Data from FDA - Curated by Toby Galbraith - Last updated 28 July 2017
4 CONTRAINDICATIONS Zorbtive® is contraindicated in patients with: active malignancy acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure [see Warnings and Precautions (5.2)] active proliferative or severe non-proliferative diabetic retinopathy hypersensitivity to somatropin or any of the excipients of Zorbtive®. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.4)] active malignancy (4) acute critical illness (4) active proliferative or severe non-proliferative diabetic retinopathy (4) hypersensitivity to somatropin or any of the excipients in Zorbtive® (4)
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Neoplasms [see Warnings and Precautions (5.1)] Acute Critical Illness [see Warnings and Precautions (5.2)] Impaired Glucose Intolerance/Diabetes Mellitus [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.4)] Lipoatrophy [see Warnings and Precautions (5.5)] Fluid Retention and Arthralgia [see Warnings and Precautions (5.6)] Carpel Tunnel Syndrome [see Warnings and Precautions (5.7)] Pancreatitis [see Warnings and Precautions (5.8)] Hypoadrenalism [see Warnings and Precautions (5.9)] Hypothyroidism [see Warnings and Precautions (5.10)] Intracranial Hypertension [see Warnings and Precautions (5.11)] Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.12)] Most common adverse reactions (> 20%) are: peripheral edema, facial edema, arthralgia, injection site pain, flatulence, and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot always be directly compared to the rates in the clinical trials of another drug, and may not reflect the adverse reaction rates observed in practice. In a double-blind, randomized, placebo-controlled clinical trial, 32 patients were exposed to Zorbtive® for 4 weeks. Of the 41 patients enrolled in the trial, 16 patients received Zorbtive® (0.1 mg/kg per day) plus supportive oral diet, 16 patients received subcutaneous Zorbtive® (0.1 mg/kg per day) plus supportive oral diet plus oral glutamine (30 grams per day), and 9 patients received placebo with specialized oral diet and oral glutamine (30 grams per day). The most common adverse reactions occurring in greater than 20% of patients treated with Zorbtive® alone and at a higher frequency than in the control group include peripheral edema, facial edema, arthralgia, injection site pain, flatulence, and abdominal pain. Table 2 summarizes adverse reactions that occurred in at least 10% of patients receiving Zorbtive®, alone or in combination with glutamine and at a higher incidence than in the control group. Table 2: Adverse Reactionsoccurring at in ≥10% of Zorbtive® -treated patients and at a higher incidence than control in a Randomized, Placebo Controlled Trial of Zorbtive® in Adult Patients with Short Bowel Syndrome: 4 Week Treatment Period Treatment Group Adverse Reaction Zorbtive® alone Zorbtive® + Glutamine Control (Placebo + Glutamine) n=16 n (%) n=16 n (%) n=9 n (%) Peripheral edema 11 (69) 13 (81) 1 (11) Facial edema 8 (50) 7 (44) 0 (0) Arthralgia 7 (44) 5 (31) 0 (0) Injection site pain 5 (31) 0 (0) 0 (0) Flatulence 4 (25) 4 (25) 2 (22) Abdominal pain 4 (25) 2 (13) 1 (11) Injection site reaction 3 (19) 4 (25) 1 (11) Vomiting 3 (19) 3 (19) 1 (11) Pain 3 (19) 1 (6) 1 (11) Nausea 2 (13) 5 (31) 0 (0) After 4 weeks of treatment with Zorbtive® patients were discharged for follow-up on a supportive oral diet supplemented either with glutamine or glutamine placebo, and subjects were re-evaluated as outpatients 12 weeks later. No new adverse drug reactions were observed in the follow up period. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Zorbtive® or other somatropin products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Zorbtive®: headache gynecomastia Other somatropin products: new onset impaired glucose tolerance, new onset type 2 diabetes mellitus, exacerbation of preexisting diabetes mellitus, diabetic ketoacidosis, diabetic coma [see Warnings and Precautions (5.3)] serious systemic hypersensitivity reactions, including anaphylaxis and angioedema [see Warnings and Precautions (5.4)]. pancreatitis [see Warnings and Precautions 5.8)] leukemia
Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended dosage is 0.1 mg/kg subcutaneously once daily to a maximum daily dose of 8 mg for 4 weeks. (2.1) See full prescribing information for information on dosage titration and management of fluid retention and arthralgia/carpal tunnel syndrome (2.1); and step-by-step instructions on preparation and administration of the injection. (2.2, 2.3, 2.4) 2.1 Recommended Dosage The recommended dosage of Zorbtive® in adults is 0.1 mg/kg subcutaneously once daily to a maximum daily dose of 8 mg for 4 weeks. Dosage Titration for Fluid Retention and Arthralgia/Carpal Tunnel Syndrome [see Warnings and Precautions (5.6, 5.7)] For moderate toxicity, treat symptomatically with analgesics or reduce the dosage of Zorbtive® to 0.05 mg/kg (maximum total dose of 4 mg) subcutaneously once daily. For severe toxicity, discontinue Zorbtive® for up to 5 days. Upon resolution of symptoms, resume Zorbtive® at 0.05 mg/kg (maximum total dose of 4 mg) subcutaneously once daily. Permanently discontinue Zorbtive®, if severe toxicity recurs or does not disappear within 5 days. 2.2 Preparation Instructions Zorbtive® is provided in a package that contains all items required to reconstitute and inject the drug [see How Supplied/Storage and Handling (16)]. Prepare Zorbtive® using the following steps. 1.Determine the volume needed for the prescribed dosage based on the patient's weight and recommended dosage. Patient weight should be rounded to the nearest kilogram when determining dose. Table 1 below provides the volume of diluent to be added for the reconstitution and concentration of the reconstituted solution for Zorbtive® vial 8.8 mg. Table 1: Reconstitution of Injection Adult Patient Weight (kg) Volume of diluent to be added for the reconstitution (mL) Concentration of reconstituted solution (mg/mL) More than 44 kg 1 mL 8.8 mg/mL Less than or equal to 44 kg 2 mL 4.4 mg/mL 2.Use appropriate aseptic technique when preparing and administering Zorbtive®. 3.Reconstitute the vial(s) of Zorbtive® with either 1 mL or 2 mL of Bacteriostatic Water for Injection, USP (containing Benzyl Alcohol) using a 3 mL syringe. Inject the appropriate amount of diluent into the vial of Zorbtive® aiming the liquid against the glass vial wall. For patients unable to receive Benzyl Alcohol, Zorbtive® may be reconstituted with Sterile Water for Injection, USP [see Warnings and Precautions (5.12)]. 4.Gently swirl the vial in circles until the contents are dissolved completely. DO NOT SHAKE. 5.Visually inspect the reconstituted solution. The final reconstituted solution should be clear and colorless. Discard the vial if the solution is cloudy or contains particulate matter. 2.3 Administration Instructions Withdraw the required volume of the reconstituted solution using a 1 mL syringe with a 29-gauge needle. Inject the full contents of the syringe subcutaneously at a 90° angle into the top side of the thigh, the areas around the belly button, the back of the upper arms, and the buttocks or hips. Rotate injection sites and do not give injections into areas where the skin is tender, bruised, red, or hard. 2.4 Storage of Diluted Solution Once reconstituted with Bacteriostatic Water for Injection, USP (containing Benzyl Alcohol), Zorbtive® should be stored under refrigeration (2 to 8°C/36 to 46°F) and for no more than 14 days. Do not freeze. If Zorbtive® is reconstituted with Sterile Water for Injection, USP, the reconstituted solution should be used immediately and any unused solution should be discarded.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Zorbtive® use in pregnant women to inform any drug associated risks. In animal reproduction studies, no fetal harm was reported with subcutaneous administration of somatropin during the period of organogenesis in rats and rabbits at doses of approximately up to 5 and 10 times, respectively, the recommended human dose of 0.1 mg/kg/day [see Data]. The estimated background risk of major birth defects and miscarriages for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproduction studies of somatropin have been performed in rats and rabbits. Administration of somatropin to rats and rabbits during the period of organogenesis at subcutaneous doses of approximately up to 5 and 10 times the recommended human dosage of 0.1 mg/kg/day, based on body surface area, respectively, have revealed no evidence of harm to the fetus due to somatropin. In a pre- and post-natal development study in rats, subcutaneous doses of approximately up to 5 times the recommended human dosage of 0.1 mg/kg/day (based on body surface area) had no adverse effect on pre- and post-natal development. 8.2 Lactation Risk Summary There are no data on the presence of somatropin in human milk. Limited published literature reports no adverse effects on breastfed infants with maternal administration of somatropin. No decrease in milk production or change in milk content during treatment with somatropin has been reported. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Zorbtive® and any potential adverse effects on the breastfed infant from Zorbtive® or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Zorbtive® in the treatment for short bowel syndrome in pediatric patients have not been established. Zorbtive® is contraindicated in patients with active malignancy. In pediatric cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropins after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms [see Warnings and Precautions (5.1)]. Cases of pancreatitis have been reported in patients receiving somatropin treatment, with some evidence supporting a greater risk in pediatric patients compared with adults, particularly females with Turner syndrome [see Warnings and Precautions (5.8)]. The syndrome of intracranial hypertension (IH), with papilledema, visual changes, headache, and nausea and/or vomiting has been reported in a small number of pediatric patients with growth failure treated with somatropins [see Warnings and Precautions (5.11)]. Zorbtive® is not approved for use in neonates or infants. Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (when reconstituted with Bacteriostatic Water for Injection, USP, Zorbtive® contains 9 mg of benzyl alcohol per mL) [see Warnings and Precautions (5.12)]. Zorbtive® is a recombinant human growth hormone and therefore may increase growth and cause growth-related problems (e.g. slipped capital femoral epiphysis) in the patients receiving it, particularly pediatric patients whose epiphyses are not yet closed. 8.5 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.
|Date Last Revised||12-06-2017|
|Type||HUMAN PRESCRIPTION DRUG|
|Storage and handling||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.|
|Marketing authorisation holder||EMD Serono, Inc.|