Zorbtive

somatropin (rDNA origin)

Dosage Form: injection
Zorbtive®

[somatropin (rDNA origin) for injection]

Zorbtive 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 8.8 mg vials for multi-dose administration. 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.

Zorbtive - 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-1 (IGF-1).

MECHANISM OF ACTION IN SHORT BOWEL SYNDROME (SBS) PATIENTS

Intestinal mucosa contains receptors for growth hormone and for insulin-like growth factor-1 (IGF-1), 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-1.

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.

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 0.1 mg/kg/day for 4 weeks. During the double-blind treatment portion of the trial, the glutamine was given at a daily dose of 30 g. 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 both Zorbtive®-treated groups than in the group treated with Zorbtive® placebo. These changes are tabulated in Table 1.

Table 1:  Results for Endpoints after 4 weeks of Treatment

	SOD[GLN] 1	r-hGH + SOD 1	r-hGH + SOD[GLN] 1
1 SOD[GLN] = Specialized Oral Diet supplemented with Glutamine ; r-hGH + SOD = Human Growth Hormone plus Specialized Oral Diet; r-hGH + SOD[GLN] = Human Growth Hormone plus Specialized Oral Diet supplemented with Glutamine
*   p = 0.043, treatment comparison between r-hGH + SOD versus SOD[GLN]
** p <0.001, treatment comparison between r-hGH + SOD[GLN] versus SOD[GLN]
Total IPN volume (L/wk)
Mean at Baseline	13.5	10.3	10.5
Mean Change	-3.8	-5.9	-7.7
Treatment Differences (with GLN)		-2.1*	-3.9**
Total IPN Calories (kcal/wk)
Mean at Baseline	8570.4	7634.7	7895.0
Mean Change	-2633.3	-4338.3	-5751.2
Treatment Differences (with GLN)		-1705.0	-3117.9
Frequency of IPN or SLE (days/wk)
Mean at Baseline	5.9	5.1	5.4
Mean Change	-2.0	-3.0	-4.2
Treatment Differences (with GLN)		-1.0	-2.2

Indications and Usage for Zorbtive

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 (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.

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. Somatropin inhibits 11ß-hydroxysteroid dehydrogenase type 1 (11 ßHSD-1) in adipose/ hepatic tissue and may significantly impact the metabolism of cortisol and cortisone. As a consequence, in patients treated with somatropin, previously undiagnosed primary (and secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of the 11 ßHSD-1 enzyme.

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.

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 III SBS study. To be listed in Table 2, an adverse event must have occurred in more than 10% of subjects in any treatment group.

Table 2:  Controlled Trial Adverse Events – 4 Week Treatment Period

Adverse Experiences	SOD[GLN]1 n=9 n (%)	r-hGH+SOD1 n=16 n (%)	r-hGH+SOD[GLN]1 n=16 n (%)
1 SOD[GLN] = Specialized Oral Diet supplemented with Glutamine; r-hGH + SOD = Human Growth Hormone plus Specialized Oral Diet; r-hGH + SOD[GLN] = Human Growth Hormone plus Specialized Oral Diet supplemented with Glutamine
Total Number of Subjects with At Least One AE	8 (89)	16 (100)	16 (100)
Body as a Whole, General Disorders	4 (44)	15 (94)	15 (94)
Edema, Peripheral	1 (11)	11 (69)	13 (81)
Edema, Facial	0 (0)	8 (50)	7 (44)
Pain	1 (11)	3 (19)	1 (6)
Chest Pain	0 (0)	3 (19)	0 (0)
Fever	2 (22)	0 (0)	1 (6)
Back Pain	1 (11)	1 (6)	0 (0)
Flu-like Disorder	1 (11)	0 (0)	1 (6)
Malaise	0 (0)	2 (13)	0 (0)
Edema, Generalized	0 (0)	2 (13)	0 (0)
Abdomen Enlarged	1 (11)	0 (0)	0 (0)
Allergic Reaction	1 (11)	0 (0)	0 (0)
Rigors (Chills)	1 (11)	0 (0)	0 (0)
Gastrointestinal System Disorders	6 (67)	12 (75)	12 (75)
Flatulence	2 (22)	4 (25)	4 (25)
Abdominal Pain	1 (11)	4 (25)	2 (13)
Nausea	0 (0)	2 (13)	5 (31)
Tenesmus	3 (33)	1 (6)	3 (19)
Vomiting	1 (11)	3 (19)	3 (19)
Hemorrhoids	1 (11)	1 (6)	0 (0)
Mouth Dry	1(11)	1 (6)	0 (0)
Musculoskeletal System Disorders	1 (11)	7 (44)	7 (44)
Arthralgia	0 (0)	7 (44)	5 (31)
Myalgia	1 (11)	2 (13)	0 (0)
Resistance Mechanism Disorders	4 (44)	6 (38)	3 (19)
Infection	3 (33)	0 (0)	1 (6)
Infection Bacterial	1 (11)	3 (19)	0 (0)
Infection Viral	0 (0)	1 (6)	2 (13)
Moniliasis	0 (0)	2 (13)	0 (0)
Application Site Disorders	1 (11)	5 (31)	4 (25)
Injection Site Reaction	1 (11)	3 (19)	4 (25)
Injection Site Pain	0 (0)	5 (31)	0 (0)
Central and Peripheral Nervous System Disorders	2 (22)	4 (25)	4 (25)
Dizziness	0 (0)	1 (6)	2 (13)
Headache	1 (11)	1 (6)	1 (6)
Hypoasthesia	1 (11)	1 (6)	1 (6)
Skin and Appendages Disorders	2 (22)	4 (25)	4 (25)
Rash	0 (0)	1 (6)	2 (13)
Pruritis	1 (11)	0 (0)	1 (6)
Sweating Increased	0 (0)	2 (13)	0 (0)
Nail Disorder	1 (11)	0 (0)	0 (0)
Respiratory System Disorders	1 (11)	1 (6)	5 (31)
Rhinitis	1 (11)	0 (0)	3 (19)
Metabolic and Nutritional Disorders	1 (11)	3 (19)	1 (6)
Dehydration	1 (11)	3 (19)	0 (0)
Thirst	1 (11)	0 (0)	0 (0)
Urinary System Disorders	1 (11)	2 (13)	1 (6)
Pyelonephritis	1 (11)	0 (0)	0 (0)
Psychiatric Disorders	2 (22)	1 (6)	0 (0)
Depression	2 (22)	0 (0)	0 (0)
Reproductive Disorders, Female	1 (11)	2 (13)	0 (0)
Breast Pain Female	1 (11)	1 (6)	0 (0)
Hearing and Vestibular Disorders	0 (0)	0 (0)	2 (13)
Ear or Hearing Symptoms	0 (0)	0 (0)	2 (13)

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 III 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

Adverse Experiences	SOD[GLN]1 n=9 n (%)	r-hGH+SOD1 n=15 n (%)	r-hGH+SOD[GLN]1 n=16 n (%)
1 SOD[GLN] = Specialized Oral Diet supplemented with Glutamine ;r-hGH + SOD = Human Growth Hormone plus Specialized Oral Diet; r-hGH + SOD[GLN] = Human Growth Hormone plus Specialized Oral Diet supplemented with Glutamine
Total Number of Subjects with At Least One AE	7 (78)	12 (80)	13 (81)
Gastrointestinal System Disorders	3 (33)	7 (47)	7 (44)
Nausea	2 (22)	3 (20)	0 (0)
Vomiting	0 (0)	2 (13)	3 (19)
Abdominal Pain	0 (0)	3 (20)	1 (6)
Tenesmus	1 (11)	0 (0)	3 (19)
Pancreatitis	1 (11)	0 (0)	1 (6)
Constipation	1 (11)	0 (0)	0 (0)
Crohn's Disease Aggravated	1 (11)	0 (0)	0 (0)
Gastric Ulcer	1 (11)	0 (0)	0 (0)
Gastrointestinal Fistula	1 (11)	0 (0)	0 (0)
Resistance Mechanism Disorders	5 (56)	6 (40)	5 (31)
Infection Bacterial	3 (33)	0 (0)	2 (13)
Infection Viral	1 (11)	3 (20)	1 (6)
Infection	1 (11)	1 (7)	2 (13)
Sepsis	0 (0)	3 (20)	1 (6)
Body as a Whole, General Disorders	1 (11)	4 (27)	2 (13)
Fever	1 (11)	2 (13)	1 (6)
Fatigue	0 (0)	2 (13)	0 (0)
Respiratory System Disorders	1 (11)	2 (13)	4 (25)
Rhinitis	0 (0)	1 (7)	3 (19)
Laryngitis	1 (11)	0 (0)	0 (0)
Pharyngitis	1 (11)	0 (0)	0 (0)
Reproductive Disorders, Female	1 (11)	0 (0)	4 (25)
Vaginal Fungal Infection	1 (11)	0 (0)	0 (0)
Skin and Appendages Disorders	1 (11)	2 (13)	2 (13)
Rash	1 (11)	1 (7)	0 (0)
Musculoskeletal System Disorders	0 (0)	2 (13)	2 (13)
Arthralgia	0 (0)	2 (13)	2 (13)
Psychiatric Disorders	1 (11)	0 (0)	1 (6)
Depression	1 (11)	0 (0)	0 (0)
Insomnia	1 (11)	0 (0)	0 (0)
Urinary System Disorders	2 (22)	0 (0)	0 (0)
Pyelonephritis	1 (11)	0 (0)	0 (0)
Renal Calculus	1 (11)	0 (0)	0 (0)
Application Site Disorders	1 (11)	0 (0)	0 (0)
Injection Site Reaction	1 (11)	0 (0)	0 (0)
Liver and Biliary System Disorders	1 (11)	0 (0)	0 (0)
Hepatic Function Abnormal	1 (11)	0 (0)	0 (0)
Vascular Extracardiac Disorders	1 (11)	0 (0)	0 (0)
Vascular Disorder	1 (11)	0 (0)	0 (0)

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

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