The free base of sermorelin has the empirical formula C 149 H 246 N 44 O 42 S and a molecular weight of 3,358 daltons.

Geref® is a sterile, non-pyrogenic, lyophilized powder intended for subcutaneous injection after reconstitution with Sodium Chloride Injection, USP. The reconstituted solution has a pH of 5.0 to 5.5.

Geref® is available in vials. The quantitative composition per vial is:

0.5 mg vial: Each vial contains 0.5 mg sermorelin (as the acetate) and 5 mg mannitol. The pH is adjusted with dibasic sodium phosphate and monobasic sodium phosphate buffer.
1.0 mg vial: Each vial contains 1.0 mg sermorelin (as the acetate) and 5 mg mannitol. The pH is adjusted with dibasic sodium phosphate and monobasic sodium phosphate buffer.

CLINICAL PHARMACOLOGY
Geref® (sermorelin acetate for injection) increases plasma growth hormone (GH) concentration by stimulating the pituitary gland to release GH. Geref® is similar to the native hormone (GRF [1-44]-NH 2 ) in its ability to stimulate GH secretion in humans.

Pharmacokinetics

Absorption

In subcutaneous administration of 2 mg sermorelin to 12 normal volunteers, peak concentrations of sermorelin were reached in 5-20 minutes. The mean absolute bioavailability after SC administration is about 6%.

Distribution

After intravenous administration of 0.25-1.0 mg Geref® to 12 normal volunteers, the mean volume of distribution ranged between 23.7-25.8 liters.

Metabolism

No metabolism studies have been performed in humans.

Elimination

Sermorelin is rapidly cleared from the circulation, with clearance values in adults ranging between 2.4-2.8 L/min. The halflife of Geref® is short, 11-12 minutes after either intravenous or subcutaneous administration.

Special Populations

Gender/Age: No gender data are available in pediatric patients. In normal adults, the clearance of sermorelin in men and women is similar. No age data are available.

Renal/Hepatic Insufficiency: No data are available.

CLINICAL STUDIES
In one multicenter, open-label clinical study in prepubertal children with idiopathic growth hormone deficiency, 110 children were administered Geref® 0.03 mg (30 mcg) per kg per day by subcutaneous injection. Fifty-six patients were evaluable for efficacy at 12 months. Fifty-four patients were considered unevaluable: 24 for eligibility criteria violations; 10 for protocol discontinuation criteria and 20 for failing to satisfy the efficacy criteria at 6 months for continuing in the study. Fifty-six of all 110 patients and 47 of 56 patients in the evaluable patient subset who initiated and continued with Geref® therapy up to 12 months demonstrated an increase of 2 cm/year or more over the baseline height velocity (HV). For the 56 patients in the evaluable patient subset, mean height velocity (± SD) increased from 4.1 ± 1.0 cm/year at baseline to 8.0 ± 1.5 cm/year at 6 months and 7.2 ± 1.3 cm/year at 12 months, an increase of 3.1 ± 1.4 cm/year (p = 0.0001). Mean height standard deviation score (± SD) increased from -3.71 ± 0.92 at baseline to -3.21 ± 0.91 at 12 months, an increase of 0.50 ± 0.23 over the 12 month period (p = 0.0001). Mean changes in bone age at 12 months were proportional to gains in height (1.04 ± 0.58, (DELTA)BA/(DELTA)HA, n=42).

INDICATIONS AND USAGE
Geref® (sermorelin acetate for injection) is indicated for the treatment of idiopathic growth hormone deficiency in children with growth failure. Most of these short, slowly growing children retain pituitary responsiveness to growth hormone releasing hormone.

Selection of Patients and Evaluation of Growth
All children should be pre-pubescent and treatment should be initiated at a bone age of

CONTRAINDICATIONS
Geref® (sermorelin acetate for injection) should not be used by patients with a known sensitivity to sermorelin or any of the excipients.

WARNINGS
Following reconstitution of Geref® (sermorelin acetate for injection) with the diluent provided, the solution should be administered immediately. Any unused solution should be discarded.

PRECAUTIONS

General: Geref® (sermorelin acetate for injection) therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of growth disorders.

The growth response of children treated with Geref® should be evaluated on a periodic basis and children with a poor or waning response should be considered for treatment with growth hormone. The effect of Geref® therapy beyond one year and on final adult height remains to be determined.

In clinical studies, the incidence of hypothyroidism during Geref® therapy was 6.5%. In the largest clinical study, 8 of 110 enrolled patients were on thyroid replacement therapy prior to Geref® therapy and an additional 5 after initiating therapy. Untreated hypothyroidism can jeopardize the response to Geref®. Therefore, thyroid hormone determinations should be performed before the initiation and throughout the duration of Geref® therapy. Thyroid hormone replacement therapy should be initiated when indicated.

Bone age should be monitored periodically during Geref® administration, especially in patients who are pubertal and/or receiving concomitant thyroid replacement therapy. Under these circumstances, epiphyseal maturation may progress rapidly.

Patients with growth hormone deficiency secondary to an intracranial lesion were not studied in clinical trials. It is not recommended that such patients be treated with Geref®.

As with the administration of any peptide, local or systemic allergic reactions may occur. Parents/Patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.

Laboratory Tests: Serum levels of inorganic phosphorus, alkaline phosphatase, GH and IGF-1 may increase with Geref® therapy.

Drug Interaction: Concomitant glucocorticoid therapy may inhibit the response to Geref®. There was no evidence in the controlled studies of Geref®'s interaction with drugs commonly used in the treatment of routine pediatric problems/illnesses. However, formal drug interactions studies have not been conducted.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies for carcinogenicity and impairment of fertility have not been performed with Geref®. There has been no evidence from studies to date of Geref®-induced genetic toxicity.

Pregnancy: Pregnancy Category C. During teratology studies Geref® produced minor variations in fetuses of rats and rabbits when given at a dose of 0.5 mg/kg/day. This dose is approximately 3 and 6 times the daily human dose calculated on a body surface area (mg/m 2 ) basis, for rats and rabbits, respectively. There are no adequate and well controlled studies in pregnant women. Geref® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Women: It is not known whether Geref® is excreted in human milk. Because many drugs are excreted in human milk, cautions should be exercised when Geref® is administered to a nursing women.

Information For Patients: Patients being treated with Geref® and/or their parents should be informed of the potential benefits and risks associated with treatment. If home use is determined to be desirable by the physician, instructions on appropriate use should be given, including a review of the contents of the Patient Information Insert. This information is intended to aid in the safe and effective administration of the medication. It is not a disclosure of all possible adverse or intended effects.

If home use is prescribed, a puncture resistant container for the disposal of used syringes and needles should be recommended to the patient. Patients and/or parents should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes (see Patient Information Insert).

ADVERSE REACTIONS
A large proportion of patients develop anti-GRF antibodies at least once during treatment with Geref® (sermorelin acetate for injection). The significance of these antibodies is not clear and often a positive test at one growth assessment will become negative by the next assessment. The presence of antibodies does not appear to affect growth or appear to be related to a specific adverse reaction profile. No generalized allergic reactions to Geref® have been reported.

The most common treatment-related adverse event (occurring in about 1 patient in 6) is local injection reaction characterized by pain, swelling or redness. Of 350 patients exposed to Geref® in clinical trials, three discontinued therapy due to injection reactions. Other treatment-related adverse events had individual occurrence rates of less than 1% and include: headache, flushing, dysphagia, dizziness, hyperactivity, somnolence and urticaria.

When administered intravenously for diagnostic use, the following adverse reactions have been noted: flushing of the face, injection site pain, redness and/or swelling, nausea, headache, vomiting, dysgeusia, pallor and tightness in the chest.

DRUG ABUSE AND DEPENDENCE
The clinical pharmacology suggests that Geref® is very unlikely to be associated with drug abuse or dependence and there have been no reports of this from clinical trials.

OVERDOSAGE
The recommended dosage of Geref® (sermorelin acetate for injection) should not be exceeded.

DOSAGE AND ADMINISTRATION
A dosage of 0.03 mg (30 mcg) per kg of body weight once daily at bedtime by subcutaneous injection is recommended. It is also recommended that subcutaneous injection sites be periodically rotated.

Treatment with Geref® should be discontinued when the epiphyses are fused. Patients who fail to respond adequately while on Geref® therapy should be evaluated to determine the cause of unresponsiveness.

Height should be assessed at least every six months during treatment. During Geref® therapy, care shoud be taken to ensure that the child continues to grow at a rate consistent with the child's age and stage of development, and treatment with Geref® should be reevaluated if the response is inadequate. Treatment with growth hormone should be considered for children with a poor or waning response to Geref®.

To prevent possible contamination, wipe the rubber vial stopper with an antiseptic solution before puncturing it with the needle. It is recommended that Geref® be administered using sterile, disposable syringes and needles. The syringes should be of small enough volume that the prescribed dose can be drawn from the vial with reasonable accuracy.

After determining the appropriate patient dose, reconstitute each vial of Geref® with 0.5-1.0 mL of Sodium Chloride Injection, USP.

To reconstitute Geref®, inject the diluent into the vial of Geref® aiming the liquid against the glass vial wall. Swirl the vial with a GENTLE rotary motion until contents are dissolved completely. Do not administer Geref® if particles are visible in the reconstituted solution or if the reconstituted solution is cloudy.

HOW SUPPLIED
Before Reconstitution --Vials of Geref® (sermorelin acetate for injection) should be stored refrigerated (2°-8°C/36°-46°F). Expiration dates are stated on the labels.

After Reconstitution --When reconstituted with Sodium Chloride Injection, USP, the reconstituted solution should be administered immediately. Any unused solution should be discarded.

Geref® (sermorelin acetate for injection) is a sterile, nonpyrogenic, lyophilized powder supplied in packages containing:

1 vial 0.5 mg Geref® and 1 vial 2 mL Sodium Chloride Injection, USP NDC 44087-4005-1

1 vial 1.0 mg Geref® and 1 vial 2 mL Sodium Chloride Injection, USP NDC 44087-4010-1