing the amount of testosterone that the body makes. This helps slow or stop the growth of cancer cells and helps relieve symptoms such as painful/difficult urination.

Histrelin is also used in children to treat early puberty (central precocious puberty). It helps to slow abnormally fast bone development so that height and growth rate are near normal and to stop or reverse signs of early puberty (such as breast/pubic hair growth in girls, pubic hair growth in boys). Histrelin works by reducing the amount of testosterone in boys and estrogen in girls. This medication is used until the doctor decides it is time for puberty to resume.

HOW TO USE: Read the Patient Information Leaflet that comes with the histrelin implant. If you have any questions, consult your doctor.

Your doctor will surgically place the medicated implant under the skin of your upper arm. The implant releases histrelin into your blood slowly and continuously over 12 months. After 12 months, your doctor will remove the implant and replace it with a new one. Consult your doctor for details.

It is very important to keep the bandage in place for several days until the surgical incision heals. Keep the incision clean and dry. Avoid bathing and swimming for 24 hours after the procedure. Also avoid any heavy lifting, bumping of the incision site, or physical activity for 7 days after the procedure.

When you first start this medication, new or worsening symptoms may occur. This is a normal response by your body to this drug. Such symptoms should get better after the first month of treatment. Girls being treated for early puberty may notice vaginal bleeding or an increase in breast size or pubic hair. Boys being treated for early puberty may notice an increase in pubic hair. Tell the doctor if the symptoms persist or worsen after 1 month.

New or worsening symptoms may also occur at the beginning of treatment for prostate cancer. Tell your doctor immediately if you experience any of the following serious side effects: bone pain, numbness/tingling/weakness of the arms/legs, blood in the urine, painful/difficult urination, unusual weakness, inability to move. If you have prostate cancer that has spread to the spine or caused problems urinating due to blockage, you may require closer monitoring by your doctor, especially when you first start treatment.

SIDE EFFECTS: Irritation at the implant site (such as bruising, pain, redness), mood swings, or headache may occur. In men using this medication for prostate cancer, hot flashes (flushing), increased sweating, night sweats, tiredness, swelling of the ankles/feet, or constipation may occur. In girls using this medication for early puberty, breast tenderness or abnormal vaginal bleeding may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Infrequently, breast tenderness/swelling may occur in men and boys as a result of lowered testosterone levels. Shrinking of the testicles and reduced sexual interest/ability may also occur in men. Talk to your doctor if these effects occur.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

If you are a man using this medication for prostate cancer, tell your doctor immediately if any of these unlikely but serious side effects occur: new/worsening bone pain, easily broken bones.

Rarely, a very serious problem with the pituitary gland (pituitary apoplexy) has been reported with similar drugs, usually in the first 2 weeks after starting treatment. Seek immediate medical attention if any of these very serious side effects occur: sudden severe headache, sudden severe mental/mood changes (e.g., severe confusion, difficulty concentrating), vision changes, severe vomiting, fainting.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using histrelin, tell your doctor or pharmacist if you are allergic to it; or to similar drugs (e.g., leuprolide); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history.

If you are a man using this medication for prostate cancer, histrelin may weaken your bones and increase your risk for bone loss (osteoporosis) if used for a long time. Before using this medication, tell your doctor or pharmacist if you have osteoporosis or if you have any of the following risk factors for osteoporosis: long-term alcohol use, smoking, family history of osteoporosis and broken bones, use of certain medications (e.g., corticosteroids such as prednisone, certain anti-seizure drugs such as phenytoin).

This product is not approved for use in women. Histrelin must not be used during pregnancy. It may harm an unborn baby. Consult your doctor for details.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Laboratory and/or medical tests (such as blood testosterone level, PSA blood test if using for prostate cancer, blood testosterone/estradiol level, height, bone age if using for early puberty) should be performed periodically to monitor your progress. Consult your doctor for more details.

If you have radiology tests (X-rays, MRI), the histrelin implant will not be affected or affect the results of these tests. This implant does not show up on X-ray examination. However, make sure radiology personnel and all your doctors know you use this product.

MISSED DOSE: Infrequently, the implant can come out of the upper arm. If this occurs or you suspect that this has occurred, call your doctor. Keep all appointments so your doctor can make sure the implant is in place and working.

To help prevent a missed dose, mark your calendar to keep track of when to schedule the placement of your next implant.

STORAGE: Before implantation, the product should be refrigerated between 36-46 degrees F (2-8 degrees C). Protect from light and do not freeze.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.