| OMNITROPE [Somatropin] Side Effects and Warnings |
Omnitrope (somatropin [rDNA origin])
What is Omnitrope?
Omnitrope (somatropin [rDNA origin]), is a recombinant human growth
hormone product indicated for long-term treatment of pediatric patients
who have growth failure due to an inadequate secretion of endogenous
growth hormone, and for long-term replacement therapy in adults with
GHD of either childhood- or adult onset.
Is Omnitrope a generic biologic?
No. Omnitrope is not rated as therapeutically equivalent to (and
therefore substitutable for) any of the other approved human growth
hormone products. Omnitrope is more appropriately characterized as a
"follow-on protein product."
What is a follow-on protein product?
The term follow-on protein products generally refers to protein and
peptide products that are intended to be sufficiently similar to a product
already approved or licensed to permit the applicant to rely for approval
on certain existing scientific knowledge about the safety and
effectiveness of the approved protein product. Follow-on protein
products may be produced through biotechnology or derived from natural
sources.
Is this FDA's first approval of a follow-on protein product?
No. FDA has approved other follow-on protein products under section
505 of the Food, Drug, and Cosmetic Act. These include GlucaGen
(glucagon recombinant for injection), Hylenex (hyaluronidase
recombinant human), Hydase and Amphadase (hyaluronidase), and
Fortical (calcitonin salmon recombinant) Nasal Spray.
Does todayÂ’s approval of Omnitrope create a new pathway for follow-
on versions of all protein products?
No. The approval of Omnitrope in a 505(b)(2) application does not
establish a pathway for approval of follow-on products for biological
products licensed under section 351 of the Public Heath Service Act, nor
does it mean that more complex and/or less well understood proteins
approved as drugs under the Food, Drug, and Cosmetic Act could be
approved as follow-on products.
The majority of protein products are licensed as biological products under
the Public Health Service Act, not approved as drugs under the Food,
Drug, and Cosmetic Act. There is no abbreviated approval pathway
analogous to 505(b)(2) or 505(j) of the Act for protein products licensed
under section 351 of the Public Health Service Act. Such a pathway for
the approval or licensure of follow-on protein products under the Public
Health Service Act would require new legislation.
Why could FDA approve Omnitrope as a follow-on product?
Among other things, human growth hormone (hGH) has several
characteristics that enable one rhGH product to be adequately compared
to another for purposes of approval under section 505(b)(2) of the Act.
For example:
* hGH is well characterized and non-glycosylated (in other words,
sugar molecules are not added to the protein, which would increase the
complexity of a protein and make it more difficult to compare the
structures from one version of the protein to another using standard
tools such as mass spectrometry)
* The primary structure of hGH is known, and physicochemical tests
exist for the determination of an hGH productÂ’s secondary and tertiary
structures (how the protein folds upon itself)
* Clinically relevant bioassays and qualified biomarkers are available
for hGH
* hGH has a long and well documented history of clinical use as a
replacement for endogenous growth hormone deficiency
* hGHÂ’s mechanism of drug action is known, and its human toxicity
profile is well understood
Has FDA's authority to approve follow-on protein products been
questioned?
FDA has received citizen petitions raising regulatory, legal, and scientific
issues associated with these approvals and requesting that the Agency
use a public process to obtain input from industry. FDA has used a public
process to gather additional information. This process consisted of
convening two public meetings (September 2004 and February 2005)
and establishing a related public docket for the submission of written
comments (docket # 2004N-0355)
In conjunction with today's approval, FDA issued a response to the
questions raised in the citizen petitions and in the public process that
apply to the approval of this recombinant human growth hormone
product.
Approval of Omnitrope does not involve the regulatory and legal
questions that may be associated with approval of follow-on products
licensed under the Public Health Service Act. It also does not raise the
scientific issues, of the type identified during the public meetings and in
the public comments, that are associated with protein products that
have unknown or multiple active ingredients (rhGH products have one
known active ingredient, somatropin); protein products that have an
unknown mechanism of action (rhGHÂ’s mechanism of action related to
hGH's efficacy for pediatric and adult GHD is well understood); protein
products that are difficult to characterize (currently available
technologies allow rhGH to be extensively characterized); or protein
products that are glycosylated (rhGH is not glycosylated).
Why has it taken so long to take an action on Omnitrope?
Sandoz submitted its new drug application for Omnitrope in July 2003. In
August 2004, the FDA notified Sandoz in a letter that it had completed its
review of the Omnitrope application but was unable to reach a final
decision because of uncertainty about scientific and legal issues relating
to follow-on protein products raised in the citizen petitions and expected
to be addressed through a public process.
FDA has now completed its analysis of the issues pertaining to the
Omnitrope approval that were raised in the citizen petitions and in the
public meetings and docket. The Agency has also reviewed additional
data submitted recently to the Omnitrope NDA. FDA has determined that
the Sandoz application provides the evidence of safety and effectiveness
necessary for approval under the Act.
Was there a court case involved with this application?
Yes, Sandoz, Inc. filed a lawsuit against the FDA in September 2005. On
April 10, 2006, a federal judge in Washington, D.C. ruled that the FDA
must make a decision on the Omnitrope application.
What is a 505(b)(2) application?
Section 505(b)(2) of the Food, Drug, and Cosmetic Act permits an
applicant to rely for approval of a drug on information from published
scientific literature or on the fact that the agency has already found a
similar drug to be safe and effective. A 505(b)(2) application, like an
application under 505(j) for approval of a generic drug, can only be
approved when the applicable patent and marketing exclusivity
protections for the innovator drug have expired.
What is section 351 of the Public Health Service Act?
Biological products such as vaccines, blood products, allergenic products,
and certain other products such as monoclonal antibodies are licensed
by FDA under section 351 of the Public Health Service Act. There is no
abbreviated approval pathway similar to 505(b)(2) or 505(j) for products
licensed under the Public Health Service Act.
Does FDA believe it has the authority to develop an abbreviated
pathway for licensed biological products?
For products approved under section 505 of the Food, Drug, and
Cosmetic Act, FDA believes there is existing authority to allow
applications for follow-on protein products to be approved under section
505(b)(2) of the Act through a process that relies on the earlier approval
of the innovator product. In contrast, there is no abbreviated approval
pathway analogous to 505(b)(2) or 505(j) of the Act for protein products
licensed under section 351 of the Public Health Service Act.
What is Omnitrope?
OMNITROPE™ (somatropin [rDNA origin]) for injection is a polypeptide
hormone of recombinant DNA origin. It has 191 amino acid residues and
a molecular weight of 22,125 daltons. The amino acid sequence of the
product is identical to that of human growth hormone of pituitary origin
(somatropin). OMNITROPE™ is synthesized in a strain of Escherichia coli
that has been modified by the addition of the gene for human growth
hormone.
OMNITROPE™ is a sterile white lyophilized powder intended for
subcutaneous injection. OMNITROPE™ 5.8 mg is dispensed in a vial
containing 5.8 mg of somatropin (approximately 17.4 IU), glycine (27.6
mg), disodium hydrogen phosphate heptahydrate (2.09 mg), and sodium
dihydrogen phosphate dihydrate (0.56 mg). The product is supplied with
a vial containing 1.14 mL diluent (Bacteriostatic Water for Injection
containing 1.5% benzyl alcohol as a preservative). After reconstitution of
the lyophilized powder, the solution has a concentration of 5 mg/mL
(approx. 15 IU/mL). OMNITROPE™ 1.5 mg is dispensed in a vial
containing 1.5 mg of somatropin (approximately 4.5 IU), glycine (27.6
mg), disodium hydrogen phosphate heptahydrate (0.88 mg), and sodium
dihydrogen phosphate dihydrate (0.21 mg). The product is provided with
a vial containing 1.13 mL of diluent (Sterile Water for Injection). After
reconstitution of the lyophilized powder, the solution has a concentration
of 1.33 mg/mL (approx. 4 IU/mL). The reconstituted somatropin solution
has an osmolality of approximately 300 mOsm/kg, and a pH of
approximately 7.0. The concentration of the reconstituted solution varies
by strength and presentation).
In vitro, preclinical, and clinical tests have demonstrated that
somatropins are therapeutically equivalent to human growth hormone of
pituitary origin and achieve similar pharmacokinetic profiles in normal
adults. In pediatric patients who have growth hormone deficiency (GHD),
treatment with somatropin stimulates linear growth and normalizes
concentrations of Insulin-like Growth Factor -I (IGF-I).
In adults with GHD, treatment with somatropin results in reduced fat
mass, increased lean body mass, metabolic alterations that include
beneficial changes in lipid metabolism, and normalization of IGF-I
concentrations:
1. Tissue Growth
A. Skeletal Growth: Somatropin stimulates skeletal growth in pediatric
patients with
GHD. The measurable increase in body length after
administration of somatropin results from an effect on the
epiphyseal plates of long bones. Concentrations of IGF-I, which
may play a role in skeletal growth, are generally low in the serum
of pediatric patients with GHD, but tend to increase during
treatment with OMNITROPETM. Elevations in mean serum alkaline
phosphatase concentration are also seen.
B. Cell Growth: It has been shown that there are fewer skeletal muscle
cells in
short-statured pediatric patients who lack endogenous growth
hormone as compared with the normal pediatric population.
Treatment with somatropin results in an increase in both the
number and size of muscle cells.
2. 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 somatropin.
3. Carbohydrate Metabolism
Pediatric patients with hypopituitarism sometimes experience fasting
hypoglycemia that is
improved by treatment with somatropin. Large doses of growth hormone
may impair glucose
tolerance.
4. Lipid Metabolism
In GHD patients, administration of somatropin has resulted in lipid
mobilization,
reduction in body fat stores, and increased plasma fatty acids.
5. Mineral Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus.
Serum concentrations of
inorganic phosphate are increased in patients with GHD after therapy
with somatropin. Serum
calcium is not significantly altered by somatropin. Growth hormone could
increase calciuria.
6. Body Composition
Adult GHD patients treated with somatropin at the recommended adult
dose (see DOSAGE
AND ADMINISTRATION) demonstrate a decrease in fat mass and an
increase in lean body
mass.
NDA 21-426 Agreed upon text
4
When these alterations are coupled with the increase in total body
water, the overall effect of
somatropin is to modify body composition, an effect that is maintained
with continued treatment.
INDICATIONS AND USAGE
OMNITROPE™ is indicated for:
• Long-term treatment of pediatric patients who have growth failure
due to an inadequate
secretion of endogenous growth hormone.
• Long-term replacement therapy in adults with growth hormone
deficiency (GHD) of either
childhood- or adult- onset etiology. GHD should be confirmed by an
appropriate growth
hormone stimulation test.
CONTRAINDICATIONS
OMNITROPE™ should not be used when there is any evidence of
neoplastic activity.
Intracranial lesions must be inactive and antitumor therapy complete
prior to the institution of
therapy. OMNITROPE™ should be discontinued if there is evidence of
tumor growth.
Growth hormone should not be used for growth promotion in pediatric
patients with fused
epiphyses.
Growth hormone should not be initiated to treat patients with acute
critical illness due to
complications following open heart or abdominal surgery, multiple
accidental traumas, or to
patients having acute respiratory failure. Two placebo-controlled clinical
trials in non-growth
hormone deficient adult patients with these conditions revealed a
significant increase in mortality
among somatropin-treated patients compared to those receiving placebo
(see WARNINGS).
Growth hormone is contraindicated in patients with Prader-Willi
syndrome who are severely
obese or have severe respiratory impairment.
Treatment with OMNITROPE™ is contraindicated in case of
hypersensitivity to somatropin or
to any of the excipients.
NDA 21-426 Agreed upon text
8
WARNINGS
The OMNITROPE™ 5.8 mg presentation contains benzyl alcohol as a
preservative. It should not
be used in newborns.
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 traumas, or with acute respiratory failure.
The safety of continuing
growth hormone treatment in patients receiving replacement doses for
approved indications who
concurrently develop these illnesses has not been established.
Therefore, the potential benefit of
treatment continuation with growth hormone in patients having acute
critical illnesses should be
weighed against the potential risk.
PRECAUTIONS
General
Treatment with OMNITROPE™, as with other growth hormone
preparations, should be directed
by physicians who are experienced in the diagnosis and management of
patients with GHD.
Patients and caregivers who will administer OMNITROPE™ in medically
unsupervised
situations should receive appropriate training and instruction on the
proper use of
OMNITROPE™ from the physician or other suitably qualified health
professional.
Patients with GHD secondary to an intracranial lesion should be
examined frequently for
progression or recurrence of the underlying disease process. Review of
literature reports of
pediatric use of somatropin replacement therapy reveals no relationship
between this therapy and
recurrence of central nervous system (CNS) tumors. In adults, it is
unknown whether there is any
relationship between somatropin treatment and CNS tumor recurrence.
Patients should be monitored carefully for any malignant transformation
of skin lesions.
Caution should be used if growth hormone is administered to patients
with diabetes mellitus, and
insulin dosage may need to be adjusted. Patients with diabetes or
glucose intolerance should be
monitored closely during treatment with OMNITROPE™. Patients with
risk factors for glucose
intolerance, such as obesity or a family history of Type II diabetes,
should be monitored closely
as well. Because growth hormone may induce a state of insulin
resistance, patients should be
observed for evidence of glucose intolerance.
In patients with hypopituitarism (multiple hormonal deficiencies)
standard hormonal
replacement therapy should be monitored closely when treatment with
OMNITROPE™ is
NDA 21-426 Agreed upon text
9
instituted. Hypothyroidism may develop during treatment with
OMNITROPE™, and inadequate
treatment of hypothyroidism may prevent optimal response to
OMNITROPE™. Therefore,
patients should have periodic thyroid function tests and be treated with
thyroid hormone when
indicated.
Pediatric patients with endocrine disorders, including GHD, have a higher
incidence of slipped
capital femoral epiphyses. Any pediatric patient with the onset of a limp
or complaints of hip or
knee pain during growth hormone therapy should be evaluated.
Progression of scoliosis can occur in patients 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. However,
growth hormone has not
been shown to increase the incidence of scoliosis.
Intracranial hypertension (IH) with papilledema, visual changes,
headache, nausea and/or
vomiting has been reported in a small number of patients treated with
growth hormone products.
Symptoms usually occurred within the first 8 weeks of the initiation of
growth hormone therapy.
In all reported cases, IH-associated signs and symptoms resolved after
termination of therapy or
a reduction of the growth hormone dose.
Funduscopic examination of patients is recommended at the initiation,
and periodically during
the course of growth hormone therapy.
Before continuing treatment as an adult, a post-pubertal GHD patient
who received growth
hormone replacement therapy in childhood should be reevaluated with
proper testing as
described in INDICATIONS AND USAGE. If continued treatment is
appropriate,
OMNITROPE™ should be administered at the reduced dose level
recommended for adult GHD
patients.
Drug Interactions
Concomitant glucocorticoid treatment may inhibit the growth-promoting
effect of growth
hormone. Pediatric GHD patients with coexisting ACTH deficiency should
have their
glucocorticoid replacement dose carefully adjusted to avoid an inhibitory
effect on growth (see
also PRECAUTIONS - General.) Limited published data indicate that
growth hormone treatment
increases cytochrome P450 (CP450) mediated antipyrine clearance in
man. These data suggest
that growth hormone administration may alter the clearance of
compounds known to be
metabolized by CP450 liver enzymes (e.g. corticosteroids, sex steroids,
anticonvulsants,
cyclosporine). Careful monitoring is advisable when growth hormone is
administered in
combination with other drugs known to be metabolized by CP450 liver
enzymes.
NDA 21-426 Agreed upon text
10
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Mutagenicity or carcinogenicity studies have not been conducted with
OMNITROPETM.
Pregnancy: Pregnancy Category B
Reproduction studies carried out with recombinant human growth
hormone (somatropin) at
doses of 0.3, 1, and 3.3 mg/kg/day administered subcutaneously (SC) in
the rat and 0.08, 0.3, and
1.3 mg/kg/day administered intramuscularly in the rabbit (highest doses
approximately 24 times
and 19 times the recommended human therapeutic levels, respectively,
based on body surface
area) resulted in decreased maternal body weight gains but were not
teratogenic. In rats receiving
SC doses during gametogenesis and up to 7 days of pregnancy, 3.3
mg/kg/day (approximately 24
times human dose) produced anestrus or extended estrus cycles in
females and fewer and less
motile sperm in males. When given to pregnant female rats (days 1 to 7
of gestation) at 3.3
mg/kg/day a very slight increase in fetal deaths was observed. At 1
mg/kg/day (approximately
seven times human dose) rats showed slightly extended estrus cycles,
whereas at 0.3 mg/kg/day
no effects were noted.
In perinatal and postnatal studies in rats, somatropin doses of 0.3, 1,
and 3.3 mg/kg/day produced
growth-promoting effects in the dams but not in the fetuses. Young rats
at the highest dose
showed increased weight gain during suckling but the effect was not
apparent by 10 weeks of
age. No adverse effects were observed on gestation, morphogenesis,
parturition, lactation,
postnatal development, or reproductive capacity of the offspring due to
somatropin. There are,
however, no adequate and well-controlled studies in pregnant women.
Because animal
reproduction studies are not always predictive of human response, this
drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
There have been no studies conducted with somatropin 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 somatropin is administered to a
nursing woman.
Geriatric Use
The safety and effectiveness of OMNITROPE™ in patients age 65 and
over has not been
evaluated in clinical studies. Elderly patients may be more sensitive to
the action of
OMNITROPE™ and may be more prone to develop adverse reactions.
ADVERSE REACTIONS
As with all protein drugs, a small number of patients may develop
antibodies to the protein.
Growth hormone antibody with binding capacity lower than 2 mg/L has
not been associated with
NDA 21-426 Agreed upon text
11
growth attenuation. In some cases when binding capacity is > 2mg/L,
interference with growth
response has been observed.
Preparations of OMNITROPETM contain a small amount of host cell
Escherichia coli peptides
(HCP). Anti-HCP antibodies are found in a small number of patients
treated with
OMNITROPETM, but these appear to be of no clinical significance.
The following events were observed during the OMNITROPETM clinical
studies conducted in
children with GHD:
Table 2. Incidence of drug-related treatment-emerged adverse events
occurring in ≥ 5%
pediatric patients with GHD during first 15 months of treatment (N=44)
Adverse event Number (%)
Hypothyroidism 7 (16%)
Elevated HbA1c 6 (14%)
Eosinophilia 5 (11%)
Hematoma 4 (9%)
Headache 3 (7%)
Hypertriglyceridemia 2 (5%)
Leg Pain 2 (5%)
In clinical trials with somatropin in GHD adults, the majority of the
adverse events consisted of
mild to moderate symptoms of fluid retention, including peripheral
swelling, arthralgia, pain and
stiffness of the extremities, peripheral edema, myalgia, paresthesia, and
hypoesthesia. These
events were reported early during therapy, and tended to be transient
and/or responsive to dosage
reduction.
The following events were observed in patients using somatropins (see
also WARNINGS and
PRECAUTIONS sections:
Short-term local injection site reactions, such as pain, numbness,
redness and swelling. The
subcutaneous administration of growth hormone at the same injection
site over a long period
may result in local lipoatrophy.
Disturbances in fluid balance (swelling), joint pain, muscle pain, stiffness
of the hands and feet,
numbness. In general, these undesirable effects occur at the beginning
of therapy with growth
hormones and also depend on the dose. They are common in adult
patients, but uncommon in
children.
Carpal tunnel syndrome in adults.
Benign intracranial hypertension, diabetes mellitus.
NDA 21-426 Agreed upon text
12
Due to the content of benzyl alcohol in OMNITROPETM, rare general
hypersensitivity reactions
are possible. No case was observed during the clinical trials.
Leukemia has been reported in small number of pediatric patients who
have been treated with
growth hormone, including growth hormone of pituitary origin and
recombinant GH. The
relationship, if any, between leukemia and growth hormone therapy is
uncertain.
OVERDOSAGE
There is little information on acute or chronic overdosage with
OMNITROPE™. Intravenously
administered growth hormone has been shown to result in an acute
decrease in plasma glucose.
Subsequently, hyperglycemia was seen. It is thought that the same
effect might occur on rare
occasions with a high dosage of OMNITROPE™ administered SC. Long-
term overdosage may
result in signs and symptoms of acromegaly consistent with
overproduction of growth hormone.
NDA 21-426 Agreed upon text
1
OMNITROPE™
(somatropin [rDNA origin]) for injection
What is Omnitrope?
Omnitrope (somatropin [rDNA origin]), is a recombinant human growth
hormone product indicated for long-term treatment of pediatric patients
who have growth failure due to an inadequate secretion of endogenous
growth hormone, and for long-term replacement therapy in adults with
GHD of either childhood- or adult onset.
Is Omnitrope a generic biologic?
No. Omnitrope is not rated as therapeutically equivalent to (and
therefore substitutable for) any of the other approved human growth
hormone products. Omnitrope is more appropriately characterized as a
"follow-on protein product."
What is a follow-on protein product?
The term follow-on protein products generally refers to protein and
peptide products that are intended to be sufficiently similar to a product
already approved or licensed to permit the applicant to rely for approval
on certain existing scientific knowledge about the safety and
effectiveness of the approved protein product. Follow-on protein
products may be produced through biotechnology or derived from natural
sources.
Is this FDA's first approval of a follow-on protein product?
No. FDA has approved other follow-on protein products under section
505 of the Food, Drug, and Cosmetic Act. These include GlucaGen
(glucagon recombinant for injection), Hylenex (hyaluronidase
recombinant human), Hydase and Amphadase (hyaluronidase), and
Fortical (calcitonin salmon recombinant) Nasal Spray.
Does todayÂ’s approval of Omnitrope create a new pathway for follow-
on versions of all protein products?
No. The approval of Omnitrope in a 505(b)(2) application does not
establish a pathway for approval of follow-on products for biological
products licensed under section 351 of the Public Heath Service Act, nor
does it mean that more complex and/or less well understood proteins
approved as drugs under the Food, Drug, and Cosmetic Act could be
approved as follow-on products.
The majority of protein products are licensed as biological products under
the Public Health Service Act, not approved as drugs under the Food,
Drug, and Cosmetic Act. There is no abbreviated approval pathway
analogous to 505(b)(2) or 505(j) of the Act for protein products licensed
under section 351 of the Public Health Service Act. Such a pathway for
the approval or licensure of follow-on protein products under the Public
Health Service Act would require new legislation.
Why could FDA approve Omnitrope as a follow-on product?
Among other things, human growth hormone (hGH) has several
characteristics that enable one rhGH product to be adequately compared
to another for purposes of approval under section 505(b)(2) of the Act.
For example:
* hGH is well characterized and non-glycosylated (in other words,
sugar molecules are not added to the protein, which would increase the
complexity of a protein and make it more difficult to compare the
structures from one version of the protein to another using standard
tools such as mass spectrometry)
* The primary structure of hGH is known, and physicochemical tests
exist for the determination of an hGH productÂ’s secondary and tertiary
structures (how the protein folds upon itself)
* Clinically relevant bioassays and qualified biomarkers are available
for hGH
* hGH has a long and well documented history of clinical use as a
replacement for endogenous growth hormone deficiency
* hGHÂ’s mechanism of drug action is known, and its human toxicity
profile is well understood
Has FDA's authority to approve follow-on protein products been
questioned?
FDA has received citizen petitions raising regulatory, legal, and scientific
issues associated with these approvals and requesting that the Agency
use a public process to obtain input from industry. FDA has used a public
process to gather additional information. This process consisted of
convening two public meetings (September 2004 and February 2005)
and establishing a related public docket for the submission of written
comments (docket # 2004N-0355)
In conjunction with today's approval, FDA issued a response to the
questions raised in the citizen petitions and in the public process that
apply to the approval of this recombinant human growth hormone
product.
Approval of Omnitrope does not involve the regulatory and legal
questions that may be associated with approval of follow-on products
licensed under the Public Health Service Act. It also does not raise the
scientific issues, of the type identified during the public meetings and in
the public comments, that are associated with protein products that
have unknown or multiple active ingredients (rhGH products have one
known active ingredient, somatropin); protein products that have an
unknown mechanism of action (rhGHÂ’s mechanism of action related to
hGH's efficacy for pediatric and adult GHD is well understood); protein
products that are difficult to characterize (currently available
technologies allow rhGH to be extensively characterized); or protein
products that are glycosylated (rhGH is not glycosylated).
Why has it taken so long to take an action on Omnitrope?
Sandoz submitted its new drug application for Omnitrope in July 2003. In
August 2004, the FDA notified Sandoz in a letter that it had completed its
review of the Omnitrope application but was unable to reach a final
decision because of uncertainty about scientific and legal issues relating
to follow-on protein products raised in the citizen petitions and expected
to be addressed through a public process.
FDA has now completed its analysis of the issues pertaining to the
Omnitrope approval that were raised in the citizen petitions and in the
public meetings and docket. The Agency has also reviewed additional
data submitted recently to the Omnitrope NDA. FDA has determined that
the Sandoz application provides the evidence of safety and effectiveness
necessary for approval under the Act.
Was there a court case involved with this application?
Yes, Sandoz, Inc. filed a lawsuit against the FDA in September 2005. On
April 10, 2006, a federal judge in Washington, D.C. ruled that the FDA
must make a decision on the Omnitrope application.
What is a 505(b)(2) application?
Section 505(b)(2) of the Food, Drug, and Cosmetic Act permits an
applicant to rely for approval of a drug on information from published
scientific literature or on the fact that the agency has already found a
similar drug to be safe and effective. A 505(b)(2) application, like an
application under 505(j) for approval of a generic drug, can only be
approved when the applicable patent and marketing exclusivity
protections for the innovator drug have expired.
What is section 351 of the Public Health Service Act?
Biological products such as vaccines, blood products, allergenic products,
and certain other products such as monoclonal antibodies are licensed
by FDA under section 351 of the Public Health Service Act. There is no
abbreviated approval pathway similar to 505(b)(2) or 505(j) for products
licensed under the Public Health Service Act.
Does FDA believe it has the authority to develop an abbreviated
pathway for licensed biological products?
For products approved under section 505 of the Food, Drug, and
Cosmetic Act, FDA believes there is existing authority to allow
applications for follow-on protein products to be approved under section
505(b)(2) of the Act through a process that relies on the earlier approval
of the innovator product. In contrast, there is no abbreviated approval
pathway analogous to 505(b)(2) or 505(j) of the Act for protein products
licensed under section 351 of the Public Health Service Act.
What is Omnitrope?
OMNITROPE™ (somatropin [rDNA origin]) for injection is a polypeptide
hormone of recombinant DNA origin. It has 191 amino acid residues and
a molecular weight of 22,125 daltons. The amino acid sequence of the
product is identical to that of human growth hormone of pituitary origin
(somatropin). OMNITROPE™ is synthesized in a strain of Escherichia coli
that has been modified by the addition of the gene for human growth
hormone.
OMNITROPE™ is a sterile white lyophilized powder intended for
subcutaneous injection. OMNITROPE™ 5.8 mg is dispensed in a vial
containing 5.8 mg of somatropin (approximately 17.4 IU), glycine (27.6
mg), disodium hydrogen phosphate heptahydrate (2.09 mg), and sodium
dihydrogen phosphate dihydrate (0.56 mg). The product is supplied with
a vial containing 1.14 mL diluent (Bacteriostatic Water for Injection
containing 1.5% benzyl alcohol as a preservative). After reconstitution of
the lyophilized powder, the solution has a concentration of 5 mg/mL
(approx. 15 IU/mL). OMNITROPE™ 1.5 mg is dispensed in a vial
containing 1.5 mg of somatropin (approximately 4.5 IU), glycine (27.6
mg), disodium hydrogen phosphate heptahydrate (0.88 mg), and sodium
dihydrogen phosphate dihydrate (0.21 mg). The product is provided with
a vial containing 1.13 mL of diluent (Sterile Water for Injection). After
reconstitution of the lyophilized powder, the solution has a concentration
of 1.33 mg/mL (approx. 4 IU/mL). The reconstituted somatropin solution
has an osmolality of approximately 300 mOsm/kg, and a pH of
approximately 7.0. The concentration of the reconstituted solution varies
by strength and presentation).
In vitro, preclinical, and clinical tests have demonstrated that
somatropins are therapeutically equivalent to human growth hormone of
pituitary origin and achieve similar pharmacokinetic profiles in normal
adults. In pediatric patients who have growth hormone deficiency (GHD),
treatment with somatropin stimulates linear growth and normalizes
concentrations of Insulin-like Growth Factor -I (IGF-I).
In adults with GHD, treatment with somatropin results in reduced fat
mass, increased lean body mass, metabolic alterations that include
beneficial changes in lipid metabolism, and normalization of IGF-I
concentrations:
1. Tissue Growth
A. Skeletal Growth: Somatropin stimulates skeletal growth in pediatric
patients with
GHD. The measurable increase in body length after
administration of somatropin results from an effect on the
epiphyseal plates of long bones. Concentrations of IGF-I, which
may play a role in skeletal growth, are generally low in the serum
of pediatric patients with GHD, but tend to increase during
treatment with OMNITROPETM. Elevations in mean serum alkaline
phosphatase concentration are also seen.
B. Cell Growth: It has been shown that there are fewer skeletal muscle
cells in
short-statured pediatric patients who lack endogenous growth
hormone as compared with the normal pediatric population.
Treatment with somatropin results in an increase in both the
number and size of muscle cells.
2. 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 somatropin.
3. Carbohydrate Metabolism
Pediatric patients with hypopituitarism sometimes experience fasting
hypoglycemia that is
improved by treatment with somatropin. Large doses of growth hormone
may impair glucose
tolerance.
4. Lipid Metabolism
In GHD patients, administration of somatropin has resulted in lipid
mobilization,
reduction in body fat stores, and increased plasma fatty acids.
5. Mineral Metabolism
Somatropin induces retention of sodium, potassium, and phosphorus.
Serum concentrations of
inorganic phosphate are increased in patients with GHD after therapy
with somatropin. Serum
calcium is not significantly altered by somatropin. Growth hormone could
increase calciuria.
6. Body Composition
Adult GHD patients treated with somatropin at the recommended adult
dose (see DOSAGE
AND ADMINISTRATION) demonstrate a decrease in fat mass and an
increase in lean body
mass.
NDA 21-426 Agreed upon text
4
When these alterations are coupled with the increase in total body
water, the overall effect of
somatropin is to modify body composition, an effect that is maintained
with continued treatment.
INDICATIONS AND USAGE
OMNITROPE™ is indicated for:
• Long-term treatment of pediatric patients who have growth failure
due to an inadequate
secretion of endogenous growth hormone.
• Long-term replacement therapy in adults with growth hormone
deficiency (GHD) of either
childhood- or adult- onset etiology. GHD should be confirmed by an
appropriate growth
hormone stimulation test.
CONTRAINDICATIONS
OMNITROPE™ should not be used when there is any evidence of
neoplastic activity.
Intracranial lesions must be inactive and antitumor therapy complete
prior to the institution of
therapy. OMNITROPE™ should be discontinued if there is evidence of
tumor growth.
Growth hormone should not be used for growth promotion in pediatric
patients with fused
epiphyses.
Growth hormone should not be initiated to treat patients with acute
critical illness due to
complications following open heart or abdominal surgery, multiple
accidental traumas, or to
patients having acute respiratory failure. Two placebo-controlled clinical
trials in non-growth
hormone deficient adult patients with these conditions revealed a
significant increase in mortality
among somatropin-treated patients compared to those receiving placebo
(see WARNINGS).
Growth hormone is contraindicated in patients with Prader-Willi
syndrome who are severely
obese or have severe respiratory impairment.
Treatment with OMNITROPE™ is contraindicated in case of
hypersensitivity to somatropin or
to any of the excipients.
NDA 21-426 Agreed upon text
8
WARNINGS
The OMNITROPE™ 5.8 mg presentation contains benzyl alcohol as a
preservative. It should not
be used in newborns.
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 traumas, or with acute respiratory failure.
The safety of continuing
growth hormone treatment in patients receiving replacement doses for
approved indications who
concurrently develop these illnesses has not been established.
Therefore, the potential benefit of
treatment continuation with growth hormone in patients having acute
critical illnesses should be
weighed against the potential risk.
PRECAUTIONS
General
Treatment with OMNITROPE™, as with other growth hormone
preparations, should be directed
by physicians who are experienced in the diagnosis and management of
patients with GHD.
Patients and caregivers who will administer OMNITROPE™ in medically
unsupervised
situations should receive appropriate training and instruction on the
proper use of
OMNITROPE™ from the physician or other suitably qualified health
professional.
Patients with GHD secondary to an intracranial lesion should be
examined frequently for
progression or recurrence of the underlying disease process. Review of
literature reports of
pediatric use of somatropin replacement therapy reveals no relationship
between this therapy and
recurrence of central nervous system (CNS) tumors. In adults, it is
unknown whether there is any
relationship between somatropin treatment and CNS tumor recurrence.
Patients should be monitored carefully for any malignant transformation
of skin lesions.
Caution should be used if growth hormone is administered to patients
with diabetes mellitus, and
insulin dosage may need to be adjusted. Patients with diabetes or
glucose intolerance should be
monitored closely during treatment with OMNITROPE™. Patients with
risk factors for glucose
intolerance, such as obesity or a family history of Type II diabetes,
should be monitored closely
as well. Because growth hormone may induce a state of insulin
resistance, patients should be
observed for evidence of glucose intolerance.
In patients with hypopituitarism (multiple hormonal deficiencies)
standard hormonal
replacement therapy should be monitored closely when treatment with
OMNITROPE™ is
NDA 21-426 Agreed upon text
9
instituted. Hypothyroidism may develop during treatment with
OMNITROPE™, and inadequate
treatment of hypothyroidism may prevent optimal response to
OMNITROPE™. Therefore,
patients should have periodic thyroid function tests and be treated with
thyroid hormone when
indicated.
Pediatric patients with endocrine disorders, including GHD, have a higher
incidence of slipped
capital femoral epiphyses. Any pediatric patient with the onset of a limp
or complaints of hip or
knee pain during growth hormone therapy should be evaluated.
Progression of scoliosis can occur in patients 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. However,
growth hormone has not
been shown to increase the incidence of scoliosis.
Intracranial hypertension (IH) with papilledema, visual changes,
headache, nausea and/or
vomiting has been reported in a small number of patients treated with
growth hormone products.
Symptoms usually occurred within the first 8 weeks of the initiation of
growth hormone therapy.
In all reported cases, IH-associated signs and symptoms resolved after
termination of therapy or
a reduction of the growth hormone dose.
Funduscopic examination of patients is recommended at the initiation,
and periodically during
the course of growth hormone therapy.
Before continuing treatment as an adult, a post-pubertal GHD patient
who received growth
hormone replacement therapy in childhood should be reevaluated with
proper testing as
described in INDICATIONS AND USAGE. If continued treatment is
appropriate,
OMNITROPE™ should be administered at the reduced dose level
recommended for adult GHD
patients.
Drug Interactions
Concomitant glucocorticoid treatment may inhibit the growth-promoting
effect of growth
hormone. Pediatric GHD patients with coexisting ACTH deficiency should
have their
glucocorticoid replacement dose carefully adjusted to avoid an inhibitory
effect on growth (see
also PRECAUTIONS - General.) Limited published data indicate that
growth hormone treatment
increases cytochrome P450 (CP450) mediated antipyrine clearance in
man. These data suggest
that growth hormone administration may alter the clearance of
compounds known to be
metabolized by CP450 liver enzymes (e.g. corticosteroids, sex steroids,
anticonvulsants,
cyclosporine). Careful monitoring is advisable when growth hormone is
administered in
combination with other drugs known to be metabolized by CP450 liver
enzymes.
NDA 21-426 Agreed upon text
10
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Mutagenicity or carcinogenicity studies have not been conducted with
OMNITROPETM.
Pregnancy: Pregnancy Category B
Reproduction studies carried out with recombinant human growth
hormone (somatropin) at
doses of 0.3, 1, and 3.3 mg/kg/day administered subcutaneously (SC) in
the rat and 0.08, 0.3, and
1.3 mg/kg/day administered intramuscularly in the rabbit (highest doses
approximately 24 times
and 19 times the recommended human therapeutic levels, respectively,
based on body surface
area) resulted in decreased maternal body weight gains but were not
teratogenic. In rats receiving
SC doses during gametogenesis and up to 7 days of pregnancy, 3.3
mg/kg/day (approximately 24
times human dose) produced anestrus or extended estrus cycles in
females and fewer and less
motile sperm in males. When given to pregnant female rats (days 1 to 7
of gestation) at 3.3
mg/kg/day a very slight increase in fetal deaths was observed. At 1
mg/kg/day (approximately
seven times human dose) rats showed slightly extended estrus cycles,
whereas at 0.3 mg/kg/day
no effects were noted.
In perinatal and postnatal studies in rats, somatropin doses of 0.3, 1,
and 3.3 mg/kg/day produced
growth-promoting effects in the dams but not in the fetuses. Young rats
at the highest dose
showed increased weight gain during suckling but the effect was not
apparent by 10 weeks of
age. No adverse effects were observed on gestation, morphogenesis,
parturition, lactation,
postnatal development, or reproductive capacity of the offspring due to
somatropin. There are,
however, no adequate and well-controlled studies in pregnant women.
Because animal
reproduction studies are not always predictive of human response, this
drug should be used
during pregnancy only if clearly needed.
Nursing Mothers
There have been no studies conducted with somatropin 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 somatropin is administered to a
nursing woman.
Geriatric Use
The safety and effectiveness of OMNITROPE™ in patients age 65 and
over has not been
evaluated in clinical studies. Elderly patients may be more sensitive to
the action of
OMNITROPE™ and may be more prone to develop adverse reactions.
ADVERSE REACTIONS
As with all protein drugs, a small number of patients may develop
antibodies to the protein.
Growth hormone antibody with binding capacity lower than 2 mg/L has
not been associated with
NDA 21-426 Agreed upon text
11
growth attenuation. In some cases when binding capacity is > 2mg/L,
interference with growth
response has been observed.
Preparations of OMNITROPETM contain a small amount of host cell
Escherichia coli peptides
(HCP). Anti-HCP antibodies are found in a small number of patients
treated with
OMNITROPETM, but these appear to be of no clinical significance.
The following events were observed during the OMNITROPETM clinical
studies conducted in
children with GHD:
Table 2. Incidence of drug-related treatment-emerged adverse events
occurring in ≥ 5%
pediatric patients with GHD during first 15 months of treatment (N=44)
Adverse event Number (%)
Hypothyroidism 7 (16%)
Elevated HbA1c 6 (14%)
Eosinophilia 5 (11%)
Hematoma 4 (9%)
Headache 3 (7%)
Hypertriglyceridemia 2 (5%)
Leg Pain 2 (5%)
In clinical trials with somatropin in GHD adults, the majority of the
adverse events consisted of
mild to moderate symptoms of fluid retention, including peripheral
swelling, arthralgia, pain and
stiffness of the extremities, peripheral edema, myalgia, paresthesia, and
hypoesthesia. These
events were reported early during therapy, and tended to be transient
and/or responsive to dosage
reduction.
The following events were observed in patients using somatropins (see
also WARNINGS and
PRECAUTIONS sections:
Short-term local injection site reactions, such as pain, numbness,
redness and swelling. The
subcutaneous administration of growth hormone at the same injection
site over a long period
may result in local lipoatrophy.
Disturbances in fluid balance (swelling), joint pain, muscle pain, stiffness
of the hands and feet,
numbness. In general, these undesirable effects occur at the beginning
of therapy with growth
hormones and also depend on the dose. They are common in adult
patients, but uncommon in
children.
Carpal tunnel syndrome in adults.
Benign intracranial hypertension, diabetes mellitus.
NDA 21-426 Agreed upon text
12
Due to the content of benzyl alcohol in OMNITROPETM, rare general
hypersensitivity reactions
are possible. No case was observed during the clinical trials.
Leukemia has been reported in small number of pediatric patients who
have been treated with
growth hormone, including growth hormone of pituitary origin and
recombinant GH. The
relationship, if any, between leukemia and growth hormone therapy is
uncertain.
OVERDOSAGE
There is little information on acute or chronic overdosage with
OMNITROPE™. Intravenously
administered growth hormone has been shown to result in an acute
decrease in plasma glucose.
Subsequently, hyperglycemia was seen. It is thought that the same
effect might occur on rare
occasions with a high dosage of OMNITROPE™ administered SC. Long-
term overdosage may
result in signs and symptoms of acromegaly consistent with
overproduction of growth hormone.
NDA 21-426 Agreed upon text
1
OMNITROPE™
(somatropin [rDNA origin]) for injection
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