NDA 21-597, NDA 20-604/S-026
`Page 4
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`
`Zorbtive™
`
`[somatropin (rDNA origin) for injection]
`
`DESCRIPTION
`Zorbtive™[somatropin (rDNA origin) for injection] is a human growth hormone (hGH) produced by
`recombinant DNA technology. Zorbtive™ has 191 amino acid residues and a molecular weight of
`22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human
`pituitary GH. Zorbtive™ is produced by a mammalian cell line (mouse C127) that has been modified
`by the addition of the hGH gene. Zorbtive™ is secreted directly through the cell membrane into the
`cell-culture medium for collection and purification.
`
`Zorbtive™ is a highly purified preparation. Biological potency is determined by measuring the
`increase in the body weight induced in hypophysectomized rats.
`
`Zorbtive™ is available in 4 mg, 5 mg and 6 mg vials for single dose administration. Zorbtive™ is also
`available in 8.8 mg vials for multi-dose administration. Each 4 mg vial contains 4.0 mg (approximately
`12 IU) somatropin, 27.3 mg sucrose, 0.9 mg phosphoric acid. Each 5 mg vial contains 5.0 mg
`(approximately 15 IU) somatropin, 34.2 mg sucrose and 1.2 mg phosphoric acid. Each 6 mg vial
`contains 6.0 mg (approximately 18 IU) somatropin, 41.0 mg sucrose and 1.4 mg phosphoric acid.
`Each 8.8 mg vial contains 8.8 mg (approximately 26.4 IU) somatropin, 60.19 mg sucrose and 2.05 mg
`phosphoric acid. The pH is adjusted with sodium hydroxide or phosphoric acid to give a pH of 7.4 to
`8.5 after reconstitution.
`
`CLINICAL PHARMACOLOGY
`Zorbtive™ [somatropin (rDNA origin) for injection] is an anabolic and anticatabolic agent which
`exerts its influence by interacting with specific receptors on a variety of cell types including myocytes,
`hepatocytes, adipocytes, lymphocytes, and hematopoietic cells. Some, but not all of its effects, are
`mediated by insulin-like growth factor-I (IGF-I).
`
`MECHANISM OF ACTION IN SHORT BOWEL SYNDROME (SBS) PATIENTS
`Intestinal mucosa contains receptors for growth hormone and for insulin-like growth factor-I (IGF-I),
`which is known to mediate many of the cellular actions of growth hormone. Thus, the actions of
`growth hormone on the gut may be direct or mediated via the local or systemic production of IGF
`
`In human clinical studies the administration of growth hormone has been shown to enhance the
`transmucosal transport of water, electrolytes, and nutrients.
`
`PHARMACOKINETICS
`Subcutaneous Absorption: The absolute bioavailability of Zorbtive™ [somatropin (rDNA origin) for
`injection] after subcutaneous administration of a formulation not equivalent to the marketed
`formulation was determined to be 70-90%. The t½ (Mean ± SD) after subcutaneous administration is
`significantly longer than that seen after intravenous administration in normal male volunteers down-
`regulated with somatostatin (3.94 ± 3.44 hrs. vs. 0.58 ± 0.08 hrs.), indicating that the subcutaneous
`absorption of the clinically tested formulation of the compound is slow and rate-limiting.
`
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`NDA 21-597, NDA 20-604/S-026
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`Distribution: The steady-state volume of distribution (Mean ± SD) following IV administration of
`Zorbtive™ in healthy volunteers is 12.0 ± 1.08 L.
`
`Metabolism: Although the liver plays a role in the metabolism of GH, GH is primarily cleaved in the
`kidney. GH undergoes glomerular filtration and, after cleavage within the renal cells, the peptides and
`amino acids are returned to the systemic circulation.
`
`Elimination: The t½ (Mean ± SD) in nine patients with HIV-associated wasting with an average weight
`of 56.7 ± 6.8 kg, given a fixed dose of 6.0 mg recombinant hGH (r-hGH) subcutaneously was 4.28 ±
`2.15 hrs. The renal clearance of r-hGH after subcutaneous administration in nine patients with HIV-
`associated wasting was 0.0015 ± 0.0037 L/h. No significant accumulation of r-hGH appears to occur
`after 6 weeks of dosing as indicated.
`
`Special Populations:
`Pediatric: Available evidence suggests that r-hGH clearances are similar in adults and children, but no
`pharmacokinetic studies have been conducted in children with short bowel syndrome.
`
`Gender: Biomedical literature indicates that a gender-related difference in the mean clearance of r-hGH
`could exist (clearance of r-hGH in males > clearance of r-hGH in females). However, no gender-based
`analysis is available in normal volunteers or patients with short bowel syndrome.
`
`Race: No data are available.
`
`Renal Insufficiency: It has been reported that individuals with chronic renal failure tend to have
`decreased r-hGH clearance compared to normals, but there are no data on Zorbtive™ use in the
`presence of renal insufficiency.
`
`Hepatic Insufficiency: A reduction in r-hGH clearance has been noted in patients with severe liver
`dysfunction. However, the clinical significance of this in short bowel syndrome patients is unknown.
`CLINICAL STUDIES
`A randomized, double blind, controlled, parallel-group Phase III clinical study evaluated the efficacy
`and safety of the administration of Zorbtive™ in subjects with Short Bowel Syndrome (SBS) who
`were dependent on intravenous parenteral nutrition (IPN) for nutritional support. The primary
`endpoint was the change in weekly total IPN volume defined as the sum of the volumes of IPN,
`supplemental lipid emulsion (SLE), and intravenous hydration fluid. The secondary endpoints were the
`change in weekly IPN caloric content and the change in the frequency of IPN administration per week.
`Subjects received either Zorbtive™ placebo with the nutritional supplement, glutamine (n=9),
`Zorbtive™ without glutamine (n=16) or Zorbtive™ with glutamine (n=16). All 3 groups received a
`specialized diet. Following a two-week equilibration period, treatment was administered in a double
`blind manner over a further period of four weeks. The dosing of Zorbtive™ was approximately
`0.1mg/kg/day for 4 weeks. During the double-blind treatment portion of the trial, the glutamine was
`given at a daily dose of 30g. The mean baseline IPN volume, mean IPN caloric content, and mean
`frequency of IPN administration are provided in Table 1. Mean reductions in IPN volume, IPN caloric
`content and the frequency of IPN administration in each patient group were significantly greater in
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`both Zorbtive™-treated groups than in group treated with Zorbtive™ placebo. These changes are
`tabulated in Table 1.
`
`
`Table 1 Results for Endpoints after 4 weeks of Treatment
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`NDA 21-597, NDA 20-604/S-026
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`rhGH + SOD[GLN] 1
`
`
`
`10.5
`-7.7
`-3.9**
`
`
`7895.0
`-5751.2
`-3117.9
`
`
`
`
`
`
`
`SOD[GLN] 1
`
`
`13.5
`-3.8
`
`
`
`8570.4
`-2633.3
`
`
`rhGH + SOD 1
`
`
`10.3
`-5.9
`-2.1*
`
`
`7634.7
`-4338.3
`-1705.0
`
`
`
`
`Total IPN volume (L/wk)
` Mean at Baseline
` Mean Change
` Treatment differences (with GLN)
`
`Total IPN Calories (kcal/wk)
` Mean at Baseline
` Mean Change
` Treatment differences (with GLN)
`
`
`
`
`
`Frequency of IPN or SLE
`(days/week)
`5.4
`5.1
`5.9
` Mean at Baseline
`-4.2
`-3.0
`-2.0
` Mean Change
`-2.2
`-1.0
`
` Treatment differences (with GLN)
`1 SOD[GLN] = Specialized Oral Diet supplemented with Glutamine ; rhGH + SOD = Human Growth Hormone plus
`Specialized Oral Diet; rhGH + SOD[GLN] = Human Growth Hormone plus Specialized Oral Diet supplemented with
`Glutamine
`* p = 0.043, treatment comparison between rhGH + SOD versus SOD[GLN]
`** p <0.001, treatment comparison between rhGH + SOD[GLN] versus SOD[GLN]
`
`INDICATIONS AND USAGE
`Zorbtive™ [somatropin (rDNA origin) for injection] is indicated for the treatment of Short Bowel
`Syndrome in patients receiving specialized nutritional support. Zorbtive™ therapy should be used in
`conjunction with optimal management of Short Bowel Syndrome.
`
`Specialized nutritional support may consist of a high carbohydrate, low-fat diet, adjusted for individual
`patient requirements and preferences. Nutritional supplements may be added according to the
`discretion of the treating physician. Optimal management of Short Bowel Syndrome may include
`dietary adjustments, enteral feedings, parenteral nutrition, fluid and micronutrient supplements, as
`needed.
`
`CONTRAINDICATIONS
`Growth hormone therapy should not be initiated in patients with acute critical illness due to
`complications following open heart or abdominal surgery, multiple accidental trauma or 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).
`
`Zorbtive™ is contraindicated in patients with active neoplasia (either newly diagnosed or recurrent).
`Any anti-tumor therapy should be completed prior to starting therapy with Zorbtive™. Zorbtive™
`[somatropin (rDNA origin) for injection] reconstituted with Bacteriostatic Water for Injection, USP
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`NDA 21-597, NDA 20-604/S-026
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`(0.9% Benzyl Alcohol) should not be administered to patients with a known sensitivity to Benzyl
`Alcohol. (See « WARNINGS »).
`
`Zorbtive™ is contraindicated in patients with a known hypersensitivity to growth hormone.
`
`WARNINGS
`Benzyl Alcohol as a preservative in Bacteriostatic Water for Injection, USP has been associated with
`toxicity in newborns. If sensitivity to the diluent occurs, Zorbtive™ [somatropin (rDNA origin) for
`injection] may be reconstituted with Sterile Water for Injection, USP. When Zorbtive™ is
`reconstituted in this manner, the reconstituted solution should be used immediately and any unused
`portion should be discarded.
`
`See CONTRAINDICATIONS for information regarding increased mortality in growth hormone-
`treated patients with acute critical illnesses in intensive care units due to complications following open
`heart or abdominal surgery, multiple accidental trauma or 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 developing acute critical illnesses should be
`weighed against the potential risk.
`
`PRECAUTIONS
`General: Zorbtive™ [somatropin (rDNA origin) for injection] therapy should be carried out under the
`regular guidance of a physician who is experienced in the diagnosis and management of short bowel
`syndrome.
`
`Patients should be informed that allergic reactions are possible and that prompt medical attention
`should be sought if an allergic reaction occurs.
`
`Recombinant human growth hormone (r-hGH) has been associated with acute pancreatitis.
`
`The use of somatropin has been associated with cases of new onset impaired glucose intolerance, new
`onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in
`patients receiving somatropin. Some patients developed diabetic ketoacidosis and diabetic coma. In
`some patients, these conditions improved when somatropin was discontinued, while in others the
`glucose intolerance persisted. Some patients necessitated initiation or adjustment of antidiabetic
`treatment while on somatropin. Patients with other risk factors for glucose intolerance should be
`monitored closely during Zorbtive™ therapy.
`
`No cases of intracranial hypertension (IH) have been observed among patients with short bowel
`syndrome treated with Zorbtive™. The syndrome of IH, with papilledema, visual changes, headache,
`and nausea and/or vomiting has been reported in a small number of children with growth failure treated
`with growth hormone products. Nevertheless, funduscopic evaluation of patients is recommended at
`the initiation and periodically during the course of Zorbtive™ therapy.
`
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`Increased tissue turgor (swelling, particularly in the hands and feet) and musculoskeletal discomfort
`(pain, swelling and/or stiffness) may occur during treatment with Zorbtive™, but may resolve
`spontaneously, with analgesic therapy, or after reducing the frequency of dosing (see DOSAGE AND
`ADMINISTRATION).
`
`Carpal tunnel syndrome may occur during treatment with somatropin. If the symptoms of carpal
`tunnel syndrome do not resolve by decreasing the dose or frequency of somatropin, it is recommended
`that treatment be discontinued.
`
`Information For Patients: Patients being treated with Zorbtive™ should be informed of the potential
`benefits and risks associated with treatment. Patients should be instructed to contact their physician
`should they experience any side effects or discomfort during treatment with Zorbtive™.
`
`It is recommended that Zorbtive™ be administered using sterile, disposable syringes and needles.
`Patients should be thoroughly instructed in the importance of proper disposal and cautioned against
`any reuse of needles and syringes. An appropriate container for the disposal of used syringes and
`needles should be employed.
`
`Patients should be instructed to rotate injection sites to avoid localized tissue atrophy.
`
`Drug Interactions: Formal drug interaction studies have not been conducted.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies for carcinogenicity
`have not been performed with Zorbtive™. There is no evidence from animal studies to date of
`Zorbtive™-induced mutagenicity or impairment of fertility.
`
`Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits.
`Doses up to 5 to 10 times the human dose, based on body surface area, have revealed no evidence of
`impaired fertility or harm to the fetus due to Zorbtive™. 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 Women: It is not known whether Zorbtive™ is excreted in human milk. Because many drugs
`are excreted in human milk, caution should be exercised when Zorbtive™ is administered to a nursing
`woman.
`
`Pediatric Use: There are no formal studies in pediatric patients with short bowel syndrome.
`
`Geriatric Use : Clinical studies with Zorbtive™ did not include sufficient numbers of subjects aged 65
`and over to determine whether they respond differently from younger subjects. Elderly patients may
`be more sensitive to growth hormone action, and may be more prone to develop adverse reactions.
`Thus, dose selection for an elderly patient should be cautious, usually starting at a lower dose.
`
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`ADVERSE REACTIONS
`Table 2 summarizes the number of subjects by system-organ class who experienced an adverse event
`during the 4-week treatment period of the Phase 3 SBS study. To be listed in Table 2, an adverse event
`must have occurred in more than 10% of subjects in any treatment group.
`
`NDA 21-597, NDA 20-604/S-026
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`Table 2: Controlled Trial Adverse Events – 4 Week Treatment Period
`rhGH+SOD1
`SOD[GLN]1
`N=9
`N=16
`n (%)
`n (%)
`8 (89)
`16 (100)
`
`Adverse Experiences*
`Total Number of Subjects with At Least
`One AE
`Body as a Whole: General Disorders
`Edema, Peripheral
`Edema, Facial
`Pain
`Chest Pain
`Fever
`Back Pain
`Flu-like Disorder
`Malaise
`Edema, Generalized
`Abdomen Enlarged
`Allergic Reaction
`Rigors (Chills)
`Gastrointestinal System Disorders
`Flatulence
`Abdominal Pain
`Nausea
`Tenesmus
`Vomiting
`Hemorrhoids
`Mouth Dry
`Musculoskeletal System Disorders
`Arthralgia
`Myalgia
`Resistance Mechanism Disorders
`Infection
`Infection Bacterial
`Infection Viral
`Moniliasis
`Application Site Disorders
`Injection Site Reaction
`Injection Site Pain
`Central and Peripheral Nervous System
`Disorders
`Dizziness
`Headache
`Hypoasthesia
`Skin and Appendages Disorders
`Rash
`Pruritis
`Sweating Increased
`Nail Disorder
`
`rhGH+SOD[GLN]1
`N=16
`n (%)
`16 (100)
`
`15 (94)
`13 (81)
`7 (44)
`1 (6)
`0 (0)
`1 (6)
`0 (0)
`1 (6)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`12 (75)
`4 (25)
`2 (13)
`5 (31)
`3 (19)
`3 (19)
`0 (0)
`0 (0)
`7 (44)
`5 (31)
`0 (0)
`3 (19)
`1 (6)
`0 (0)
`2 (13)
`0 (0)
`4 (25)
`4 (25)
`0 (0)
`4 (25)
`
`2 (13)
`1 (6)
`1 (6)
`4 (25)
`2 (13)
`1 (6)
`0 (0)
`0 (0)
`
`4 (44)
`1 (11)
`0 (0)
`1 (11)
`0 (0)
`2 (22)
`1 (11)
`1 (11)
`0 (0)
`0 (0)
`1 (11)
`1 (11)
`1 (11)
`6 (67)
`2 (22)
`1 (11)
`0 (0)
`3 (33)
`1 (11)
`1 (11)
`1(11)
`1 (11)
`0 (0)
`1 (11)
`4 (44)
`3 (33)
`1 (11)
`0 (0)
`0 (0)
`1 (11)
`1 (11)
`0 (0)
`2 (22)
`
`0 (0)
`1 (11)
`1 (11)
`2 (22)
`0 (0)
`1 (11)
`0 (0)
`1 (11)
`
`15 (94)
`11 (69)
`8 (50)
`3 (19)
`3 (19)
`0 (0)
`1 (6)
`0 (0)
`2 (13)
`2 (13)
`0 (0)
`0 (0)
`0 (0)
`12 (75)
`4 (25)
`4 (25)
`2 (13)
`1 (6)
`3 (19)
`1 (6)
`1 (6)
`7 (44)
`7 (44)
`2 (13)
`6 (38)
`0 (0)
`3 (19)
`1 (6)
`2 (13)
`5 (31)
`3 (19)
`5 (31)
`4 (25)
`
`1 (6)
`1 (6)
`1 (6)
`4 (25)
`1 (6)
`0 (0)
`2 (13)
`0 (0)
`
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`NDA 21-597, NDA 20-604/S-026
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`rhGH+SOD[GLN]1
`rhGH+SOD1
`SOD[GLN]1
`N=16
`N=16
`N=9
`Adverse Experiences*
`n (%)
`n (%)
`n (%)
`5 (31)
`1 (6)
`1 (11)
`Respiratory System Disorders
`3 (19)
`0 (0)
`1 (11)
`Rhinitis
`1 (6)
`3 (19)
`1 (11)
`Metabolic and Nutritional Disorders
`0 (0)
`3 (19)
`1 (11)
`Dehydration
`0 (0)
`0 (0)
`1 (11)
`Thirst
`1 (6)
`2 (13)
`1 (11)
`Urinary System Disorders
`0 (0)
`0 (0)
`1 (11)
`Pyelonephritis
`0 (0)
`1 (6)
`2 (22)
`Psychiatric Disorders
`0 (0)
`0 (0)
`2 (22)
`Depression
`0 (0)
`2 (13)
`1 (11)
`Reproductive Disorders, Female
`0 (0)
`1 (6)
`1 (11)
`Breast Pain Female
`2 (13)
`0 (0)
`0 (0)
`Hearing and Vestibular Disorders
`2 (13)
`0 (0)
`0 (0)
`Ear or Hearing Symptoms
`1 SOD[GLN] = Specialized Oral Diet supplemented with Glutamine; rhGH + SOD = Human Growth Hormone plus
`Specialized Oral Diet; rhGH + SOD[GLN] = Human Growth Hormone plus Specialized Oral Diet supplemented with
`Glutamine
`
`Table 3 summarizes the number of subjects by system-organ class who experienced an adverse event
`during the 12-week follow-up period of the Phase 3 SBS study. To be listed in Table 3, an adverse
`event must have occurred in more than 10% of subjects in any treatment group.
`
`Table 3: Controlled Trial Adverse Events – 12 Week Follow-Up Period
`SOD[GLN]1
`rhGH+SOD1
`Adverse Experiences
`
`N=9
`N=15
`
`n (%)
`n (%)
`Total Number of Subjects with At Least One AE
`7 (78)
`12 (80)
`Gastrointestinal System Disorders
`3 (33)
`7 (47)
` Nausea
`2 (22)
`3 (20)
` Vomiting
`0 (0)
`2 (13)
` Abdominal Pain
`0 (0)
`3 (20)
` Tenesmus
`1 (11)
`0 (0)
` Pancreatitis
`1 (11)
`0 (0)
` Constipation
`1 (11)
`0 (0)
` Crohn's Disease Aggravated
`1 (11)
`0 (0)
` Gastric Ulcer
`1 (11)
`0 (0)
` Gastrointestinal Fistula
`1 (11)
`0 (0)
`Resistance Mechanism Disorders
`5 (56)
`6 (40)
` Infection Bacterial
`3 (33)
`0 (0)
` Infection Viral
`1 (11)
`3 (20)
` Infection
`1 (11)
`1 (7)
` Sepsis
`0 (0)
`3 (20)
`Body as a Whole: General Disorders
`1 (11)
`4 (27)
` Fever
`1 (11)
`2 (13)
` Fatigue
`0 (0)
`2 (13)
`Respiratory System Disorders
`1 (11)
`2 (13)
` Rhinitis
`0 (0)
`1 (7)
` Laryngitis
`1 (11)
`0 (0)
` Pharyngitis
`1 (11)
`0 (0)
`
`rhGH+SOD[GLN]1
`N=16
`n (%)
`13 (81)
`7 (44)
`0 (0)
`3 (19)
`1 (6)
`3 (19)
`1 (6)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`5 (31)
`2 (13)
`1 (6)
`2 (13)
`1 (6)
`2 (13)
`1 (6)
`0 (0)
`4 (25)
`3 (19)
`0 (0)
`0 (0)
`
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`
`
`Reproductive Disorders, Female
` Vaginal Fungal Infection
`Skin and Appendages Disorders
` Rash
`Musculoskeletal System Disorders
` Arthralgia
`Psychiatric Disorders
` Depression
` Insomnia
`Urinary System Disorders
` Pyelonephritis
` Renal Calculus
`Application Site Disorders
` Injection Site Reaction
`Liver and Biliary System Disorders
` Hepatic Function Abnormal
`Vascular Extracardiac Disorders
` Vascular Disorder
`
`NDA 21-597, NDA 20-604/S-026
`Page 11
`
`1 (11)
`1 (11)
`1 (11)
`1 (11)
`0 (0)
`0 (0)
`1 (11)
`1 (11)
`1 (11)
`2 (22)
`1 (11)
`1 (11)
`1 (11)
`1 (11)
`1 (11)
`1 (11)
`1 (11)
`1 (11)
`
`0 (0)
`0 (0)
`2 (13)
`1 (7)
`2 (13)
`2 (13)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`4 (25)
`0 (0)
`2 (13)
`0 (0)
`2 (13)
`2 (13)
`1 (6)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`0 (0)
`
`1 SOD[GLN] = Specialized Oral Diet supplemented with Glutamine ;rhGH + SOD = Human Growth
`Hormone plus Specialized Oral Diet; rhGH + SOD[GLN] = Human Growth Hormone plus Specialized
`Oral Diet supplemented with Glutamine
`
`Adverse events that occurred in 1% to less than 10% of study participants receiving Zorbtive™ in the
`placebo-controlled clinical efficacy trial are listed below by body system. The list of adverse events
`has been compiled regardless of casual relationship to Zorbtive™.
`
`Body as a Whole, General: edema, periorbital edema
`Gastrointestinal System: melena, rectal hemorrhage, mouth disorder, steatorrhea
`Musculoskeletal System: arthritis, arthropathy, bursitis, cramps
`Resistance Mechanism Disorders: fungal infection
`Application Site Disorders: reaction pain, inflammation at injection sites
`Central and Peripheral Nervous System: parasthesia, phantom pain, visual field defect
`Respiratory System: bronchospasm, dyspnea, pharyngitis, respiratory disorder, respiratory infection
`Platelet Bleeding and Clotting Disorders: purpura, prothrombin decrease
`Skin and Appendages: skin disorder, increased sweating, alopecia, bullous eruption
`Psychiatric: insomnia
`Metabolic and Nutritional: hypomagnesemia,
`Urinary System Disorders: dysuria, urinary tract infection, abnormal urine
`Reproduction Disorders Female: breast enlargement, vaginal fungal infection
`Heart Rate and Rhythm Disorders: tachycardia
`Vascular (Extra Cardiac) Disorders: vasodilatation
`
`The safety profile of patients receiving Zorbtive™ with glutamine was similar to the safety profile of
`patients receiving Zorbtive™ without glutamine. During the baseline period, 88% of patients
`receiving Zorbtive™ with glutamine, 88% of patients receiving Zorbtive™ without glutamine, and
`78% of patients receiving Zorbtive™ placebo with glutamine reported baseline signs and symptoms
`(BSS). During the treatment period, 100% of patients receiving Zorbtive™ with and without
`glutamine reported at least one adverse event (AE), whereas 89% of patients receiving Zorbtive™
`
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`Page 12
`
`
`placebo with glutamine reported at least one AE. During the follow-up period 81% of patients
`receiving Zorbtive™ with glutamine, 80% of patients receiving Zorbtive™ without glutamine and
`78% of patients receiving Zorbtive™ placebo with glutamine experienced at least one AE.
`Comparison of the number of serious adverse events (SAEs) before and during treatment demonstrates
`that this subject population experiences numerous BSSs and AEs due to their underlying conditions
`and parenteral nutrition complications. Four subjects (25%) receiving Zorbtive™ without glutamine
`and one subject (11%) in receiving Zorbtive™ placebo with glutamine experienced at least one SAE
`during the treatment period (Zorbtive™ without glutamine: chest pain, purpura, fungal infection,
`pharyngitis ; Zorbtive™ placebo with glutamine: hemorrhoids). None of the subjects receiving
`Zorbtive™ with glutamine experienced SAEs during the treatment period. During the follow-up
`period, 3 subjects (19%) receiving Zorbtive™ with glutamine, 5 subjects (33%) receiving Zorbtive™
`without glutamine and 3 subjects (33%) receiving Zorbtive™ placebo with glutamine experienced at
`least one SAE. There were no deaths in this study.
`
`OVERDOSAGE
`Glucose intolerance can occur with overdosage. Long-term overdosage with growth hormone could
`result in signs and symptoms of acromegaly.
`
`DOSAGE AND ADMINISTRATION
`Zorbtive™ should be administered to patients with short bowel syndrome (SBS) at a dose of
`approximately 0.1 mg/kg subcutaneously daily to a maximum of 8 mg daily. Administration for more
`than 4 weeks has not been adequately studied.
`Injections should be administered daily for 4 weeks. Changes to concomitant medications should be
`avoided. Patients and physicians should monitor for adverse events. Treat moderate fluid retention
`and arthralgias symptomatically or dose reduce by 50%. Discontinue Zorbtive™ for up to 5 days for
`severe toxicities. Upon resolution of symptoms, resume at 50% of original dose. Permanently
`discontinue treatment if severe toxicity recurs or does not disappear within 5 days.
`
`Injection sites should be rotated.
`
`
`Safety and effectiveness in pediatric patients with short bowel syndrome have not been established.
`
`Each vial of Zorbtive™ 4 mg, 5 mg or 6 mg is reconstituted with 0.5 to 1 mL Sterile Water for
`Injection, USP. Each vial of Zorbtive™ 8.8 mg is reconstituted in 1 to 2 mL of Bacteriostatic Water
`for Injection, USP (0.9% Benzyl Alcohol preserved). See Table 4 below for expected concentration
`after reconstitution. Approximately 10% mechanical loss can be associated with reconstitution and
`administration from multi-dose vials. For patients sensitive to benzyl alcohol, see « WARNINGS » .
`
`
`Page 9
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`

`
`
`Table 4: Expected Concentration After Reconstitution (mg/mL)
`
`
`NDA 21-597, NDA 20-604/S-026
`Page 13
`
`
`4 mg
`5 mg
`6 mg
`8.8 mg
`
`0.5 mL
`8
`10
`12
`--
`
`1 mL
`4
`5
`6
`8.8
`
`2 mL
`--
`--
`--
`4.4
`
`
`
`
`
`To reconstitute Zorbtive™, inject the diluent into the vial of Zorbtive™ aiming the liquid against the
`glass vial wall. Swirl the vial with a gentle rotary motion until contents are dissolved completely. The
`Zorbtive™ solution should be clear immediately after reconstitution. DO NOT INJECT Zorbtive™ if
`the reconstituted product is cloudy immediately after reconstitution (Zorbtive™ 4 mg, 5 mg, 6 mg or
`8.8 mg) or after refrigeration (only Zorbtive™ 8.8 mg). The reconstituted Zorbtive™ 8.8 mg can be
`refrigerated (2-8oC/36-46oF) for up to 14 days. Occasionally, after refrigeration, small colorless
`particles may be present in the Zorbtive™ 8.8 mg solution. This is not unusual for proteins like
`Zorbtive™. Allow refrigerated solution to come to room temperature prior to administration. A
`standard insulin-type subcutaneous syringe is recommended for administration.
`
`STABILITY AND STORAGE
`Before reconstitution: Vials of Zorbtive™ and diluent should be stored at room temperature, (15°-
`30°C/59°-86°F). Expiration dates are stated on product labels.
`After Reconstitution with Sterile Water for Injection, USP: The reconstituted solution should be used
`immediately and any unused portion should be discarded .
`After Reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol): The
`reconstituted solution should be stored under refrigeration (2-8oC/36-46oF) for up to 14 days. Avoid
`freezing reconstituted vials of Zorbtive™.
`
`HOW SUPPLIED
`Zorbtive™ [somatropin (rDNA origin) for injection] is available in the following forms:
`Zorbtive™ vials containing 4 mg (approximately 12 IU) somatropin (mammalian-cell) with Sterile
`Water for Injection, USP, 1mL. Package of 7 vials.
`NDC 44087-0004-7
`Zorbtive™ vials containing 5 mg (approximately 15 IU) somatropin (mammalian-cell) with Sterile
`Water for Injection, USP, 1mL. Package of 7 vials.
`NDC 44087-0005-7
`Zorbtive™ vials containing 6 mg (approximately 18 IU) somatropin (mammalian-cell) with Sterile
`Water for Injection, USP, 1mL. Package of 7 vials.
`NDC 44087-0006-7
`Zorbtive™ vial containing 8.8 mg (approximately 26.4 IU) somatropin (mammalian-cell) with
`Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol), 10mL. Package of 1 vial.
`
`
`
`
`
`
`
`
`
`NDC 44087-0088-1
`
`Manufactured for: Serono, Inc., Rockland, MA 02370
`Rx Only BX Rated
`Revised November 2003
`
`Page 10