GENOTROPIN 1.5 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 1.5 mg (approximately 4.5 IU), glycine 27.6 mg, sodium dihydrogen phosphate anhydrous 0.3 mg, and disodium phosphate anhydrous 0.3 mg; the rear chamber contains 1.13 mL water for injection.

GENOTROPIN 5.8 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 5.8 mg (approximately 17.4 IU), glycine 2.2 mg, mannitol 1.8 mg, sodium dihydrogen phosphate anhydrous 0.32 mg, and disodium phosphate anhydrous 0.31 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and mannitol 45 mg in 1.14 mL water for injection.

GENOTROPIN 13.8 mg is dispensed in a two-chamber cartridge. The front chamber contains recombinant somatropin 13.8 mg (approximately 41.4 IU), glycine 2.3 mg, mannitol 14.0 mg, sodium dihydrogen phosphate anhydrous 0.47 mg, and disodium phosphate anhydrous 0.46 mg; the rear chamber contains 0.3% m-Cresol (as a preservative) and mannitol 32 mg in 1.13 mL water for injection.

GENOTROPIN MINIQUICK™ is dispensed as a single-use syringe device containing a two-chamber cartridge. GENOTROPIN MINIQUICK™ is available as individual doses of 0.2 mg to 2.0 mg in 0.2-mg increments. The front chamber contains recombinant somatropin 0.22 to 2.2 mg (approximately 0.66 to 6.6 IU), glycine 0.23 mg, mannitol 1.14 mg, sodium dihydrogen phosphate 0.05 mg, and disodium phosphate anhydrous 0.027 mg; the rear chamber contains mannitol 12.6 mg in water for injection 0.275 mL.

GENOTROPIN is a highly purified preparation. The reconstituted recombinant somatropin solution has an osmolality of approximately 300 mOsm/kg, and a pH of approximately 6.7. The concentration of the reconstituted solution varies by strength and presentation (see HOW SUPPLIED section).

CLINICAL PHARMACOLOGY
In vitro, preclinical, and clinical tests have demonstrated that GENOTROPIN Lyophilized Powder is therapeutically equivalent to human growth hormone of pituitary origin and achieves similar pharmacokinetic profiles in normal adults. Treatment of growth hormone-deficient (GHD) pediatric patients with GENOTROPIN stimulates linear growth and normalizes concentrations of IGF-I (Insulin-like Growth Factor/Somatomedin-C). Treatment of GHD adults with GENOTROPIN results in reduced fat mass, increased lean body mass, metabolic alterations that include beneficial changes in lipid metabolism, and normalization of IGF-I concentrations.

In addition, the following actions have been demonstrated for GENOTROPIN and/or somatropin.

Tissue Growth
Skeletal Growth: GENOTROPIN stimulates skeletal growth in pediatric patients with GHD. The measurable increase in body length after administration of GENOTROPIN results from an effect on the epiphyseal plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are generally low in the serum of pediatric GHD patients but tend to increase during treatment with GENOTROPIN. Elevations in mean serum alkaline phosphatase concentration are also seen.
Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as compared with the normal pediatric population. Treatment with somatropin results in an increase in both the number and size of muscle cells.

Protein Metabolism
Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with GENOTROPIN.

Carbohydrate Metabolism
Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with GENOTROPIN. Large doses of growth hormone may impair glucose tolerance.

Lipid Metabolism
In GHD patients, administration of somatropin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.

Mineral Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus. Serum concentrations of inorganic phosphate are increased in patients with GHD after therapy with GENOTROPIN. Serum calcium is not significantly altered by GENOTROPIN. Growth hormone could increase calciuria.

Body Composition
Adult GHD patients treated with GENOTROPIN at the recommended adult dose (see DOSAGE AND ADMINISTRATION ) demonstrate a decrease in fat mass and an increase in lean body mass. When these alterations are coupled with the increase in total body water, the overall effect of GENOTROPIN is to modify body composition, an effect that is maintained with continued treatment.

PHARMACOKINETICS

Absorption
Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN to adult GHD patients, approximately 80% of the dose was systemically available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been observed in healthy adult male subjects.

In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN was 35% greater than that for 1.3 mg/mL GENOTROPIN. The mean (± standard deviation) peak (C max ) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL, respectively.

In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN. The mean C max levels were 21.0 ng/mL and 16.3 ng/mL, respectively.

Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN at a concentration of 1.3 mg/mL, with a one- to four-week washout period between injections. Mean C max levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.

There are no data on the bioequivalence between the 12 mg/mL formulation and either the 1.3 mg/mL or the 5.3 mg/mL formulations.

Distribution
The mean volume of distribution of GENOTROPIN following administration of GHD adults was estimated to be 1.3 (± 0.8) L/kg.

Metabolism
The metabolic fate of GENOTROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN in normal adults is 0.4 hours, whereas subcutaneously administered GENOTROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.

Excretion
The mean clearance of subcutaneously administered GENOTROPIN in 16 GHD adult patients was 0.3 (± 0.11) L/hrs/kg.

Special Populations
Pediatric The pharmacokinetics of GENOTROPIN are similar in GHD pediatric and adult patients.

Gender: No gender studies have been performed in pediatric patients; however, GHD adults, the absolute bioavailability of GENOTROPIN was similar in males and females.

Race: No studies have been conducted with GENOTROPIN to assess pharmacokinetic differences among races.

Renal or hepatic insufficiency: No studies have been conducted with GENOTROPIN in these patient populations.

Table 1
Mean SC pharmacokinetic parameters in adult GHD patients Bioavailability
(%)
(N = 15) T max
(hours)
(N = 16) CL/F
(L/hr × kg)
(N = 16) Vss/F
(L/kg)
(N = 16) T ½
(hours)
(N = 16)
Mean 80.5 5.9 0.3 1.3 3.0
(± SD) * (± 1.65) (± 0.11) (± 0.80) (± 1.44)
95% Cl 70.5 - 92.1 5.0 - 6.7 0.2 - 0.4 0.9 - 1.8 2.2 - 3.7
T max = time of maximum plasma concentration
CL/F = plasma clearance
Vss/F = volume of distribution
T ½ = terminal half-life
SD = standard deviation
Cl = confidence interval
* The absolute bioavailability was estimated under the assumption that the log-transformed data follow a normal distribution. The mean and standard deviation of the log-transformed data were mean = 0.22 (± 0.241).

CLINICAL STUDIES IN ADULT GHD PATIENTS
GENOTROPIN Lyophilized Powder was compared with placebo in six randomized clinical trials involving a total of 172 adult GHD patients. These trials included a 6-month double-blind treatment period, during which 85 patients received GENOTROPIN and 87 patients received placebo, followed by an open-label treatment period in which participating patients received GENOTROPIN for up to a total of 24 months. GENOTROPIN was administered as a daily SC injection at a dose of 0.04 mg/kg week for the first month of treatment and 0.08 mg/kg/week for subsequent months.

Beneficial changes in body composition were observed at the end of the 6-month treatment period for the patients receiving GENOTROPIN as compared with the placebo patients. Lean body mass, total body water, and lean/fat ratio increased while total body fat mass and waist circumference decreased. These effects on body composition were maintained when treatment was continued beyond 6 months. Bone mineral density declined after 6 months of treatment but returned to baseline values after 12 months of treatment.

INDICATIONS AND USAGE
GENOTROPIN Lyophilized Powder is indicated for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone. Other causes of short stature should be excluded.

GENOTROPIN is indicated for long-term replacement therapy in adults with GHD of either childhood- or adult-onset etiology. GHD should be confirmed by an appropriate growth hormone stimulation test.

CONTRAINDICATIONS
GENOTROPIN Lyophilized Powder should not be used when there is any evidence of neoplastic activity. Intracranial lesions must be inactive and antitumor therapy complete prior to the institution of therapy. GENOTROPIN should be discontinued if there is evidence of tumor growth. Growth hormone should not be used for growth promotion in pediatric patients with fused epiphyses.

Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs 19.3%) among somatropin treated patients (doses 5.3 to 8 mg/day) compared to those receiving placebo (see WARNINGS ).

WARNINGS
The 5.8 mg and 13.8 mg presentations of GENOTROPIN Lyophilized Powder contain m-Cresol as a preservative. These products should not be used by patients with a known sensitivity to this preservative. The GENOTROPIN 1.5 mg and GENOTROPIN MINIQUICK presentations are preservative-free. (See HOW SUPPLIED section.)

See CONTRAINDICATIONS for information or increased mortality in patients with acute critical illnesses in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma, or with acute respiratory failure. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients having acute critical illnesses should be weighed against the potential risk.

PRECAUTIONS

General
Treatment with GENOTROPIN Lyophilized Powder, as with other growth hormone preparations, should be directed by physicians who are experienced in the diagnosis and management of patients with GHD.

Patients and caregivers who will administer GENOTROPIN in medically unsupervised situations should receive appropriate training and instruction on the proper use of GENOTROPIN from the physician or other suitably qualified health professional.

Patients with GHD secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process. Review of literature reports of pediatric use of somatropin replacement therapy reveals no relationship between this therapy and recucrrence of central nervous system (CNS) tumors. In adults, it is unknown whether there is any relationship between somatropin treatment and CNS tumor recurrence.

Patients should be monitored carefully for any malignant transformation of skin lesions.

Caution should be used if growth hormone is administered to patients with diabetes mellitus, and insulin dosage may need to be adjusted. Because growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose intolerance should be monitored closely during treatment with GENOTROPIN.

In patients with hypopituitarism (multiple hormonal deficiencies) standard hormonal replacement therapy should be monitored closely when treatment with GENOTROPIN is instituted. Hypothyroidism may develop during treatment with GENOTROPIN, and inadequate treatment of hypothyroidism may prevent optimal response to GENOTROPIN. Therefore, patients should have periodic thyroid function tests and be treated with thyroid hormone when indicated.

Pediatric patients with endocrine disorders, including GHD, have a higher incidence of slipped capital femoral epiphyses. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during growth hormone therapy should be evaluated.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with growth hormone products. Symptoms usually occurred within the first 8 weeks of the initiation of growth hormone therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the growth hormone dose. Funduscopic examination of patients is recommended at the initiation, and periodically during the course of, growth hormone therapy.

Before continuing treatment as an adult, a post-pubertal GHD patient who received growth hormone replacement therapy in childhood should be reevaluated with proper testing as described in INDICATIONS AND USAGE . If continued treatment is appropriate, GENOTROPIN should be administered at the reduced dose level recommended for adult GHD patients.

Drug Interactions
Concomitant glucocorticoid treatment may inhibit the growth-promoting effect of growth hormone. Pediatric GHD patients with coexisting ACTH deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth. See also PRECAUTIONS - General . Limited published data indicate that growth hormone treatment increases cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that growth hormone administration may alter the clearance of compounds known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when growth hormone is administered in combination with other drugs known to be metabolized by CP450 liver enzymes.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with rhGH. No potential mutagenicity of rhGH was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells growth in vitro (mouse L5178Y cells), and chromosomal damage in intact animals (bone marrow cells in rats). See PREGNANCY section for effect on fertility.

Pregnancy: Pregnancy Category B
Reproduction studies carried out with GENOTROPIN at doses of 0.3, 1, and 3.3 mg/kg/day administered SC in the rat and 0.08, 0.3, and 1.3 mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic. In rats receiving SC doses during gametogenesis and up to 7 days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day (approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted.

In perinatal and postnatal studies in rats, GENOTROPIN doses of 0.3, 1, and 3.3 mg/kg/day produced growth-promoting effects in the dams but not in the fetuses. Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offsprings due to GENOTROPIN. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers
There have been no studies conducted with GENOTROPIN in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GENOTROPIN is administered to a nursing woman.

ADVERSE REACTIONS
As with all protein drugs, a small number of patients may develop antibodies to the protein. Growth hormone antibody with binding lower than 2 mg/L has not been associated with growth attenuation. In some cases when binding capacity is > 2 mg/L, interference with growth response has been observed.

In 419 pediatric patients evaluated in clinical studies with GENOTROPIN Lyophilized Powder, 244 had been treated previously with GENOTROPIN or other growth hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously treated patients at baseline. Three of the six became negative for anti-HGH antibodies during 6 to 12 months of treatment with GENOTROPIN. Of the remaining 413 patients, eight (1.9%) developed detectable anti-HGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients.

Preparations of GENOTROPIN contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients treated with GENOTROPIN, but these appear to be of no clinical significance.

In clinical studies with GENOTROPIN in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild hyperglycemia.

Leukemia has been reported in a small number of pediatric patients who have been treated with growth hormone, including growth hormone of pituitary origin and recombinant somatropin. The relationship, if any, between leukemia and growth hormone therapy is uncertain.

In clinical trials with GENOTROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction.

Table 2 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN. Also presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials.

Table 2
Adverse events reported by >/= 5% of 1,145 adult GHD patients during clinical trials of
GENOTROPIN and placebo, grouped by duration of treatment Double Blind Phase Open Label Phase
GENOTROPIN
Adverse Event Placebo
0-6 mo.
n = 572
% Patients GENOTROPIN
0-6 mo.
n = 573
% Patients 6-12 mo.
n = 63
% Patients 12-18 mo.
n = 63
% Patients 18-24 mo.
n = 60
% Patients
Swelling, peripheral 5.1 17.5 * 5.6 0 1.7
Arthralgia 4.2 17.3 * 6.9 6.3 3.3
Upper respiratory infection 14.5 15.5 13.1 15.9 13.3
Pain, extremities 5.9 14.7 * 6.7 1.6 3.3
Edema, peripheral 2.6 10.8 * 3.0 0 0
Paresthesia 1.9 9.6 * 2.2 3.2 0
Headache 7.7 9.9 6.2 0 0
Stiffness of extremities 1.6 7.9 * 2.4 1.6 0
Fatigue 3.8 5.8 4.6 6.3 1.7
Myalgia 1.6 4.9 * 2.0 4.8 6.7
Back pain 4.4 2.8 3.4 4.8 5.0
* increased significantly when compared to placebo, P n = number of patients receiving treatment during the indicated period.
% = percentage of patients who reported the event during the indicated period.

In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN. Of the 3,031 patients receiving GENOTROPIN, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia.

OVERDOSAGE
There is little information on acute or chronic overdosage with GENOTROPIN Lyophilized Powder. Intravenously administered growth hormone has been shown to result in an acute decrease in plasma glucose. Subsequently, hyperglycemia was seen. It is thought that the same effect might occur on rare occasions with a high dosage of GENOTROPIN administered SC. Long-term overdosage may result in signs and symptoms of acromegaly consistent with overproduction of growth hormone.

DOSAGE AND ADMINISTRATION
The dosage of GENOTROPIN Lyophilized Powder must be adjusted for the individual patient. The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.

Pediatric GHD Patients: Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.

Adult GHD Patients: The recommended dosage at the start of therapy is not more than 0.04 mg/kg/week. The dose may be increased at 4- to 8-week intervals according to individual patient requirements to a maximum of 0.08 mg/kg/week, depending upon patient tolerance of treatment. Clinical response, side effects, and determination of age-adjusted serum IGF-I may be used as guidance in dose titration. This approach will tend to result in weight-adjusted doses that are larger for women compared with men and smaller for older and obese patients.

GENOTROPIN must not be injected intravenously.

GENOTROPIN is supplied in a two-chamber cartridge, with the lyophilized powder in the front chamber and a diluent in the rear chamber. A reconstitution device is used to mix the diluent and powder.

Follow the directions for reconstitution provided with each device. Do not shake ; shaking may cause denaturation of the active ingredient.

All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If the solution is cloudy, the contents MUST NOT be injected.

Patients and caregivers who will administer GENOTROPIN in medically unsupervised situations should receive appropriate training and instruction on the proper use of GENOTROPIN from the physician or other suitably qualified health professional.

STABILITY AND STORAGE
Except as noted below, store GENOTROPIN Lyophilized Powder under refrigeration at 2° to 8°C (36° to 46°F). Do not freeze. Protect from light.

The 1.5 mg cartridge of GENOTROPIN contains a diluent with no preservative. After reconstitution, the cartridge may be stored under refrigeration for up to 24 hours. Use once only and discard any remaining solution.

The 5.8 mg and 13.8 mg cartridges of GENOTROPIN contain a diluent with a preservative. Thus, after reconstitution, they may be stored under refrigeration for up to 21 days.

1.5 mg two-chamber cartridge (without preservative)

concentration of 1.3 mg/mL (approximately 4 IU/mL)

Preassembled in a GENOTROPIN INTRA-MIX™ Growth Hormone Reconstitution Device and packaged with a pressure release needle

Package of 5 NDC 0013-2606-94

5.8 mg two-chamber cartridge (with preservative)

concentration of 5 mg/mL (approximately 15 IU/mL)

For use with the GENOTROPIN PEN™ 5 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER™ Growth Hormone Reconstitution Device

Package of 5 NDC 0013-2626-94
Package of 1 NDC 0013-2626-81

Preassembled in a GENOTROPIN INTRA-MIX™ Growth Hormone Reconstitution Device and packaged with a pressure release needle

Package of 5 NDC 0013-2616-94
Package of 1 NDC 0013-2616-81

13.8 mg two-chamber cartridge (with preservative)

concentration of 12 mg/mL (approximately 36 IU/mL)

For use with the GENOTROPIN PEN™ 12 Growth Hormone Delivery Device and/or the GENOTROPIN MIXER Growth Hormone Reconstitution Device

Package of 5 NDC 0013-2646-94
Package of 1 NDC 0013-2646-81

GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)

After reconstitution, each GENOTROPIN MINIQUICK delivers a fixed volume of 0.25 mL, regardless of strength. Available in the following strengths, each in a package of 7:

0.2 mg NDC 0013-2649-02

0.4 mg NDC 0013-2650-02

0.6 mg NDC 0013-2651-02

0.8 mg NDC 0013-2652-02

1.0 mg NDC 0013-2653-02

1.2 mg NDC 0013-2654-02

1.4 mg NDC 0013-2655-02

1.6 mg NDC 0013-2656-02

1.8 mg NDC 0013-2657-02

2.0 mg NDC 0013-2658-02