Lqdmscle
Pro Bodybuilder
(Total posts: 135)
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posted July 06, 2000 05:49 AM
  
The only side effect you'll get is behind your ass, smaller wallet.1
PA 9171 FSAMP
HUMATROPE �
SOMATROPIN (rDNA ORIGIN) FOR INJECTION
VIALS
and
CARTRIDGES FOR USE WITH THE
HumatroPen
TM
INJECTION DEVICE
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. 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 mg, 12 mg, and 24 mg cartridges contain
respectively: mannitol 18 mg, 36 mg, and 72 mg; glycine 6 mg, 12 mg, and 24 mg;
dibasic sodium phosphate 1.36 mg, 2.72 mg, and 5.43 mg. Each cartridge is supplied in a
combination package with an 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 mg, 12 mg, and 24 mg
cartridges respectively.
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 and patients with Turner
syndrome with Humatrope produces increased growth rate and IGF-I (Insulin-likeഊ2
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 A1C levels 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.ഊ3
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
Summary of Somatropin Parameters in the Normal Population
Cmax
(ng/mL)
t1/2
(hr)
AUC0-f
(ng�hr/mL)
Cls
(L/kg�hr)
V�
(L/kg)
0.02 mg (0.05 IU * )/kg
iv
MEAN
SD
415
75
0.363
0.053
156
33
0.135
0.029
0.0703
0.0173
0.1 mg (0.27 IU * )/kg
im
MEAN
SD
53.2
25.9
4.93
2.66
495
106
0.215
0.047
1.55
0.91
0.1 mg (0.27 IU * )/kg
sc
MEAN
SD
63.3
18.2
3.81
1.40
585
90
0.179
0.028
0.957
0.301
Abbreviations: Cmax = maximum concentration; t1/2 = half-life; AUC0-f = area under the curve; Cls = systemic
clearance;
V� = volume distribution; iv = intravenous; SD = standard deviation; im = intramuscular; sc =
subcutaneous.
* Based on previous International Standard of 2.7 IU = 1 mgഊ4
1
10
100
1000
Plasma
Concentration
(ng/
mL)
0 6 12 18
Time (hours)
0.02 mg/kg intravenous injection
0.10 mg/kg intramuscular injection
0.1 mg/kg subcutaneous injection
Single Dose Average Plasma Concentrations
vs Time in Normal Adult Volunteers
Mean +/- SE (n=8)
Effects of Humatrope treatment in adults with growth hormone deficiency
Two multicenter trials in adult onset growth hormone deficiency (n=98) and two
studies in childhood onset growth hormone deficiency (n=67) were designed to assess the
effects of replacement therapy with Humatrope. The primary efficacy measures were
body composit ion (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<0.001) and a decrease in body fat (-3.27
versus 0.56 kg, p<0.001). Similar changes were seen in childhood onset growth
hormone deficient patients. These significant changes in lean body mass persistedഊ5
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<0.001). Adult onset patients
reported significant improvements as compared to placebo in the following 2 of 6
possible health related domains: physical mobility and social isolation (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<0.005) and work performance (Watts, p<0.01) (J Clin Endocrinol Metab
1995; 80:552-557).
Table 2
Changes a in Nottingham Health Profile Scores b in Adult Onset Growth Hormone Deficient Patients
Outcome
Measure
Placebo
(6 Months)
Humatrope
Therapy
(6 Months)
Significance
Energy Level -11.4 -15.5 NS
Physical Mobility -3.1 -10.5 p <0.01
Social Isolation 0.5 -4.7 p <0.01
Emotional Reactions -4.5 -5.4 NS
Sleep -6.4 -3.7 NS
Pain -2.8 -2.9 NS
a = An improvement in score is indicated by a more negative change in the score.
b = To account for multiple analyses, appropriate statistical methods were applied and the required level of
significance is 0.01.
NS = not significant
Effects of growth hormone treatment in patients with Turner syndrome
One long-term, randomized, open-label multicenter concurrently controlled study, two
long-term, open-label mult icenter, historically controlled studies and one long-term,
randomized, dose-response study were conducted to evaluate the efficacy of growth
hormone for the treatment of patients with short stature due to Turner syndrome.
In the randomized study, GDCT, comparing growth hormone-treated patients to a
concurrent control group who received no growth hormone, the growth hormone-treated
patients who received a dose of 0.3 mg/kg/week given 6 times per week from a mean age
of 11.7 years for a mean duration of 4.7 years attained a mean near final height of 146.0 r
6.2 cm (n=27, mean r SD) as compared to the control group who attained a near final
height of 142.1 r 4.8 cm (n=19). By analysis of covariance � *, the effect of growth
hormone therapy was a mean height increase of 5.4 cm (p = 0.001).
In two of the studies (85-023 and 85-044), the effect of long-term growth hormone
treatment (0.375 mg/kg/week given either 3 times per week or daily) on adult height was
� *Analysis of covariance includes adjustments for baseline height relative to age and for mid-parental
height.ഊ6
determined by comparing adult heights in the treated patients with those of age-matched
historical controls with Turner syndrome who never received any growth-promoting
therapy. The greatest improvement in adult height was observed in patients who received
early growth hormone treatment and estrogen after age 14 years. In Study 85-023, this
resulted in a mean adult height gain of 7.4 cm (mean duration of GH therapy of 7.6 years)
vs. matched historical controls by analysis of covariance.
In Study 85-044, patients treated with early growth hormone therapy were randomized
to receive estrogen replacement therapy (conjugated estrogens, 0.3 mg escalating to 0.625
mg daily) at either age 12 or 15 years. Compared with matched historical controls, early
GH therapy (mean duration of GH therapy 5.6 years) combined with estrogen
replacement at age 12 years resulted in an adult height gain of 5.9 cm (n=26), whereas
patients who initiated estrogen at age 15 years (mean duration of GH therapy 6.1 years)
had a mean adult height gain of 8.3 cm (n=29). Patients who initiated GH therapy after
age 11 (mean age 12.7 years; mean duration of GH therapy 3.8 years) had a mean adult
height gain of 5.0 cm (n=51).
In a randomized blinded dose-response study, GDCI, patients were treated from a mean
age of 11.1 years for a mean duration of 5.3 years with a weekly dose of either 0.27
mg/kg or 0.36 mg/kg administered 3 or 6 times weekly. The mean near final height of
patients receiving growth hormone was 148.7 � 6.5 cm (n=31). When compared to
historical control data, the mean gain in adult height was approximately 5 cm.
In some studies, Turner syndrome patients (n=181) treated to final adult height
achieved statistically significant average height gains ranging from 5.0 - 8.3 cm.
Table 3
Summary Table of Efficacy Results
Study/
Group
Study
Design a
N at
Adult
Height
GH
Age (yr)
Estrogen
Age (yr)
GH
Duration
(yr)
Adult Height
Gain (cm)b
GDCT RCT 27 11.7 13 4.7 5.4
85-023 MHT 17 9.1 15.2 7.6 7.4
85-044: A* MHT 29 9.4 15 6.1 8.3
B* 26 9.6 12.3 5.6 5.9
C* 51 12.7 13.7 3.8 5
GDCI RDT 31 11.1 8-13.5 5.3 ~5 c
a RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-
response trial.
b Analysis of covariance vs controls
c Compared with historical data
* A: GH age <11 yr, estrogen age 15 yr
B: GH age <11 yr, estrogen age 12 yr
C: GH age >11 yr, estrogen at month 12
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.
Humatrope is indicated for the treatment of short stature associated with Turner
syndrome in patients whose epiphyses are not closed.ഊ7
Adult Patients
? ?
Humatrope is indicated for replacement of endogenous growth
hormone in adults with growth hormone deficiency who meet both of the following two
criteria:
1. Adult Onset: Patients who have growth hormone deficiency 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 growth hormone deficiency confirmed as an adult before replacement therapy
with Humatrope is started.
and
2. Biochemical diagnosis of growth hormone deficiency, by means of a negative
response to a standard growth hormone stimulation test [maximum peak < 5 ng/mL when
measured by RIA (polyclonal antibody) or < 2.5 ng/mL when measured by IRMA
(monoclonal antibody)].
CONTRAINDICATIONS
Humatrope should not be used for growth promotion in pediatric patients with closed
epiphyses.
Humatrope should not be used or should be discontinued when there is any evidence of
active malignancy. Anti-malignancy treatment must be complete with evidence of
remission prior to the inst itution of therapy.
Humatrope should not be reconstituted with the supplied Diluent for Humatrope for use
by patients with a known sensitivity to either Metacresol or glycerin.
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 5.3-8 mg/day) compared to those receiving placebo (see WARNINGS).
WARNING
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 q to 8 q C (36 q to 46 q 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 q to 8 q C
[36 q to 46 q 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 Humatropeഊ8
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 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
? ?
Therapy with Humatrope should be directed by physicians who are
experienced in the diagnosis and management of patients with growth hormone
deficiency, Turner syndrome or adult patients with either childhood-onset or adult-onset
growth hormone deficiency.
Patients with preexisting tumors or with 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 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.
Pediatric Patients (see General Precautions)
? ?
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.
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. Skeletal abnormalities
including scoliosis are commonly seen in untreated Turner syndrome patients.
Patients with Turner syndrome should be evaluated carefully for otitis media and other
ear disorders since these patients have an increased risk of ear or hearing disorders (see
Adverse Reactions). Patients with Turner syndrome are at risk for cardiovascular
disorders (e.g. stroke, aortic aneurysm, hypertension) and these conditions should be
monitored closely.ഊ9
Patients with Turner syndrome have an inherently increased risk of developing
autoimmune thyroid disease. Therefore, patients should have periodic thyroid function
tests and be treated as indicated (see General Precautions).
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea
and/or vomiting has been reported in a small number of pediatric 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. Patients with Turner
syndrome may be at increased risk for development of IH.
Adult Patients (see General Precautions)
? ?
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 growth hormone-deficient
adults.
Experience in patients above 60 years is lacking.
Experience with prolonged treatment in adults is limited.
Drug Interactions
? ?
Excessive glucocorticoid therapy may prevent optimal response to
somatropin. If glucocorticoid replacement therapy is required, the glucocorticoid dosage
and compliance should be monitored carefully to avoid either adrenal insufficiency or
inhibition of growth promoting effects.
Limited published data indicate that growth hormone (GH) treatment increases
cytochrome P450 (CP450) mediated antipyrine clearance in man. These data suggest that
GH 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 GH is administered in combination with other
drugs known to be metabolized by CP450 liver enzymes.
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.
Information for Patients
?
Patients being treated with growth hormone and/or their
parents should be informed of the potential risks and benefits associated with treatment.
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.ഊ10
Patients and/or parents should be thoroughly instructed in the importance of proper
needle disposal. A puncture resistant container should be used for the disposal of used
needles and/or syringes (consistent with applicable state requirements). Needles and
syringes must not be reused (see Information for the Patient insert).
ADVERSE REACTIONS
Growth-Hormone Deficient Pediatric Patients
? ?
As with all protein pharmaceuticals, a small percentage of patients may develop
antibodies to the protein. During the first six months of Humatrope therapy in 314 naive
patients, only 1.6% developed specific antibodies to Humatrope (binding capacity t 0.02
mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of
this same study, 2 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.
Turner Syndrome Patients
?
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 4). Other adverse events of special interest to Turner
syndrome patients were not significantly different between treatment groups (Table 4). A
similar increase in otitis media was observed in an 18 month placebo-controlled trial.ഊ11
Table 4
Treatment-Emergent Events of Special Interest by Treatment Group in Turner Syndrome
Treatment Group
Adverse Event Overall hGH 1 Untreated 2 Significance
Total Number of Patients 136 74 62
Surgical Procedure 50 (36.8%) 33 (44.6%) 17 (27.4%) p<0.05
Otitis Media 48 (35.3%) 32 (43.2%) 16 (25.8%) p<0.05
Ear Disorders 16 (11.8%) 13 (17.6%) 3 ( 4.8%) p<0.05
Bone Disorder 13 ( 9.6%) 6 ( 8.1%) 7 (11.3%) NS
Edema
Conjunctival 1 ( 0.7%) 0 1 ( 1.6%) NS
Non-specific 3 ( 2.2%) 2 ( 2.7%) 1 ( 1.6%) NS
Facial 1 ( 0.7%) 1 ( 1.4%) 0 NS
Peripheral 6 ( 4.4%) 5 ( 6.8%) 1 ( 1.6%) NS
Hyperglycemia 0 0 0 NS
Hypothyroidism 15 (11.0%) 10 (13.5%) 5 ( 8.1%) NS
Increased Nevi 3 10 ( 7.4%) 8 (10.8%) 2 ( 3.2%) NS
Lymphedema 0 0 0 NS
1 Dose = 0.3 mg/kg/week
2 Open label study
3 Includes any nevi coded to the following preferred terms: melanosis, skin hypertrophy, or skin benign
neoplasm.
NS = not significant
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 5 (adult onset
patients) and in Table 6 (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.ഊ12
Table 5
Treatment-Emergent Adverse Events with >5% Overall Incidence in Adult Onset Growth Hormone
Deficient Patients Treated with Humatrope for 18 Months as Compared with 6 Month Placebo and
12 Month Humatrope Exposure
18 Months Exposure [Placebo
(6 Months)/hGH (12 Months)](N=46)
18 Months hGH Exposure
(N=52)
Adverse Event n % n %
Edema
a
7 15.2 11 21.2
Arthralgia 7 15.2 9 17.3
Paresthesia 6 13.0 9 17.3
Myalgia 6 13.0 7 13.5
Pain 6 13.0 7 13.5
Rhinitis 5 10.9 7 13.5
Peripheral Edema
b 8 17.4 6 11.5
Back Pain 5 10.9 5 9.6
Headache 5 10.9 4 7.7
Hypertension 2 4.3 4 7.7
Acne 0 0 3 5.8
Joint Disorder 1 2.2 3 5.8
Surgical Procedure 1 2.2 3 5.8
Flu Syndrome 3 6.5 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.
a p = 0.04 as compared to placebo (6 months)
b p = 0.02 as compared to placebo (6 months)
Table 6
Treatment-Emergent Adverse Events with >5% Overall Incidence in Childhood Onset Growth
Hormone Deficient Patients Treated with Humatrope for 18 Months as Compared with 6 Month
Placebo and 12 Month Humatrope Exposure
18 Months Exposure [Placebo
(6 Months)/hGH (12 Months)](N=35)
18 Months hGH Exposure
(N=32)
Adverse Event n % n %
Flu Syndrome 8 22.9 5 15.6
AST Increased a 2 5.7 4 12.5
Headache 4 11.4 3 9.4
Asthenia 1 2.9 2 6.3
Cough Increased 0 0 2 6.3
Edema 3 8.6 2 6.3
Hypesthesia 0 0 2 6.3
Myalgia 2 5.7 2 6.3
Pain 3 8.6 2 6.3
Rhinitis 2 5.7 2 6.3
ALT Increased 2 5.7 2 6.3
Respiratory Disorder 2 5.7 1 3.1
Gastritis 2 5.7 0 0
Pharyngitis 5 14.3 1 3.1
Abbreviations: hGH = Humatrope; N = number of patients receiving treatment in the period stated; n =
number of patients reporting each treatment-emergent adverse event; ALT = alanine amino transferase,
formerly SGPT; AST = aspartate amino transferase, formerly SGOT.
a p = 0.03 as compared to placebo (6 months)ഊ13
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
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.
OptionsGrowth 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.
Adult Patients ?
Show Growth hormone-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
or to maintain the IGF-I response below the upper limit of normal IGF-I levels, matched
for age and sex. To minimize the occurrence of adverse events in patients with increasing
age or excessive body weight, dose reductions may be necessary.
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.ഊ14
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 and the diluent connector which accompany the cartridge and should not be
reconstituted with the Diluent for Humatrope provided with Humatrope Vials. (See
WARNING section). See the HumatroPen
��
User Guide 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 HumatroPen allows the somatropin dosage volume to be dialed in increments of
0.048 mL per click of dosage knob, and the maximum dosage volume that can be injected
is 0.576 mL (based on a 12 click maximum). (See Table 7 for additional information).
Table 7
Concentration of Reconstituted Humatrope Solutions, Incremental Dosage and
Maximum Injectable Dose for Each Cartridge
Cartridge Somatropin
Concentration
Dose per click of
dosage knob
Maximum Injectable
Dose
6 mg 2.08 mg/mL 0.1 mg 1.2 mg
12 mg 4.17 mg/mL 0.2 mg 2.4 mg
24 mg 8.33 mg/mL 0.4 mg 4.8 mg
This cartridge has been designed for use only with the HumatroPen. A sterile
disposable needle should be used for each administration of Humatrope.
STABILITY AND STORAGE
Vials�
Before Reconstitution ? Vials of Humatrope and Diluent for Humatrope are stable when
refrigerated (2 q to 8 q 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 q to 8 q C (36� to 46�F). Avoid freezing the reconstituted vial of
Humatrope.
After Reconstitution with Sterile Water, USP ? Use only one dose per Humatrope vial
and discard the unused portion. If the solution is not used immediately, it must be
refrigerated (2 q to 8 q C [36 q to 46 q F]) and used within 24 hours.ഊ15
Cartridges�
Before Reconstitution�Cartridges of Humatrope and Diluent for Humatrope are stable
when refrigerated (2 q to 8 q C [36 q to 46 q 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 q to 8 q C [36 q to
46 q F]). Store the HumatroPen without the needle attached. Avoid freezing the
reconstituted cartridge of Humatrope.
HOW SUPPLIED
Vials:
5 mg (No. 7335)? (6s) NDC 0002-7335-16, and 5-mL vials of Diluent for Humatrope
(No. 7336)
Cartridges:
Cartridge Kit (MS8089) NDC 0002-8089-01
6 mg cartridge (VL7554), and prefilled syringe of Diluent for Humatrope (VL7557)
Cartridge Kit (MS8090) NDC 0002-8090-01
12 mg cartridge (VL7555), and prefilled syringe of Diluent for Humatrope (VL7558)
Cartridge Kit (MS8091) NDC 0002-8091-01
24 mg cartridge (VL7556), and prefilled syringe of Diluent for Humatrope (VL7558)
Literature revised March, 1999
Manufactured by Lilly France S.A.
F-67640 Fegersheim, France
for Eli Lilly and Company
Indianapolis, IN 46285, USA
PA 9171 FSAMP Printed in USA IP: Logged |
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