Nafarelin Acetate for Central Precocious Puberty

Nafarelin acetate is a potent agonistic analog of gonadotropin-releasing hormone (GnRH). At the onset of administration, nafarelin stimulates the release of the pituitary gonadotropins, LH and FSH, resulting in a temporary increase of gonadal steroidogenesis. Repeated dosing abolishes the stimulatory effect on the pituitary gland.

Twice daily administration leads to decreased secretion of gonadal steroids by about 4 weeks; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent.

In children, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 45 minutes. Following a single dose of 400 μg base, the observed peak concentration was 2.2 ng/mL, whereas following a single dose of 600 μg base, the observed peak concentration was 6.6 ng/mL. The average serum half-life of nafarelin following intranasal administration of a 400 μg dose was approximately 2.5 hours. It is not known and cannot be predicted what the pharmacokinetics of nafarelin will be in children given a dose above 600 μg.

In adult women, nafarelin acetate was rapidly absorbed into the systemic circulation after intranasal administration. Maximum serum concentrations (measured by RIA) were achieved between 10 and 40 minutes. Following a single dose of 200 μg base, the observed average peak concentration was 0.6 ng/mL (range 0.2 to 1.4 ng/mL), whereas following a single dose of 400 μg base, the observed average peak concentration was 1.8 ng/mL (range 0.5 to 5.3 ng/mL). Bioavailability from a 400 μg dose averaged 2.8% (range 1.2 to 5.6%). The average serum half-life of nafarelin following intranasal administration was approximately 3 hours. About 80% of nafarelin acetate was bound to plasma proteins at 4°C. Twice daily intranasal administration of 200 or 400 μg of SYNAREL in 18 healthy women for 22 days did not lead to significant accumulation of the drug. Based on the mean Cmin levels on Days 15 and 22, there appeared to be dose proportionality across the two dose levels.

After subcutaneous administration of 14C-nafarelin acetate to men, 44–55% of the dose was recovered in urine and 18.5–44.2% was recovered in feces. Approximately 3% of the administered dose appeared as unchanged nafarelin in urine. The 14C serum half-life of the metabolites was about 85.5 hours. Six metabolites of nafarelin have been identified of which the major metabolite is Tyr-D(2)-Nal-Leu-Arg-Pro-Gly-NH2(5-10). The activity of the metabolites, the metabolism of nafarelin by nasal mucosa, and the pharmacoki netics of the drug in hepatically- and renally-impaired patients have not been determined.

There appeared to be no significant effect of rhinitis, i.e., nasal congestion, on the systemic bioavailability of SYNAREL; however, if the use of a nasal decongestant for rhinitis is necessary during treatment with SYNAREL, the d econgestant should not be used until at least 2 hours following dosing with SYNAREL.

When used regularly in girls and boys with central precocious puberty (CPP) at the recommended dose, SYNAREL suppresses LH and sex steroid hormone levels to prepubertal levels, affects a corresponding arrest of secondary sexual development, and slows linear growth and skeletal maturation. In some cases, initial estrogen withdrawal bleeding may occur, generally within 6 weeks after initiation of therapy. Thereafter, menstruation should cease.

In clinical studies the peak response of LH to GnRH stimulation was reduced from a pubertal response to a prepubertal response ( < 15 mlU/mL) within one month of treatment.

Linear growth velocity, which is commonly pubertal in children with CPP, is reduced in most children within the first year of treatment to values of 5 to 6 cm/year or less. Children with CPP are frequently taller than their chronological age peers; height for chronological age approaches normal in most children during the second or third year of treatment with SYNAREL. Skeletal maturation rate (bone age velocity—change in bone age divided by change in chronological age) is usually abnormal (greater than 1) in children with CPP; in most children, bone age velocity approaches normal (1) during the first year of treatment. This results in a narrowing of the gap between bone age and chronological age, usually by the second or third year of treatment. The mean predicted adult height increases.

In clinical trials, breast development was arrested or regressed in 82% of girls, and genital development was arrested or regressed in 100% of boys. Because pubic hair growth is largely controlled by adrenal androgens, which are unaffected by n afarelin, pubic hair development was arrested or regressed only in 54% of girls and boys.

Reversal of the suppressive effects of SYNAREL has been demonstrated to occur in all children with CPP for whom one-year post-treatment follow-up is available (n=69). This demonstration consisted of the appearance or return of menses, the return of pubertal gonadotropin and gonadal sex steroid levels, and/or the advancement of secondary sexual development. Semen analysis was normal in the two ejaculated specimens obtained thus far from boys who have been taken off therapy to resume puberty. Fertility has not been documen ted by pregnancies and the effect of long-term use of the drug on fertility is not known.

SYNAREL
(nafarelin acetate) Nasal Spray

Patient Instructions for Use

Introduction

The doctor has prescribed SYNAREL Nasal Solution to treat your child's abnormally early sexual development, which is called central precocious puberty. This pamphlet has two purposes:

1. to review information your doctor has given you about SYNAREL; and
2. to give you information about how to use SYNAREL properly.

Please read this pamphlet carefully. If you still have questions after reading it or if you have questions at any time during your child's treatment with SYNAREL, be sure to check with your child's doctor.

“Central precocious puberty” is called by that name because it is sexual development and growth (puberty) which happens at an abnormally young age (precocious). It is caused by early awakening of a small gland in the brain. Since the brain is part of the “central nervous system,” this early sexual development is called “central.”

In children, SYNAREL is used to relieve the symptoms of central precocious puberty (CPP). CPP is normal puberty that happens at an abnormally young age. In children who are going through puberty (whether it's normal puberty or CPP), a small gland at the base of the brain makes some normal substances that cause the ovaries in girls to make estrogen and progesterone, the female hormones. In boys, it causes the testes to make testosterone, the male hormone. Estrogen and testosterone are the hormones that make girls and boys change into adults. These changes are mainly of 2 kinds: sexual development and a growth spurt. Sexual development includes things like breast and sexual hair growth and menstruation in girls, and growth of sexual organs, sexual hair and facial hair, and voice deepening in boys. The growth spurt during puberty occurs when estrogen (girls) and testosterone (boys) make the long bones of the body grow, so that the child gets taller quickly. When this growth spurt starts at a young age as it does in CPP, children become too tall for their age, but are usually shorter than average as adults.

SYNAREL helps relieve the symptoms of CPP by temporarily preventing the small gland at the base of the brain from making and sending its substances to the ovaries and testes. The ovaries and testes stop producing their hormones as long as SYNAREL is taken regularly, and puberty is interrupted.

Important Information about SYNAREL

1. Your child should not use SYNAREL if she/he is allergic to GnRH or GnRH agonist analogues or to any of the ingredients of SYNAREL (nafarelin acetate, benzalkonium chloride, acetic acid, sodium hydroxide, hydrochloric acid, sorbitol, purified water).
2. SYNAREL is a prescription medicine that should be used according to the doctor's directions. SYNAREL comes as a special nasal spray that gives a measured amount of medicine. To be effective, SYNAREL must be used every day, twice a day, until you and your child's doctor decide that resumption of puberty is desired for your child. If your child doesn't take the right amount every day, or if she/he doesn't take SYNAREL on the regular prescribed schedule, pubertal development may be restarted and/or the beneficial effects on height may be lost.
3. Menstrual flow may occur in girls during the first six weeks of treatment, whether or not they had been menstruating before starting treatment with SYNAREL. Menstrual flow should stop soon after the first six weeks.
4. In children receiving SYNAREL for central precocious puberty, some signs of puberty (for example breast enlargement in girls) may increase during the first month of treatment. This is a normal effect of the drug. You should continue treatment at the prescribed dose.
5. It is all right for your child to use a nasal decongestant spray while she/he is being treated with SYNAREL if you follow these simple rules. Use SYNAREL first. Wait at least 2 hours after using SYNAREL before your child uses the decongestant spray.
6. Your child should avoid sneezing during or immediately after using SYNAREL, if possible, since sneezing may impair drug absorption.

Proper Use of SYNAREL for Treatment of Central Precocious Puberty

1. When your child starts to use SYNAREL she/he should continue taking it every day as prescribed. Do not miss any dose.
2. Unless your child's doctor has given you special instructions, Central Precocious Puberty patients should follow the steps for using SYNAREL twice each day in both nostrils, about 12 hours between doses:
   • two sprays in each nostril (4 sprays total) in the morning (for example, 7 a.m.);
   • two sprays in each nostril (4 sprays total) in the evening (for example, 7 p.m.).
     The head should be tilted slightly back, and you should wait about 30 seconds between sprays into the same nostril. More detailed instructions follow.
3. Treatment for central precocious puberty should continue until you and your child's doctor decide that it is appropriate for puberty to resume.
4. Because it is so important that your child not miss a single dose of SYNAREL, here are some suggestions to help you remember:
   • Keep your child's SYNAREL in a place where you will be reminded for her/him to use it each morning and each evening next to your toothbrush is one possibility.
   • Keep track of each dose on a calendar.
   • Make a note on your calendar on the day you start a new bottle of SYNAREL. You can also mark directly on the bottle the date it was started. Be sure to refill your child's prescription before the 7 days are up so you will have a new bottle on hand.
5. A bottle of SYNAREL for central precocious puberty patients should not be used for longer than 7 days, unless your child's doctor specifically tells you it may be used for a longer time. If the doctor tells you to use a bottle only for 7 days, then a small amount of liquid will be left in the bottle. Do not try to use up the leftover amount because your child might get too low a dose, which could interfere with the effectiveness of the treatment. Dispose of the used bottle properly and do not reuse.
6. If the doctor increases your child's daily dose of SYNAREL, then one bottle will not last the standard 7 days. Please discuss this with your child's doctor to be sure that you have an adequate supply for uninterrupted treatment with SYNAREL.

Preparation of the SYNAREL Nasal Spray unit

For use in your nose only.

Before you use a bottle of SYNAREL nasal spray for the first time, you will need to prime it. This will ensure that you get the right dose of medicine each time you use it.

Important Tips about using SYNAREL

• Your pump should produce a fine mist, which can only happen by a quick and firm pumping action. It is normal to see some larger droplets of liquid within the fine mist. However, if SYNAREL comes out of the pump as a thin stream of liquid instead of a fine mist, SYNAREL may not work as well, and you should talk to your pharmacist.
• Be sure to clean the Spray Tip before and after every use. (See Step 4). Failure to do this may result in a clogged tip that may cause you not to get the right amount of medicine that is prescribed for you.
• The pump is made to deliver only a set amount of medicine, no matter how hard you pump it.
• Do Not try to make the tiny hole in the spray tip larger. If the hole is made larger the pump will deliver a wrong dose of SYNAREL.

Figure A

To Prime the Pump:

1. Remove and save the white safety clip and the clear plastic dust cover from the spray bottle (See Figure B).

Figure B

2. Hold the bottle in an upright position away from you. Put two fingers on the “shoulders” of the spray bottle and put your thumb on the bottom of the bottle. Apply pressure evenly to the “shoulders” and push down quickly and firmly 7 to 10 times, until you see a fine spray. Usually you will see the spray after about 7 pumps. (See Figure C).

Figure C

3. The pump is now primed. Priming only needs to be done 1 time, when you start using a new bottle of SYNAREL. You will waste your medicine if you prime the pump every time you use it and may not have enough medicine for the recommended treatment period.

4. Clean the Spray Tip after Priming:

• Hold the bottle in horizontal position. Rinse spray the tip with warm water while wiping the tip with your finger or soft cloth for 15 seconds.
• Wipe the spray tip with a soft cloth or tissue to dry.
• Replace the white safety clip and the clear plastic dust cover on the spray bottle. (See Figure D).
• Do Not try to clean the spray tip using a pointed object. Do Not take apart the pump.

Figure D

How to use the SYNAREL Nasal Spray unit for the treatment of Central Precocious Puberty

5. Have your child blow their nose to clear both nostrils before SYNAREL nasal spray is used. If the child is young, you may need to clear the child's nostrils with a bulb syringe (See Figure E).

Figure E

6. Clean the Spray Tip. Remove and save the white safety clip and the clear plastic dust cover from the spray bottle (See Figure F).

Hold the bottle in horizontal position. Rinse the spray tip with warm water while wiping the tip with your finger or soft cloth for 15 seconds. Wipe the spray tip with a soft cloth or tissue to dry.

Do Not try to clean the spray tip using a pointed object.

Do Not try to take apart the pump.

Figure F

7. The child's head should be bent back a little and the spray tip put into one nostril. The tip should not reach too far into the nose. Aim the spray tip toward the back and outer side of the nose (See Figure G).

Figure G

8. Close the other nostril with a finger (See Figure H).

Figure H

9. Apply pressure evenly to the “shoulders” and push down quickly and firmly. Pump the sprayer 1 time, at the same time as the child sniffs in gently. Wait about 30 seconds and apply one more spray in the same nostril. Repeat this process in the other nostril, for a total of four sprays. If the sprayer fails to deliver the dose clean the spray tip (See Step 6 Clean the Spray Tip).

10.Remove the spray tip from the child's nose after all sprays are completed. Keep the child's head tilted backwards for a few seconds. This lets the SYNAREL spray spread over the back of the nose (See Figure I).

Figure I

11. Clean the Spray Tip after use (See Step 4).

Figure J

It is important that you clean the spray tip before and after every use. Failure to do this may result in a clogged tip that may cause you to get the wrong dose of medicine.

Important Reminder: Treatment with SYNAREL must be uninterrupted with no missed doses to be effective.

Make sure you use SYNAREL exactly as your doctor tells you to. Make sure to note the date you start each bottle so you do not run out of medicine and miss doses.

Keep out of the reach of children and use carefully as directed.

• Storage Instructions:
• Store SYNAREL at 59°F to 86°F (15°C to 30°C).
• Store the SYNAREL bottle upright.
• Keep SYNAREL out of the light.
• Do not freeze SYNAREL.