Zorbtive

Zorbtive is part of the drug class:

• Somatropin and somatropin agonists

If you use Zorbtive to treat short bowel syndrome, avoid drinking fruit juices or soda beverages. Follow the instructions of your doctor or nutrition counselor about what types of liquids you should drink while using Zorbtive.

Avoid drinking alcohol if you have short bowel syndrome. Alcohol can irritate your stomach and could make your condition worse.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• birth control pills or hormone replacement therapy

• insulin or oral diabetes medicine; or

• steroid medicine (prednisone, dexamethasone, methylprednisolone, and others).

This list is not complete. Other drugs may interact with somatropin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of a pancreas problem (pancreatitis) like very bad stomach pain, very bad back pain, or very bad upset stomach or throwing up.
• Signs of a weak adrenal gland like a very bad upset stomach or throwing up, very bad dizziness or passing out, muscle weakness, feeling very tired, mood changes, not hungry, or weight loss.
• Signs of low thyroid levels like hard stools (constipation); not able to handle cold; memory problems; mood changes; or a burning, numbness, or tingling feeling that is not normal.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Shortness of breath.
• Mood changes.
• Low mood (depression).
• Change in eyesight.
• Very bad headache.
• Chest pain.
• Numbness or tingling in the hands or feet.
• Swelling in the arms or legs.
• Bone pain.
• Very bad muscle or joint pain.
• Change in color or size of a mole.
• Blood in the urine.
• Redness or swelling where the shot is given.
• Skin breakdown where this medicine is used.
• Thinning of the skin.
• Raised pressure in the head has rarely happened with Zorbtive. The risk may be greater in patients with Turner syndrome or Prader-Willi syndrome. Signs most often happen within the first 8 weeks of starting this medicine. Call your doctor right away if you have change in eyesight, a very bad headache, upset stomach, or throwing up.

Zorbtive® is indicated for the treatment of short bowel syndrome in adult patients receiving specialized nutritional support.

Neoplasms

Zorbtive® is contraindicated in patients with active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Discontinue somatropin if there is evidence of recurrent activity [see Contraindications (4)].

In childhood 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. In adult cancer survivors, the risk of occurrence is unknown. Given the limited data available, patients under growth hormone therapy should be carefully monitored for progression or recurrence of the tumor.

The safety and effectiveness of Zorbtive® in the treatment for short bowel syndrome in pediatric patients have not been established and Zorbtive® is not approved for use in pediatric patients.

Monitor patients on somatropin therapy carefully for potential malignant changes of preexisting nevi.

Acute Critical Illness

Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3 to 8 mg per day) compared to those receiving placebo. Discontinue Zorbtive® if the patient has acute critical illness.

Impaired Glucose Tolerance/Diabetes Mellitus

The use of somatropins have been associated with cases of new onset impaired glucose intolerance, new onset type 2 diabetes mellitus and exacerbation of preexisting diabetes mellitus. Some patients developed diabetic ketoacidosis and diabetic coma. In some patients, these conditions improved when the drug was discontinued, while in others the glucose intolerance persisted. Some patients necessitated initiation or adjustment of antidiabetic treatment (e.g., insulin and/or other oral/injectable hypoglycemic agents) while on somatropin. Monitor blood glucose in patients with other risk factors for glucose intolerance during Zorbtive® therapy and adjust antidiabetic treatment, as needed.

Hypersensitivity Reactions

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products. Inform patients and caregivers that such reactions are possible and to seek prompt medical attention if a hypersensitivity reaction occurs. [see Contraindications (4)].

Lipoatrophy

When somatropins are administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Avoid tissue atrophy by rotating the injection site [see Dosage and Administration (2.3)].

Fluid Retention and Arthralgia

Increased fluid retention resulting in tissue turgor (swelling, particularly in the hands and feet) and arthralgia resulting in musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with Zorbtive®, but may resolve spontaneously or with analgesic therapy or after reducing the dosage [see Dosage and Administration (2.1)].

Carpal Tunnel Syndrome

Carpal tunnel syndrome may occur during treatment with somatropin. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the dosage of Zorbtive®, discontinue treatment [see Dosage and Administration (2.1)].

Pancreatitis

Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin treatment, with some evidence supporting a greater risk in pediatric patients compared with adults. Published literature indicates that females who have Turner syndrome may be at greater risk than other somatropin-treated pediatric patients. Pancreatitis should be considered in any somatropin-treated patient, especially a pediatric patient who develops abdominal pain. The safety and effectiveness of Zorbtive® in the treatment for short bowel syndrome in pediatric patients have not been established and Zorbtive® is not approved for use in pediatric patients.

Hypoadrenalism

Patients receiving somatropin therapy who have or are at risk for pituitary homone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of Zorbtive® therapy [see Drug Interactions (7.1)].

Hypothyroidism

Growth hormone can affect the metabolism of thyroid hormones by increasing the extrathyroidal conversion of T4 to T3 and this lowering effect on T4 may unmask incipient central hypothyroidism in hypopituitary patients. Evaluate thyroid function in patients with suspected and/or diagnosed hypopituitarism before starting Zorbtive® therapy and again following 4 weeks of treatment. If hypothyroidism is diagnosed following a course of Zorbtive® therapy, it should be corrected.

Intracranial Hypertension

No cases of intracranial hypertension (IH) have been observed among patients with short bowel syndrome treated with Zorbtive®. 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. Symptoms usually occurred within the first 8 weeks after the initiation of somatropin therapy. IH-associated signs and symptoms usually resolved after cessation of therapy or a reduction of the somatropin dosage. The safety and effectiveness of Zorbtive® in the treatment for short bowel syndrome in pediatric patients have not been established and Zorbtive® is not approved for use in pediatric patients.

Funduscopic evaluation of patients is recommended at the initiation of Zorbtive® therapy and if patients present with symptoms of IH. If papilledema is observed by funduscopy during Zorbtive® treatment, discontinue treatment.

Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative

Zorbtive® is not approved for use in neonates or infants. Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including Zorbtive® when reconstituted with Bacteriostatic Water for Injection, USP. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. 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 Use in Specific Populations (8.4)].

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)]

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.

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.

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

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.

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.

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.

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Glucose Intolerance/Diabetes Mellitus

Inform patients that new onset impaired glucose intolerance/diabetes mellitus or exacerbation of preexisting diabetes mellitus can occur and monitoring of blood glucose during treatment with Zorbtive® may be needed [see Warnings and Precautions (5.3)].

Hypersensitivity Reactions

Inform patients that local or systemic reactions are possible. Instruct patients to contact their healthcare provider should they experience any side effects or discomfort during treatment with Zorbtive® [see Warnings and Precautions (5.4)].

Administration

Administer Zorbtive® using sterile, disposable syringes and needles. Instruct patient 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.

Instruct patients to rotate injection sites to avoid localized tissue atrophy [see Warnings and Precautions (5.5)].

Refer patients to the Instructions for Use on how to prepare and administer an injection of Zorbtive.

Fluid Retention/Carpel Tunnel Syndrome

Inform patients that increased tissue turgor (swelling, particularly in the hands and feet) and musculoskeletal discomfort (pain, swelling and/or stiffness) may occur during treatment with Zorbtive® and to report to their healthcare provider any signs or symptoms that occur during treatment with Zorbtive® [see Warnings and Precautions (5.6 and 5.7)].

Pancreatitis

Inform patients that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain [see Warnings and Precautions (5.8)].

Hypoadrenalism

Inform patients who have or who are at risk for pituitary hormone deficiency(s) that hypoadrenalism may develop and to report to their healthcare provider if they experience hyperpigmentation, extreme fatigue, dizziness, weakness, or weight loss [see Warnings and Precautions (5.9)].

Hypothyroidism

Inform patients that hypothyroidism may develop and that their thyroid function may be monitored before starting Zorbtive® and again following 4 weeks of treatment [see Warnings and Precautions (5.10)].

Intracranial Hypertension

Instruct patients to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting [see Warnings and Precautions (5.11)].

Manufactured for: EMD Serono, Inc., Rockland, MA 02370

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Call your doctor if you miss more than 3 doses in a row.