CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-148
`
`APPROVED LABELING
`
`Novo Nordisk A/S Ex. 2014, P. 1
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

`

`Novo Nordisk
`
`PRODUCT INFORMATION
`
`Norditropin® cartridges
`Somatropin (rDNA origin) injection
`5 mg/1.5 mL, 10 mg/1.5 mL, or 15 mg/1.5 mL
`
`DESCRIPTION
`Norditropin® is the Novo Nordisk Pharmaceuticals, Inc. registered trademark for somatropin, a
`polypeptide hormone of recombinant DNA origin. The hormone is synthesized by a special strain of E.
`coli bacteria that has been modified by the addition of a plasmid which carries the gene for human
`growth hormone. Norditropin® contains the identical sequence of 191 amino acids constituting the
`naturally occurring pituitary human growth hormone with a molecular weight of about 22,000 Daltons.
`
`Norditropin® cartridges are supplied as solutions in ready-to-administer cartridges with a volume of 1.5
`mL.
`
`Each Norditropin® cartridge contains the following:
`5 mg/1.5 mL
`Component
`10 mg/1.5 mL
`Somatropin
`5 mg
`10 mg
`Histidine
`1 mg
`1 mg
`Poloxamer 188
`4.5 mg
`4.5 mg
`Phenol
`4.5 mg
`4.5 mg
`Mannitol
`60 mg
`60 mg
`HCI/NaOH
`q.s.
`q.s.
`Water for Injection
`ad 1.5 mL
`ad 1.5 mL
`
`15 mg/1.5 mL
`15mg
`1.7mg
`4.5mg
`4.5mg
`58mg
`q.s.
`ad 1.5 mL
`
`CLINICAL PHARMACOLOGY
`a. Tissue Growth
`The primary and most intensively studied action of somatropin is the stimulation of linear growth. This
`effect is demonstrated in patients with somatropin deficiency.
`Skeletal growth - the measmable increase in bone length after administration of somatropin
`1.
`results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have
`shown that the incorporation of sulfate into proteoglycans is not due to a direct effect of
`somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGF).
`The somatomedins, among them somatomedin C, are polypeptide hormones which are
`synthesized in the liver, kidney, and various other tissue. Somatomedin C is low in the serum of
`hypopituitary dwarfs and hypophysectomized humans or animals, but its presence can be
`demonstrated after treatment with somatropin.
`
`2.
`
`Cell growth - it has been shown that the total number of skeletal muscle cells is markedly
`decreased in short stature children lacking endogenous somatropin compared with normal
`children, and that treatment with somatropin results in an increase in both the number and size of
`muscle cells.
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`IPR2020-00324
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`3.
`
`Organ growth - somatropin influences the size of internal organs, and it also increases red cell
`mass.
`
`b. Protein Metabolism
`Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are
`reflected by nitrogen retention which can be quantitated by observing the decline in urinary nitrogen
`excretion and blood urea nitrogen following the initiation of somatropin therapy.
`
`c. Carbohydrate Metabolism
`Hypopituitary children sometimes experience fasting hypoglycemia that may be improved by treatment
`with somatropin. In healthy subjects, large doses of somatropin may impair glucose tolerance. Although
`the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking
`the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as
`somatropin levels increase.
`
`d. Fat Metabolism
`Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in
`plasma free fatty acids, cholesterol, and triglycerides. Untreated growth hormone deficiency is
`associated with increased body fat stores including increased subcutaneous adipose tissue. On
`somatropin replacement a general reduction of fat stores and of subcutaneous tissue in particular takes
`place.
`
`e. Mineral Metabolism
`Administration of somatropin results in the retention of total body potassium and phosphorus and to a
`lesser extent sodium. lhis retention is thought to be the result of cell growth. Serum levels of phosphate
`increase in patients with growth hormone deficiency after somatropin therapy due to metabolic activity
`associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the
`urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative
`calcium balance, however, may occasionally occur during somatropin treatment
`
`f. Connective Tissue Metabolism
`Somatropin stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of
`hydroxyproline.
`
`g. Pharmacokinetics
`A 180-min N infusion ofNorditropin® (33 ng'kg,'min) was given to 9 GHD patients. A mean (±SD)
`hGH steady-state serum level of approximately 23.1 (±15.0) ng,'mL was reached at 150 min and a
`mean clearance rate of approximately 2.3 (±1.8) mllmin/kg or 139 (±105) mllmin for hGH was
`obtained. Following infusion, serum hGH levels had a biexponential decay with a tenninal elimination
`half-life (f112) of approximately 21.1 (±5.1) min.
`
`In a study conducted in 18 GHD adult patients, where a SC dose of 0.024 mg'kg or 3 IU/m2 was given
`in the thigh, the mean (±SD) Cmax values of 13.8 (±5.8) and 17.1 (±10.0) ng,'mL were obtained for the
`4 and 8 mg Norditropin® vials, respectively, at approximately 4 to 5 hr. post dose. The mean apparent
`tenninal T112 values were estimated to be approximately 7 to 10 hr. However, the absolute
`bioavailability for Norditropin® after the SC route of administration is currently not known.
`Norditropin® cartridge formulation is bioequivalent to Norditropin® vial formulation.
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`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
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`INDICATIONS AND USAGE
`Norditropin® is indicated for the long-term treatment of children who have growth failure due to
`inadequate secretion of endogenous growth hormone.
`
`CONTRAINDICATIONS
`Norditropin® should not be used in subjects with closed epiphyses.
`
`Norditropin® should not be used in hypopituitary children who have evidence of actively growing
`intracranial tumors. Therapy with somatropin should be discontinued if there is evidence of recurrent
`tumor growth.
`
`Norditropin® 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
`institution of growth hormone therapy.
`
`Norditropin® should not be used in any subjects with known hypersensitivity to any of the constituents
`of the preparation.
`
`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 (41.911/o vs. 19.3%) among
`somatropin treated patients (doses 5.3-8 mg/day) compared to those receiving placebo (see
`WARNINGS).
`
`WARNINGS
`
`Norditropin® cartridges must be used with their corresponding color-coded NordiPen™ delivery
`device. A Norditropin® cartridge must not be inserted into a pen with a different color code.
`
`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
`Norditropin® should be used only by physicians with experience in the diagnosis and management of
`patients with growth hormone deficiency.
`
`Patients with growth hormone deficiency secondary to an intracranial lesion should be examined
`frequently for progression or recurrence of the underlying disease process.
`
`Because growth hormone may induce a state of insulin resistance, patients should be observed for
`evidence of glucose intolerance.
`
`Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Norditropin®. Patients
`with coexisting ACTII deficiency should have their glucocorticoid replacement dose carefully adjusted
`to avoid an inhibitory effect on growth.
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`A state of hypothyroidism may develop during Norditropin® treatment Since untreated
`hypothyroidism may interfere with the response to Norditropin®, patients should have a periodic
`thyroid fimction test and should be treated with thyroid hormone when indicated.
`
`Patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital
`epiphyses more frequently. Any child with the onset of a limp or complaints of hip or knee pain during
`growth hormone therapy should be evaluated.
`
`Intracranial hypertension (Ill) with papilledema, visual changes, headache, nausea and/or vomiting has
`been reported in a small number of patients treated with growth hormone products. Symptoms usually
`occurred within the first eight (8) weeks of the initiation of growth hormone therapy. In all reported
`cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the
`growth hormone dose. Funduscopic examination of patients is recommended at the initiation and
`periodically during the course of growth hormone therapy.
`
`Progression of scoliosis can occur in children who experience rapid growth. Because growth hormone
`increases growth rate, patients with a history of scoliosis who are treated with growth hormone should
`be monitored for progression of scoliosis.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity, mutagenicity, and fertility studies
`have not been conducted with Norditropin® cartridges.
`
`Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted with
`Norditropin® cartridge formulation. It is also not known whether Norditropin® can cause fetal harm
`when administered to a pregnant woman or can affect reproduction capacity. Norditropin® should be
`given to a pregnant woman only if clearly needed.
`
`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 Norditropin® is administered to a nursing
`woman.
`
`ADVERSE REACTIONS
`As with all protein drugs, a small percentage of patients may develop antibodies to the protein. Growth
`hormone antibody with binding capacity lower than 2 mg/L has not been associated with growth
`attenuation. In some cases, when binding capacity is greater than 2 mg/L, interference with growth
`response has been observed.
`
`In clinical trials, patients receiving Norditropin® for up to 12 months have been tested for induction of
`antibodies and 0/358 patients developed antibodies with binding capacities above
`2 mg/L. Among these patients, 165 had previously been treated with other preparations of growth
`hormone and 193 were previously untreated naive patients.
`
`Since antibodies to somatropin have the potential to inhibit finther linear growth, only patients failing to
`respond to treatment should be tested for antibodies.
`
`The following adverse events have been reported from clinical studies: headache, localized muscle pain,
`weakness, mild hyperglycemia and glucosuria.
`
`Leukemia has been reported in a small number of children who have been treated with growth hormone,
`including growth hormone of pituitary origin and recombinant somatrem and somatropin. On the basis
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`of current evidence, experts cannot conclude that growth hormone therapy is responsible for these
`occurrences. If there is any risk to an individual patient, it is minimal.
`
`Fluid retention and peripheral edema may occur.
`
`OVERDOSAGE
`The maximmn dose generally recommended should not be exceeded due to the potential risk of side
`effects.
`
`DOSAGE AND ADMINISTRATION
`The Norditropin® dosage and schedule for administration must be individualized for each patient
`Generally, subcutaneous administration in the evening, 6-7 times a week, is recommended. It is
`furthermore recommended to give the injections in the thighs and to vary the injection site on the thigh on
`a rotating basis. Dosage can be calculated according to body weight.
`
`Generally recommended dosage:
`Subcutaneous injection:
`0.024 - 0.034 mg/kg body weight, 6-7 times a week.
`
`Norditropin® cartridges must be administered using the NordiPen™ injection pen. Each
`cartridge size has a color-coded corresponding pen which is graduated to deliver the
`appropriate dose based on the concentration of Norditropin® in the cartridge.
`
`Measuring the Prescribed Dose:
`
`5 mg/1.5 mL, 10 mg/1.5 mL, and 15 mg/1.5 mL Norditropin® Cartridges
`Each cartridge ofNorditropin® must be inserted into its corresponding NordiPen™ injection pen.
`Instructions for delivering the dosage are provided in the NordiPen ™ instruction booklet.
`
`Storage:
`Norditropin® cartridges must be stored at 2-8°C/36-46°F (refrigerator). Do not freeze. Avoid direct
`light
`
`Norditropin® cartridges retain their biological potency until the date of expiry indicated on the label.
`After a Norditropin® cartridge has been inserted into the NordiPen™ injector, it must be stored in the
`pen in the refrigerator and used within 4 weeks.
`
`HOW SUPPLIED
`Norditropin® 5 mg/1.5 mL, 10 mg/1.5 mL, and 15 mg/1.5 mL cartridges:
`Norditropin® is supplied in 5 mg/1.5 mL, 10 mg/1.5 mL, or 15 mg/1.5 mL cartridges which must be
`administered using the corresponding color-coded NordiPen™ injection pen.
`
`Norditropin® 5 mg/1.5 mL cartridge (orange) NDC 0 169-7768-11
`Norditropin® 10 mg/1.5 mL cartridge (blue) NDC 0 169-7769-11
`Norditropin® 15 mg/1.5 mL cartridge (green) NDC 0 169-7770-11
`
`© Novo Nordisk NS, June 1999
`
`Revised 5/00
`
`Novo Nordisk A/S Ex. 2014, P. 6
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`

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`Rx Only
`
`For information contact:
`Novo Nordisk Pharmaceuticals Inc.
`I 00 Overlook Center, Suite 200
`Princeton, New Jersey 08540
`USA
`
`Manufactured by:
`Novo Nordisk A/S
`2880 Bagsvaerd, Denmark
`
`Novo Nordisk A/S Ex. 2014, P. 7
`Mylan Institutional v. Novo Nordisk
`IPR2020-00324
`
`