Drug Safety-related Labeling Changes (SrLC)

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SEROSTIM (BLA-020604)

(SOMATROPIN RECOMBINANT)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/24/2017 (SUPPL-74)

Approved Drug Label (PDF)

4 Contraindications

ZORBTIVE replaces SEROSTIM throughout

Additions and/or revisions underlined:

Zorbtive® is contraindicated in patients with:

• active malignancy …

•  …active proliferative or severe non-proliferative diabetic retinopathy …

5 Warnings and Precautions

PLR conversion; additions and revisions underlined as below:

5.1 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.

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.

5.2 Acute Critical Illness

Increased mortality in patients with acute critical illness … 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 … compared to those receiving placebo. Discontinue Zorbtive® if the patient has acute critical illness.

5.3 Impaired Glucose Intolerance/Diabetes Mellitus

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 …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.

5.4 Hypersensitivity Reactions

Serious systemic hypersensitivity reactions including anaphylactic reactions … Inform patients and caregivers that such reactions are possible and to seek prompt medical attention if a hypersensitivity reaction occurs.

5.5 Lipoatrophy

… tissue atrophy may result.  Avoid tissue atrophy by rotating the injection site.

5.6 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.

5.7 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.

5.8 Pancreatitis

Pediatric Patient(s) replaces child/children throughout this subsection.

Females replace girls.

… 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.

5.9 Hypoadrenalism

Patients receiving somatropin therapy who have or are at risk for pituitary hormone 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.

5.10 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.

5.11 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.

5.12 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).

6 Adverse Reactions

PLR conversion; additions and/or revisions underlined:

The following serious adverse reactions are described below and elsewhere in the labeling:

• Impaired Glucose Intolerance/Diabetes Mellitus

• Hypersensitivity Reactions Fluid Retention

• Carpel Tunnel Syndrome

• Hypoadrenalism

• Hypothyroidism

• Intracranial Hypertension

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

  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 Reactions* in a Randomized, Placebo Controlled Trial of Zorbtive® in Adult Patients with Short Bowel Syndrome: 4 Week Treatment Period Newly added table replacing previous Table 2; please refer to label for full data and details.

  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

  Zorbtive® or other somatropin products replaces SEROTSTIM.

  Zorbtive®:

• headache

• gynecomastia

  Other somatropin products:

• new onset impaired glucose tolerance …

• serious systemic hypersensitivity reactions, including anaphylaxis and angioedema

• leukemia

7 Drug Interactions

PLR conversion; additions and/or revisions underlined:

7.1 Glucocorticoids

The microsomal enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?HSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Somatropin inhibits 11?HSD-1 which can lead to reduced serum cortisol concentrations. As a consequence, in patients treated with Zorbtive®, previously undiagnosed secondary (central) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with Zorbtive®. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following the initiation of Zorbtive® therapy. However, formal drug interaction studies have not been conducted.

7.2 Cytochrome P450-Metabolized Drugs

Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450) - mediated antipyrine clearance in humans, which involves multiple isozymes including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, and CYP3A4. These data suggest that somatropin administration may alter the clearance of compounds metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, and cyclosporine). When somatropin is administered in combination with these drugs, monitor clinical response to the CYP-metabolized drug, as dosage adjustments may be required.   However, formal drug interaction studies have not been conducted.

7.3 Oral Estrogen

Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, females receiving oral estrogen replacement may have reduced efficacy from Zorbtive®. However, formal drug interaction studies have not been conducted. Monitor patients taking oral estrogens for lack of efficacy of Zorbtive®.

7.4 Insulin and/or Other Oral/Injectable Hypoglycemic Agents

Patients with diabetes mellitus who receive concomitant antidiabetic treatment with Zorbtive® may require adjustment of their doses of insulin and/or other hypoglycemic agents.  However, formal drug interaction studies have not been conducted.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; revised as below:

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. 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

PLLR conversion; revised as below:

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

Additions and/or revisions underlined:

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.

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.

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.

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).

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

Additions and/or revisions underlined:

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

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.

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®.

Administration

Administer Zorbtive® using sterile, disposable syringes and needles.  Instruct patient in the importance of proper disposal …

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 Pa 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®.

Pancreatitis

Inform patients that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain.

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.

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.

Intracranial Hypertension

Instruct patients to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting.

PATIENT INFORMATION

Newly added section; please refer to label.

12/13/2016 (SUPPL-89)

Approved Drug Label (PDF)

4 Contraindications

•     Hypersensitivity

(revision underlined)

SEROSTIM is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products.

5 Warnings and Precautions

5.1 Acute Critical Illness

(New subsection added)

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. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (42% vs. 19%) among somatropin- treated patients (doses 5.3-8 mg/day) compared to those receiving placebo

5.6 Severe Hypersensitivity

(New subsection added)

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs.

6 Adverse Reactions

(additions  underlined)

The following important adverse reactions are also described elsewhere in the labeling:

Acute Critical Illness

Neoplasms

Impaired glucose tolerance and diabetes mellitus Intracranial hypertension

Severe hypersensitivity

Fluid retention/Carpal tunnel syndrome

Lipoatrophy

Pancreatitis

6.2 Post-Marketing Experience

(additions  underlined)

Hypersensitivity: Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products.

In some patients, these conditions improved when SEROSTIM was discontinued, while in others the glucose intolerance persisted. Some of these patients required initiation or adjustment of antidiabetic treatment while on SEROSTIM.

12/13/2016 (SUPPL-90)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

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 (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo.

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. Zorbtive® is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products.

5 Warnings and Precautions

(additions underlined)

… Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs.

6 Adverse Reactions

(additions underlined)

Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products.

7 Drug Interactions

 (additions underlined)

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Counceling Information

(Extensive additions and revisions, please refer to label)