Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2717
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HUMATROPE (Kit)
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Pediatric
Patients: The Humatrope dosage
and administration schedule should be individualized for each patient. Therapy
should not be continued if epiphyseal fusion has occurred. Response to growth
hormone therapy tends to decrease with time. However, failure to increase
growth rate, particularly during the first year of therapy, should prompt
close assessment of compliance and evaluation of other causes of growth failure
such as hypothyroidism, under���nutrition and advanced bone age. Growth
hormone���deficient pediatric patients���The
recommended weekly dosage is 0.18 mg/kg (0.54 IU/kg)
of body weight. The maximal replacement weekly dosage is 0.3 mg/kg
(0.90 IU/kg) of body weight. It should be divided into equal
doses given either on 3 alternate days, 6 times
per week or daily. The subcutaneous route of administration is preferable;
intramuscular injection is also acceptable. The dosage and administration
schedule for Humatrope should
be individualized for each patient. Turner Syndrome���A weekly dosage of up to 0.375 mg/kg (1.125 IU/kg)
of body weight administered by subcutaneous injection is recommended. It should
be divided into equal doses given either daily or on 3 alternate
days. Patients
with idiopathic short stature���A
weekly dosage of up to 0.37 mg/kg of body weight administered
by subcutaneous injection is recommended. It should be divided into equal
doses given 6 to 7 times per week. Patients
with SHOX deficiency���A
weekly dosage of 0.35 mg/kg of body weight is recommended. It should be divided
into equal doses given by daily subcutaneous injection.<br/>Adult
Patients: Adult
Growth Hormone Deficiency (GHD)���Based
on the weight-based dosing utilized in the original pivotal studies described
herein, the recommended dosage at the start of therapy is not more than 0.006 mg/kg
given as a daily subcutaneous injection. The dose may be increased according
to individual patient requirements to a maximum of 0.0125 mg/kg
daily in patients. Clinical response, side effects, and determination of age-
and gender-adjusted serum IGF-I levels may be used as guidance in dose titration. Alternatively, taking into account recent literature, a starting
dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without
consideration of body weight. This dose can be increased gradually every 1-2
months by increments of approximately 0.1-0.2 mg/day, according to individual
patient requirements based on the clinical response and serum IGF-I concentrations.
During therapy, the dose should be decreased if required by the occurrence
of adverse events and/or serum IGF���I levels above the
age- and gender-specific normal range. Maintenance dosages vary considerably
from person to person. A lower starting dose and smaller dose increments should be
considered for older patients, who are more prone to the adverse effects of somatropin than
younger individuals. In addition, obese individuals are more likely to manifest
adverse effects when treated with a weight-based regimen. In order to reach
the defined treatment goal, estrogen-replete women may need higher doses than
men. Oral estrogen administration may increase the dose requirements in women.<br/>Reconstitution: Vial���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 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. Cartridge���Each cartridge of Humatrope should
only be reconstituted using the diluent syringe that accompanies the cartridge and should not be reconstituted
with the Diluent for Humatrope provided
with Humatrope Vials. See Information for the Patient for comprehensive
directions on Humatrope cartridge
reconstitution. The reconstituted 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. The somatropin concentrations
for the reconstituted Humatrope cartridges
are as follows: 2.08 mg/mL for the 6 mg
cartridge; 4.17 mg/mL for the 12 mg cartridge;
and 8.33 mg/mL for the 24 mg cartridge. This cartridge has been designed for use only with the Humatrope injection
device. A sterile disposable needle should be used for each injection of Humatrope.<br/>STABILITY
AND STORAGE:<br/>Vials: Before Reconstitution���Vials
of Humatrope and
Diluent for Humatrope are
stable when refrigerated [2��to 8��C
(36��to 46��F)]. 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 or
Bacteriostatic Water for Injection, USP and stored in a refrigerator
at 2��to 8��C (36��to 46��F).
Avoid freezing the reconstituted vial of Humatrope. After Reconstitution
with Sterile Water, USP���Use
only one dose per Humatrope vialand discard the unused portion. If the solution is not used immediately, it
must be refrigerated [2��to 8��C
(36��to 46��F)] and used within 24 hours.<br/>Cartridges: Before Reconstitution���Cartridges
of Humatrope and
Diluent for Humatrope are
stable when refrigerated [2��to 8��C
(36��to 46��F)]. Avoid freezing Diluent
for Humatrope.
Expiration dates are stated on the labels. After Reconstitution���Cartridges
of Humatrope are
stable for up to 28 days when reconstituted with Diluent
for Humatrope and
stored in a refrigerator at 2��to 8��C
(36��to 46��F). Store the Humatrope injection
device without the needle attached. Avoid freezing the reconstituted cartridge
of Humatrope.
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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. Humatrope is a highly purified preparation. Phosphoric acid and/or sodium hydroxide
may have been added to adjust the pH. Reconstituted solutions have a pH of
approximately 7.5. This product is oxygen sensitive. VIAL���Each
vial of Humatrope contains
5 mg somatropin (15 IU or 225 nanomoles); 25 mg mannitol;
5 mg glycine; and 1.13 mg dibasic sodium
phosphate. 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% Metacresol as a preservative and 1.7% glycerin. CARTRIDGE���The
cartridges of somatropin contain
either 6 mg (18 IU), 12 mg (36 IU),
or 24 mg (72 IU) of somatropin.
The 6, 12, and 24 mg cartridges contain respectively: mannitol 18,
36, and 72 mg; glycine 6, 12, and 24 mg;
dibasic sodium phosphate 1.36, 2.72, and 5.43 mg.
Each cartridge is supplied in a combination package withan accompanying syringe
containing approximately 3 mL of diluting solution. The diluent
contains Water for Injection; 0.3% Metacresol as a preservative;
and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg
cartridges, respectively.
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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 and patients with Turner syndrome
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. Untreated
patients with Turner syndrome have an increased incidence
of glucose intolerance. Administration of human growth hormone to normal adults
or patients with Turner syndrome resulted in increases in
mean serum fasting and postprandial insulin levels although mean values remained
in the normal range. In addition, mean fasting and postprandial glucose and
hemoglobin Alevels remained in the normal range. 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.<br/>Pharmacokinetics:<br/>Special
Populations:
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Patients with a known sensitivity to either Metacresol or glycerin should
not receive Humatrope reconstituted
with the supplied Diluent for Humatrope. Somatropin should
not be used for growth promotion in pediatric patients with closed epiphyses. Somatropin is
contraindicated in patients with proliferative or preproliferative diabetic
retinopathy. In general, somatropin is
contraindicated in the presence of active malignancy. Any preexisting malignancy
should be inactive and its treatment complete prior to instituting therapy
with somatropin. Somatropin should
be discontinued if there is evidence of recurrent activity. Since growth hormone
deficiency may be an early sign of the presence of a pituitary tumor (or ,
rarely, other brain tumors), the presence of such tumors should be ruled out
prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence
of an underlying intracranial tumor. Somatropin should
not be used to treat patients who have acute critical illness due to complications
following open heart surgery, abdominal surgery or multiple accidental trauma,
or those with acute respiratory failure. Two placebo���controlled
clinical trials in non���growth hormone���deficient adult patients (n=522)
with these conditions in intensive care units revealed a significant increase
in mortality (41.9% vs. 19.3%) among somatropin���treated
patients (doses 5.3 - 8 mg/day)
compared to those receiving placebo . Somatropin is
contraindicated in patients with Prader���Willi syndrome who are severely
obese or have severe respiratory impairment .
Unless patients with Prader���Willi syndrome also have a diagnosis of
growth hormone deficiency, Humatrope is
not indicated for the treatment of pediatric patients who have growth failure
due to genetically confirmed Prader���Willi syndrome.
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Vials Cartridges
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General���Therapy
with Humatrope should
be directed by physicians who are experienced in the diagnosis and management
of pediatric patients with growth hormone deficiency, Turner syndrome,
idiopathic short stature, SHOX deficiency, or adult patients with either childhood���onset
or adult���onset growth hormone deficiency. Treatment with somatropin may
decrease insulin sensitivity, particularly at higher doses in susceptible
patients. As a result, previously undiagnosed impaired glucose tolerance and
overt diabetes mellitus may be unmasked during somatropin treatment.
Therefore, glucose levels should be monitored periodically in all patients
treated with somatropin,
especially in those with risk factors for diabetes mellitus, such as obesity
(including obese patients with Prader���Willi syndrome), Turner syndrome,
or a family history of diabetes mellitus. Patients with preexisting type 1
or type 2 diabetes mellitus or impaired glucose tolerance should be monitored
closely during somatropin therapy.
The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require
adjustment when somatropin therapy
is instituted in these patients. Patients with preexisting tumors or growth hormone deficiency secondary
to an intracranial lesion should be examined routinely for progression or
recurrence of the underlying disease process. In pediatric patients, clinical
literature has revealed no relationship between somatropin replacement
therapy and central nervous system (CNS) tumor recurrence
or new extracranial tumors. However, in childhood cancer survivors, an increased
risk of a second neoplasm has been reported in patients treated with somatropin after
their first neoplasm. Intracranial tumors, in particular meningiomas, in patients
treated with radiation to the head for their first neoplasm, were most common
of these second neoplasms. In adults, it is unknown whether there is any relationship
between somatropin replacement
therapy and CNS tumor recurrence. Intracranial hypertension (IH) with papilledema, visual changes, headache,
nausea, and/or vomiting has been reported in a small number of patients treated
with somatropin products.
Symptoms usually occurred within the first eight (8) weeks after the initiation
of somatropin therapy.
In all reported cases, IH-associated signs and symptoms rapidly resolved after
cessation of therapy or a reduction of the somatropin dose.
Funduscopic examination should be performed routinely before initiating treatment
with somatropin to
exclude preexisting papilledema, and periodically during the course of somatropin therapy.
If papilledema is observed by funduscopy during somatropin treatment,
treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can
be restarted at a lower dose after IH-associated signs and symptoms have resolved.
Patients with Turner syndrome, chronic renal insufficiency, and Prader���Willi
syndrome may be at increased risk for the development of IH. In patients with hypopituitarism (multiple hormone deficiencies), standard
hormonal replacement therapy should be monitored closely when somatropin therapy
is administered. Undiagnosed/untreated hypothyroidism may prevent an optimal response
to somatropin,
in particular, the growth response in children. Patients with Turner syndrome
have an inherently increased risk of developing autoimmune thyroid disease
and primary hypothyroidism. In patients with growth hormone deficiency, central
(secondary) hypothyroidism may first become evident or worsen during somatropin treatment.
Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement
therapy should be initiated or appropriately adjusted when indicated. Patients should be monitored carefully for any malignant transformation
of skin lesions. When somatropin is
administered subcutaneously at the same site over a long period of time, tissue
atrophy may result. This can be avoided by rotating the injection site. As with any protein, 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. Pediatric
Patients���Slipped capital femoral epiphysis may occur more frequently in patients
with endocrine disorders (including pediatric growth hormone deficiency and
Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient
with the onset of a limp or complaints of hip or knee pain during somatropin therapy
should be carefully evaluated. Progression of scoliosis can occur in patients who experience rapid
growth. Because somatropin increases
growth rate, patients with a history of scoliosis who are treated with somatropin should
be monitored for progression of scoliosis. However, somatropin has
not been shown to increase the occurrence of scoliosis. Skeletal abnormalities
including scoliosis arecommonly seen in untreated Turner syndrome
patients. Scoliosis is also commonly seen in untreated patients with Prader���Willi
syndrome. Physicians should be alert to these abnormalities, which may manifest
during somatropin therapy. Patients with Turner syndrome should be evaluated carefully
for otitis media and other ear disorders since these patients have an increased
risk of ear and hearing disorders (see ADVERSE
REACTIONS). Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome.
In addition, patients with Turner syndrome should be monitored closely for
cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection,
hypertension) as these patients are also at risk for these conditions. Adult Patients���Patients with epiphyseal closure who were treated with somatropin replacement
therapy in childhood should be reevaluated according to the criteria in INDICATIONS
AND USAGE before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient
adults. Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid
retention are usually transient and dosedependant (see ADVERSE
REACTIONS). Experience with prolonged somatropin treatment in adults is limited. Information
for Patients���Patients
being treated with Humatrope (and/or
their parents) should be informed about the potential benefits and risks associated
with Humatrope treatment,
including a review of the contents of the Patient Information Insert. This
information is intended to better educate patients (and caregivers); it is
not a disclosure of all possible adverse or intended effects. Patients and caregivers who will administer Humatrope should
receive appropriate training and instruction on the proper use of Humatrope from
the physician or other suitably qualified health care professional. A puncture-resistant
container for the disposal of used needles and syringes should be strongly
recommended. Patients and/or parents should be thoroughly instructed in the
importance of proper disposal, and cautioned against any reuse of needles
and syringes. This information is intended to aid in the safe and effective
administration of the medication (see Patient
Information Insert). Laboratory
Tests���Serum levels of
inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and
IGF-I may increase during somatropin therapy. Drug Interactions���Somatropin inhibits
11��-hydroxysteroid dehydrogenase type 1 (11��HSD-1) in
adipose/hepatic tissue and may significantly impact the metabolism of cortisol
and cortisone. As a consequence, in patients treated with somatropin,
previously undiagnosed central (secondary) hypoadrenalism may be unmasked
requiring glucocorticoid replacement therapy. In addition, patients treated
with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism
may require an increase in their maintenance or stress doses; this may be
especially true for patients treated with cortisone acetate and prednisone
since conversion of these drugs to their biologically active metabolites is
dependent on the activity of the 11��HSD-1 enzyme. Excessive glucocorticoid therapy may attenuate the growth promoting
effects of somatropin in
children. Therefore, glucocorticoid replacement therapy should be carefully
adjusted in children with concomitant GH and glucocorticoid deficiency to
avoid both hypoadrenalism and an inhibitory effect on growth. Limited published data indicate that somatropin treatment
increases cytochrome P450 (CP450) mediated antipyrine clearance
in man. These data suggest that somatropin administration may alter the clearance of compounds known
to be metabolized by CP450 liver enzymes (e.g., corticosteroids,
sex steroids, anticonvulsants, cyclosporin). Careful monitoring is advisable
when somatropin is
administered in combination with other drugs known to be metabolized by CP450 liver
enzymes. However, formal drug interaction studies have not been conducted. In adult women on oral estrogen replacement, a larger dose of somatropin may
be required to achieve the defined treatment goal (see DOSAGE
AND ADMINISTRATION). In patients with diabetes mellitus requiring drug therapy, the dose
of insulin and/or oral agent may require adjustment when somatropin therapy
is initiated . 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 reproductive
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. Geriatric
Use���The safety and effectiveness
of Humatrope in
patients aged 65 and over has not been evaluated in clinical
studies. Elderly patients may be more sensitive to the action of somatropin,
and therefore may be more prone to develop adverse reactions. A lower starting
dose and smaller dose increments should be considered for older patients .
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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.)
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Somatropin
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HUMATROPE (Kit)
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Growth
Hormone-Deficient Pediatric Patients: As with all protein pharmaceuticals, a small
percentage of patients may develop antibodies to the protein. During the first
6 months of Humatrope therapy
in 314 naive patients, only 1.6% developed specific antibodies
to Humatrope (binding
capacity���0.02 mg/L). None had antibody concentrations
which exceeded 2 mg/L. Throughout 8 years
of this same study, two patients (0.6%) had binding capacity>2 mg/L.
Neither patient demonstrated a decrease in growth velocity at or near the
time of increased antibody production. It has been reported that growth attenuation
from pituitary���derived growth hormone may occur when antibody concentrations
are>1.5 mg/L. 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.<br/>Patients
with Turner Syndrome: In a randomized, concurrent controlled trial,
there was a statistically significant increase in the occurrence of otitis
media (43% vs. 26%), ear disorders (18% vs. 5%)
and surgical procedures (45% vs. 27%) in patients receiving Humatrope compared
with untreated control patients (Table 7). Other adverse
events of special interest to Turner syndrome patients were
not significantly different between treatment groups (Table 7).
A similar increase in otitis media was observed in an 18���month placebo���controlled
trial.<br/>Patients
with Idiopathic Short Stature: In the placebo���controlled study, the
adverse events associated with Humatrope therapy
were similar to those observed in other pediatric populations treated with Humatrope (Table 8).
Mean serum glucose level did not change during Humatrope treatment.
Mean fasting serum insulin levels increased 10% in the Humatrope treatment
group at the end of treatment relative to baseline values but remained within
the normal reference range. For the same duration of treatment the mean fasting
serum insulin levels decreased by 2% in the placebo group. The incidence of
above���range values for glucose, insulin, and HbAwere
similar in the growth hormone and placebo���treated groups. No patient
developed diabetes mellitus. Consistent with the known mechanism of growth
hormone action, Humatrope���treated
patients had greater mean increases, relative to baseline, in serum insulin���like
growth factor���I (IGF���I) than placebo���treated
patients at each study observation. However, there was no significant difference
between the Humatrope and
placebo treatment groups in the proportion of patients who had at least one serum
IGF���I concentration more than 2.0 SD above the age���and gender���appropriate mean (Humatrope:
9 of 35 patients [26%];
placebo: 7 of 28 patients [25%]). The adverse events observed in the dose���response
study (239 patients treated for 2 years)
did not indicate a pattern suggestive of a growth hormone dose effect. Among Humatrope dose
groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the
incidence of elevated fasting blood glucose concentrations were similar. One patient
developed abnormalities of carbohydrate metabolism (glucose intolerance and
high serum HbA) on treatment.<br/>Patients
with SHOX Deficiency: ���Clinically
significant���adverse events (adverse events previously observed in association
with growth hormone treatment in general) were assessed prospectively during
the 2-year randomized, open-label study; those observed are presented in Table 9.
In both treatment groups, the mean fasting plasma glucose concentration at
the end of the first year was similar to the baseline value and remained in
the normal range. No patient developed diabetes mellitus or had an above normal
value for fasting plasma glucose at the end of one-year of treatment.During
the 2 year study period, the proportion of patients who had at least one IGF-I
concentration greater than 2.0 SD above the age- and gender-appropriate mean
was 10 of 27 [37.0%] for the Humatrope-treated
group vs. 0 of 24 patients [0.0%] for the untreated group. The proportion
of patients who had at least one IGFBP-3 concentration greater than 2.0 SD
above the age and gender appropriate mean was 16 of 27 [59.3%] for the Humatrope treated
group vs. 7 of 24 [29.2%] for the untreated group. 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 during which patients received either Humatrope or
placebo, adult���onset growth hormone���deficient adults who received Humatrope 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 growth hormone
deficiency, edema, muscle pain, joint pain, and joint disorder were reported
early in therapy and tended to be transient or responsive to dosage titration. Two 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���5% overall incidence during 12 or 18 months of replacement
therapy with Humatrope are
shown in Table 10 (adult���onset patients) and in Table 11
(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 growth hormone deficiency. Other adverse drug events that have been reported
in growth hormone���treated patients include the following:
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If sensitivity to the diluent should occur, the vials may be reconstituted with
Bacteriostatic Water for Injection, USP or, Sterile Water
for Injection, USP. When Humatrope is
used with Bacteriostatic Water (Benzyl Alcohol preserved), the solution should
be kept refrigerated at 2��to 8��C
(36��to 46��F) and used within 14 days. Benzyl alcohol as a preservative
in Bacteriostatic Water for Injection, USP has been associated
with toxicity in newborns. When administering Humatrope to
newborns, use the Humatrope diluent
provided or if the patient is sensitive to the diluent, use Sterile Water
for Injection, USP. When Humatrope is
reconstituted with Sterile Water for Injection, USP in this
manner, use only one dose per Humatrope vial
and discard the unused portion. If the solution is not used immediately, it
must be refrigerated [2��to 8��C
(36��to 46��F)] and used within 24 hours. Cartridges should
be reconstituted only with the supplied diluent. Cartridges should not be
reconstituted with the Diluent for Humatrope provided
with Humatrope Vials,
or with any other solution. Cartridges should not be used if the patient is
allergic to Metacresol or glycerin. See CONTRAINDICATIONS for
information on increased mortality in patients with acute critical illness
due to complications following open heart surgery, abdominal surgery, or multiple
accidental trauma, or those with acute respiratory failure. The safety of
continuing somatropin 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 somatropin in
patients having acute critical illnesses should be weighed against the potential
risk. There have been reports of fatalities after initiating therapy with somatropin in
pediatric patients with Prader���Willi syndrome who had one or more of
the following risk factors: severe obesity, history of upper airway obstruction
or sleep apnea, or unidentified respiratory infection. Male patients with
one or more of these factors may be at greater risk than females. Patients
with Prader���Willi syndrome should be evaluated for signs of upper airway
obstruction and sleep apnea before initiation of treatment with somatropin.
If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or
increased snoring) and/or new onset sleep apnea, treatment should be interrupted.
All patients with Prader���Willi syndrome treated with somatropin should
also have effective weight control and be monitored for signs of respiratory
infection, which should be diagnosed as early as possible and treated aggressively
. Unless patients
with Prader���Willi syndrome also have a diagnosis of growth hormone deficiency, Humatrope is
not indicated for the treatment of pediatric patients who have growth failure
due to genetically confirmed Prader���Willi syndrome.
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Pediatric
Patients���Humatrope is
indicated for the treatment of pediatric patients who have growth failure
due to an inadequate secretion of normal endogenous growth hormone. Humatrope is
indicated for the treatment of short stature associated with Turner syndrome
in patients whose epiphyses are not closed. Humatrope is
indicated for the treatment of idiopathic short stature, also called non���growth
hormone���deficient short stature, defined by height SDS������2.25,
and associated with growth rates unlikely to permit attainment of adult height
in the normal range, in pediatric patients whose epiphyses are not closed
and for whom diagnostic evaluation excludes other causes associated with short
stature that should be observed or treated by other means. Humatrope is
indicated for the treatment of short stature or growth failure in children
with SHOX (short
stature homeobox-containing gene) deficiency whose epiphyses are not closed. Adult
Patients���Humatrope [somatropin
(rDNA origin) for injection] is indicated for replacement of endogenous growth
hormone in adults with growth hormone deficiency who meet either of the following
two criteria: 1. Adult
Onset: Patients who have growth hormone deficiency, either alone
or associated with multiple hormone deficiencies (hypopituitarism), as a result
of pituitary disease, hypothalamic disease, surgery, radiation therapy, or
trauma; or 2. Childhood
Onset: Patients who were growth hormone deficient during childhood
as a result of congenital, genetic, acquired, or idiopathic causes. In general, confirmation of the diagnosis of adult
growth hormone deficiency in both groups
usually requires an appropriate growth hormone stimulation test. However,
confirmatory growth hormone stimulation testing may not be required in patients
with congenital/genetic growth hormone deficiency or multiple pituitary hormone
deficiencies due to organic disease.
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HUMATROPE
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