Lilly announces first available therapy for Somatropin Deficiency Syndrome in adults.

INDIANAPOLIS--(HealthWire)--Aug. 8, 1996--Eli Lilly and Company announced today that is has received U.S. Food and Drug Administration permission to market Humatrope(R) (somatropin (rDNA origin) for injection) for Somatropin Deficiency Syndrome (SDS) in adults. The agency's action makes Humatrope the first therapy available for U.S. adults who suffer from SDS, frequently associated with hypopituitarism.

Humatrope is a synthetic human growth hormone (hGH) that has been used since 1987 as a replacement therapy for children who do not produce enough or any of their own hGH. The FDA cleared the new adult indication for Humatrope after reviewing clinical data from multinational studies that were submitted to the federal agency by Lilly in August 1995.

"This new use for Humatrope is an example of how continued study of a drug can offer new hope to patients who before now had no therapeutic option for their disorder," said August M. Watanabe, M.D., executive vice president of science and technology for Lilly.

SDS adults may have hypopituitarism as a result of pituitary tumors, trauma, or other pituitary disorders, or they may have been treated for growth hormone deficiency as children. Adults with SDS suffer from metabolic disorders that affect their physical mobility, socialization, and energy levels, as well as their life expectancy. Some epidemiologic studies have suggested that adults with SDS are at greater risk of cardiovascular disease than adults without the disorder.

In clinical trials, Humatrope therapy improved some of the symptoms that SDS patients experienced. Humatrope therapy resulted in an increase in lean muscle mass, a decrease in body fat, an increase in exercise capacity, and normalization of low HDL cholesterol levels in SDS patients. Patients who developed SDS in adulthood also reported, in a general, health-related quality of life questionnaire (the Nottingham Health Profile), improvements in physical mobility and social isolation, two health-related domains measured by the Profile. An increase in another domain, energy level, was also reported by adult onset SDS patients after 18 months of Humatrope therapy. The data for patients who developed SDS in childhood did not reflect Nottingham Health Profile improvements. Early in clinical trials, SDS patients taking Humatrope experienced edema and peripheral edema more frequently than patients receiving placebo. Other signs and symptoms reported during therapy include edema, joint pains or disorders, back pain, headaches, muscle aches, hypertension and rhinitis. Many of the signs and symptoms reported during therapy, however, resolved either spontaneously or in response to dosage adjustments.

Hypopituitary and somatropin deficient adults should consult with an endocrinologist regarding the potential benefits and risks of replacement therapy with Humatrope. Humatrope therapy would be a supplement to any other hormone replacement therapy that hypopituitary patients may already be receiving (for example, estrogen, thyroid or hydrocortisone).

Humatrope already has been approved for somatropin replacement therapy in adults in several countries outside the United States -- Greece, New Zealand, Sweden, Denmark, France, Germany, Spain, the Netherlands, Mexico, the United Kingdom, Norway and Finland. The drug also has been approved to treat growth hormone deficiency in children and Turner Syndrome in many countries outside the United States.

Lilly is a global research-based pharmaceutical corporation headquartered in Indianapolis, Ind., that is dedicated to creating and delivering superior health care solutions -- by combining pharmaceutical innovation, existing pharmaceutical technology, disease prevention and management and information technologies -- in order to provide customers worldwide with optimal clinical and economic outcomes. Endocrine diseases are one of five therapeutic areas in which the company is focusing its efforts.

Full prescribing information for Humatrope(R) (somatropin (rDNA origin) for injection) will be faxed immediately upon request. -0-

Description: Humatrope (somatropin (rDNA origin) for injection)) is a polypeptide hormone of recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of about 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin. Humatrope is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.

Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after reconstitution. Each vial of Humatrope contains 5 mg somatropin (15IU (see footnote) or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Phosphoric acid and/or sodium hydroxide may have been added at the time of manufacture to adjust the pH. This product is oxygen sensitive. Each vial is supplied in a combination package with an accompanying 5-mL vial of diluting solution. The diluent contains water for injection with 0.3% m-cresol as a preservative and 1.7% glycerin added at the time of manufacture.

Humatrope is a highly purified preparation. The 1.7% glycerin content makes the reconstituted product nearly isotonic at a concentration of 2 mg of Humatrope/mL diluent. Reconstituted solutions have a pH of approximately 7.5.

Clinical Pharmacology: General: Linear Growth -- Humatrope stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth hormone-deficient pediatric patients with Humatrope produces increased growth rate and IGF-I (Insulin-Like Growth Factor-I/Somatomedin-C) concentrations similar to those seen after therapy with human growth hormone of pituitary origin.

In addition, the following actions have been demonstrated for Humatrope and/or human growth hormone of pituitary origin.

A. Tissue Growth -- 1. Skeletal Growth: Humatrope stimulates skeletal growth in pediatric patients with growth hormone deficiency. The measurable increase in body length after administration of either Humatrope or human growth hormone of pituitary origin results from an effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations are also seen. 2. 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 normal pediatric populations. Treatment with human growth hormone of pituitary origin results in an increase in both the number and size of muscle cells.

B. 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 human growth hormone of pituitary origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen.

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

D. Lipid Metabolism -- In growth hormone-deficient patients, administration of human growth hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids.

E. Mineral Metabolism -- Retention of sodium, potassium, and phosphorus is induced by human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with Humatrope or human growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated with either human growth hormone of pituitary origin or Humatrope.

Pharmacokinetics: Absorption -- Humatrope has been studied following intramuscular, subcutaneous, and intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75% and 63% after subcutaneous and intramuscular administration, respectively.

Distribution -- The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg.

Metabolism -- Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products of growth hormone is returned to the systemic circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site.

Excretion -- Urinary excretion of intact Humatrope has not been measured. Small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy.

Special Populations: Geriatric -- The pharmacokinetics of Humatrope has not been studied in patients greater than 60 years of age.

Pediatric -- The pharmacokinetics of Humatrope in pediatric patients is similar to adults.

Gender -- No studies have been performed with Humatrope. The available literature indicates that the pharmacokinetics of growth hormone is similar in both men and women.

Race -- No data are available.

Renal, Hepatic insufficiency -- No studies have been performed with Humatrope.

Table 1, entitled Summary of Somatropin Parameters in the Normal Population, could not be transmitted in full and correct form by wire. Please call 317/277-6265 to request an immediate facsimile transmission of the full package insert including this table.

The figure following Table 1 entitled Single Dose Average Plasma Concentrations vs. Time in Normal Adult Volunteers, could not be transmitted in full and correct form by wire. Please call 317/277-6265 to request an immediate facsimile transmission of the full package insert including this figure.

Effects of Humatrope treatment in adults with somatropin deficiency: Two multicenter trials in adult onset somatropin deficiency (n=98) and two studies in childhood onset somatropin deficiency (n=67) were designed to assess the effects of replacement therapy with Humatrope. The primary efficacy measures were body composition (lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The Nottingham Health Profile is a general health-related quality of life questionnaire. These four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by 12 months of open-label therapy for all patients. The Humatrope dosages for all studies were identical: one month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose of 0.0125 mg/kg/day. Adult onset patients and childhood onset patients differed by diagnosis (organic versus idiopathic pituitary disease), body size (normal versus small for mean height and weight), and age (mean = 44 versus 29 years). Lean body mass was determined by bioelectrical impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analyzed by standard assay methods in a central laboratory.

Humatrope-treated adult onset patients, as compared to placebo, experienced an increase in lean body mass (2.59 versus -0.22 kg, p less than 0.001) and a decrease in body fat (-3.27 versus 0.56 kg, p less than 0.001). Similar changes were seen in childhood onset somatropin deficient patients. These significant changes in lean body mass persisted throughout the 18 month period as compared to baseline for both groups, and for fat mass in the childhood onset group. Total cholesterol decreased short term (first 3 months) although the changes did not persist. However, the low HDL cholesterol levels observed at baseline (mean = 30.1 mg/mL and 33.9 mg/mL in adult onset and childhood onset patients) normalized by the end of 18 months of therapy (a change of 13.7 and 11.1 mg/dL for the adult onset and childhood onset groups, p less than 0.001). Adult onset patients reported significant improvements (p less than 0.01) in the following 3 of 6 possible health related domains: energy level (at 18 months), physical mobility (as compared to placebo at 6 months and baseline at 18 months) and social isolation (as compared to placebo at 6 months) (Table 2). Patients with childhood onset disease failed to demonstrate improvements in Nottingham Health Profile outcomes.

Two additional studies on the effect of Humatrope on exercise capacity were also conducted. Improved physical function was documented by increased exercise capacity (VO2 max, p less than 0.005) and work performance (Watts,p less than 0.01)(J Clin Endocrinol Metab 1995; 80:552-557). -0-

                                 Table 2
               Changes in Nottingham Health Profile Scores(a)
               in Adult Onset Somatropin Deficient Patients
____________________________________________________________________
Outcome Placebo Humatrope Significance(b) Humatrope Significance(c)
Measure(6 Months)Therapy                 (18 Months)
                (6 Months)
____________________________________________________________________
Energy   -11.4   -15.5          NS         -17.8       p lt(d) 0.01
Level
____________________________________________________________________
Physical  -3.1   -10.5     p lt(d) 0.01    -11.3       p lt(d) 0.01
Mobility
____________________________________________________________________
Social     0.5    -4.7     p lt(d) 0.01     -3.7            NS
Isolation
____________________________________________________________________
Emotional -4.5    -5.4          NS          -6.7       p lt(d) 0.05
Reactions
____________________________________________________________________
Sleep     -6.4    -3.7          NS          -7.9       p lt(d) 0.05
____________________________________________________________________
Pain      -2.8    -2.9          NS          -3.8            NS
____________________________________________________________________
a = Using Bonferroni's correction the required level of
    significance is 0.01.
b = change over 6 months (between group)
c = change over 18 months (within group)
d = less than

NS = not significant

Indications and Usage: Pediatric Patients -- Humatrope is indicated for the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of normal endogenous growth hormone.

Adult Patients -- Humatrope is indicated for replacement of endogenous somatropin in adults with somatropin deficiency syndrome who meet both of the following two criteria:

1. Biochemical diagnosis of somatropin deficiency syndrome, by means of a negative response to a standard growth hormone stimulation test (maximum peak less than 5 ng/mL when measured by RIA (polyclonal antibody) or less than 2.5 ng/mL when measured by IRMA (monoclonal antibody)); and

2. Adult Onset: Patients who have somatropin deficiency syndrome, either alone or with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or

Childhood Onset: Patients who were growth hormone-deficient during childhood who have somatropin deficiency syndrome confirmed as an adult before replacement therapy with Humatrope is started.

Contraindications: Humatrope should not be used for growth promotion in pediatric patients with closed epiphyses.

Humatrope should not be used when there is any evidence of activity of a tumor. Intracranial lesions must be inactive and antitumor therapy complete prior to the institution of therapy. Humatrope should be discontinued if there is evidence of tumor growth.

Humatrope should not be reconstituted with the supplied Diluent for Humatrope by patients with a known sensitivity to either m-cresol or glycerin.

Warning: If sensitivity to the diluent should occur, the vials may be reconstituted with Sterile Water for Injection, USP. When Humatrope is reconstituted in this manner (1) use only 1 reconstituted dose per vial, (2) refrigerate the solution (36 degrees to 46 degrees F (2 degrees to 8 degrees C)) if it is not used immediately after reconstitution, (3) use the reconstituted dose within 24 hours, and (4) discard the unused portion.

Precautions: Therapy with Humatrope should be directed by physicians who are experienced in the diagnosis and management of patients with growth hormone deficiency.

Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has demonstrated no relationship between somatropin replacement therapy and CNS tumor recurrence. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence.

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

For patients with diabetes mellitus, the insulin dose may require adjustment when somatropin therapy is instituted. Because human 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 somatropin therapy.

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

Excessive glucocorticoid therapy will inhibit the growth promoting effect of human growth hormone. Patients with coexisting ACTH deficiency should have their glucocorticoid replacement dose carefully adjusted to avoid an inhibitory effect on growth.

Pediatric patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses more frequently. Any pediatric patient with the onset of a limp during growth hormone therapy should be evaluated.

Patients with epiphyseal closure who were treated with growth hormone replacement therapy in childhood should be re-evaluated according to the criteria in INDICATIONS AND USAGE before continuation of somatropin therapy at the reduced dose level recommended for somatropin-deficient adults.

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 eight (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.

Experience in patients above 60 years is lacking.

Experience with prolonged treatment in adults is limited.

Growth hormone has not been shown to increase the incidence of scoliosis. Progression of scoliosis can occur in children who experience rapid growth. Because growth hormone increases growth rate, patients with a history of scoliosis who are treated with growth hormone should be monitored for progression of scoliosis.

Carcinogenesis, Mutagenesis, Impairment of Fertility -- Long-term animal studies for carcinogenicity and impairment of fertility with this human growth hormone (Humatrope) have not been performed. There has been no evidence to date of Humatrope-induced mutagenicity.

Pregnancy -- Pregnancy Category C -- Animal reproduction studies have not been conducted with Humatrope. It is not known whether Humatrope can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Humatrope should be given to a pregnant woman only if clearly needed.

Nursing Mothers -- There have been no studies conducted with Humatrope 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 Humatrope is administered to a nursing woman.

Information for Patients -- Patients being treated with growth hormone 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 needle disposal and cautioned against any reuse of needles and syringes (see Information for the Patient insert).

Adverse Reactions: Pediatric Patients -- Approximately 2% of 481 naive and previously treated clinical trial patients treated with Humatrope have developed antibodies to growth hormone, as demonstrated by a binding capacity determination threshold greater than or equal to 30.02 mcg/mL. Nevertheless, even these patients experienced increases in linear growth and other salutary effects of Humatrope and did not experience any unusual adverse events. Although growth-limiting antibodies have been observed with other growth hormone preparations (including products of pituitary origin), antibodies in patients treated with Humatrope have not limited growth. The long-term implications of antibody development are uncertain at this time.

Of the 232 naive and previously treated clinical trial patients receiving Humatrope for 6 months or more, 4.7% had serum binding of radiolabeled growth hormone in excess of twice the binding observed in control sera when the serum samples were assayed at a tenfold dilution. Among these patients were 160 naive patients, of whom 6.9% had positive serum binding. In comparison, 74.5% of 106 naive patients treated for 6 months or more with somatrem (produced by Lilly) in a similar clinical trial had serum binding of radiolabeled growth hormone of at least twice the binding observed in control sera.

In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to human growth hormone should be carried out in any patient who fails to respond to therapy.

In studies with growth hormone-deficient pediatric patients, injection site pain was reported infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed early during the course of treatment.

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

Adult Patients -- In clinical studies in which high doses of Humatrope were administered to healthy adult volunteers, the following events occurred infrequently: headache, localized muscle pain, weakness, mild hyperglycemia, and glucosuria.

In the first 6 months of controlled blinded trials, adult-onset somatropin-deficient adults experienced a statistically significant increase in edema (Humatrope 17.3% vs. placebo 4.4%, p=0.043) and peripheral edema (11.5% vs. 0% respectively, p=0.017). In patients with adult-onset somatropin deficiency syndrome, edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration.

Two out of 113 adult onset patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction.

All treatment-emergent adverse events with greater than or equal to 35% overall incidence during 12 or 18 months of replacement therapy with Humatrope are shown in Table 3 (adult onset patients) and in Table 4 (childhood onset patients).

Adult patients treated with Humatrope who had been diagnosed with growth hormone deficiency in childhood reported side effects less frequently than those with adult-onset somatropin deficiency. -0-

                                 Table 3
                     Treatment-Emergent Adverse Events
                 with Greater Than or Equal to 35% Overall
                          Incidence in Adult Onset
        Patients Treated with Humatrope for Either 12 or 18 Months
____________________________________________________________________
                     12 Months hGH Exposure   18 Months hGH Exposure
                            (N=44)                     (N=52)
                     ______________________   ______________________
Adverse Event             n           %            n            %
____________________________________________________________________
Edema                     5         11.4          11          21.2
Arthralgia                6         13.6           9          17.3
Paresthesia               6         13.6           9          17.3
Myalgia                   4          9.1           7          13.5
Pain                      6         13.6           7          13.5
Rhinitis                  5         11.4           7          13.5
Peripheral Edema          8         18.2           6          11.5
Back Pain                 4          9.1           5           9.6
Headache                  3          6.8           4           7.7
Hypertension              2          4.6           4           7.7
Acne                      0            0           3           5.8
Joint Disorder            1          2.3           3           5.8
Surgical Procedure        1          2.3           3           5.8
Flu Syndrome              3          6.8           2           3.9
____________________________________________________________________
Abbreviations:  hGH = Humatrope; N = number of patients receiving
treatment in the period stated; n = number of patients reporting each
treatment-emergent adverse event.

                                Table 4
                     Treatment-Emergent Adverse Events
         with Greater Than or Equal to 5% Overall Incidence in
       Childhood Onset Patients Treated with Humatrope for Either
                             12 or 18 Months
____________________________________________________________________
                     12 Months hGH Exposure   18 Months hGH Exposure
                             (N=30)                    (N=32)
                     ______________________   ______________________
Adverse Event            n             %         n               %
____________________________________________________________________
Flu Syndrome             3           10.0        5            15.63
SGOT Increased           2           6.67        4            12.50
Headache                 2           6.07        3             9.38
Asthenia                 1           3.33        2             6.25
Cough Increased          0              0        2             6.25
Edema                    3          10.00        2             6.25
Hypesthesia              0              0        2             6.25
Myalgia                  2           6.67        2             6.25
Pain                     3          10.00        2             6.25
Rhinitis                 2           6.67        2             6.25
SGPT Increased           2           6.67        2             6.25
Respiratory Disorder     2           6.67        1             3.13
Gastritis                2           6.67        0                0
Pharyngitis              2           6.67        1             3.13
____________________________________________________________________
Abbreviations:  hGH = Humatrope; N = number of patients receiving
treatment in the period stated; n = number of patients reporting each
treatment-emergent adverse event; SGOT = serum glutamic oxaloacetic
transaminase, or AST; SGPT = serum glutamic pyruvic transaminase, or
ALT.

Other adverse drug events that have been reported in growth hormone-treated patients include the following: 1) Metabolic: Infrequent, mild and transient peripheral or generalized edema. 2) Musculoskeletal: Rare carpal tunnel syndrome. 3) Skin: Rare increased growth of pre-existing nevi. Patients should be monitored carefully for malignant transformation. 4) Endocrine: Rare gynecomastia. Rare Pancreatitis.

Overdosage: Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Long-term overdosage could result in signs and symptoms of gigantism/acromegaly consistent with the known effects of excess human growth hormone. (See recommended and maximal dosage instructions given below.)

Dosage and Administration: Growth hormone-deficient pediatric patients -- The recommended weekly dosage is 0.18 mg/kg (0.54 IU/kg) of body weight. It should be divided into equal doses given either on 3 alternate days or 6 times per week. The maximal replacement weekly dosage is 0.3 mg/kg (0.90 IU/kg) of body weight divided into equal doses given on 3 alternate days. The route of administration should be by subcutaneous or intramuscular injection. The dosage and administration schedule for Humatrope should be individualized for each patient.

Somatropin-deficient adult patients -- The recommended dosage at the start of therapy is not more than 0.006 mg/kg/day (0.018 IU/kg/day) given as a daily subcutaneous injection. The dose may be increased according to individual patient requirements to a maximum of 0.0125 mg/kg/day (0.0375 IU/kg/day).

During therapy, dosage should be titrated if required by the occurrence of side effects. To minimize the occurrence of adverse events in patients with increasing age or excessive body weight, dose reductions may be necessary.

Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for Humatrope. The diluent should be injected into the vial of Humatrope by aiming the stream of liquid against the glass wall. Following reconstitution, the vial should be swirled with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The resulting solution should be inspected for clarity. It should be clear. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.

Before and after injection, the septum of the vial should be wiped with rubbing alcohol or an alcoholic antiseptic solution to prevent contamination of the contents by repeated needle insertions. Sterile disposable syringes and/or needles should be used for administration of Humatrope. The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy.

Stability and Storage: Before Reconstitution -- Vials of Humatrope as well as the Diluent for Humatrope are stable when refrigerated (36 degrees to 46 degrees F (2 degrees to 8 degrees C)). Avoid freezing Diluent for Humatrope. Expiration dates are stated on the labels.

After Reconstitution -- Vials of Humatrope are stable for up to 14 days when reconstituted with Diluent for Humatrope and stored in a refrigerator at 36 degrees to 46 degrees F (2 degrees to 8 degrees C). Avoid freezing the reconstituted vial of Humatrope.

How Supplied: Vials: 5 mg (No. 7335) -- (6s) NDC 0002-7335-16, and 5-mL vials of Diluent for Humatrope (No. 7336) PA 1642 AMP (080296)

Footnote: The units per vial of Humatrope have changed from approximately 13 IU to 15 IU. This does not represent a change in product purity or the quantity (mg) of Somatropin per vial. The change in units is a result of harmonizing the defined specific activity of the current reference standard with the international WHO (World Health Organization) reference standard. The specific activity of the International Standard for Somatropin is defined as three International Units per mg of protein (previously designated as approximately 2.67 IU/mg). Humatrope is now labeled based on a specific activity of three IU/mg. This change in reference standard activity does not affect the recommended weekly dosage of 0.18 mg of Somatropin per kg of body weight for pediatric patients. However, due to the reference standard change, the weekly units administered will be measured as 0.54 IU/kg of body weight (previously approximately 0.48 IU/kg of body weight).

Humatrope(R) (somatropin, rDNA origin, for injection)

CONTACT: Eli Lilly and Company, Indianapolis

Kelly Sego, 317/277-6265