Data from FDA - Curated by EPG Health - Last updated 01 January 2017

Indication(s)

1 INDICATIONS AND USAGE SAIZEN is a recombinant human growth hormone indicated for: Pediatric: Treatment of children with growth failure due to growth hormone deficiency (GHD) (1.1) Adult: Treatment of adults with either adult onset or childhood onset GHD. (1.2) 1.1 Pediatric Patients SAIZEN [somatropin (rDNA origin) for injection] is indicated for the treatment of pediatric patients with growth failure due to inadequate secretion of endogenous growth hormone. 1.2 Adult Patients SAIZEN is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria: Adult Onset Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or Childhood Onset Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.

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Advisory information

contraindications
4 CONTRAINDICATIONS Acute Critical Illness (4) Children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment – reports of sudden death (4) Active Malignancy (4) Hypersensitivity to somatropin or excipients (4) Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy (4) Children with closed epiphyses (4) • Acute Critical Illness Treatment with pharmacologic amounts of somatropin is contraindicated 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 [see Warnings and Precautions (5.1)]. • Prader-Willi Syndrome in Children Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment [see Warnings and Precautions (5.2)]. There have been reports of sudden death when somatropin was used in such patients. SAIZEN is not indicated for the long term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. • Active Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any pre-existing malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since growth hormone deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [See Warnings and Precautions (5.3)]. • Hypersensitivity SAIZEN 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 [see Warnings and Precautions (5.6)]. • Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy. • Closed Epiphyses Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses. • Benzyl Alcohol SAIZEN 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 and Precautions (5.16)].
Adverse reactions
6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in the labeling: Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)] Fatalities in children with Prader-Willi syndrome [see Warnings and Precautions (5.2)] Neoplasms [see Warnings and Precautions (5.3)] Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)] Intracranial hypertension [see Warnings and Precautions (5.5)] Severe hypersensitivity [see Warnings and Precautions (5.6)] Fluid retention [see Warnings and Precautions (5.7)] Hypoadrenalism [see Warnings and Precautions (5.8) Hypothyroidism [see Warnings and Precautions (5.9)] Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10)] Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11)] Lipoatrophy [see Warnings and Precautions (5.13)] Pancreatitis [see Warnings and Precautions (5.15)] Benzyl alcohol [see Warnings and Precautions (5.16)] Most common adverse reactions are injection site reactions (such as pain, numbness, redness, and swelling), fluid retention, peripheral edema, arthralgia, myalgia, paresthesia, and headache. (6) 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 during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice. Growth Hormone Deficient Pediatric Patients In clinical studies in which SAIZEN was administered to growth hormone deficient children, the following reactions were infrequently seen: local reactions at the injection site (such as pain, numbness, redness and swelling), hypothyroidism, hypoglycemia, seizures, exacerbation of preexisting psoriasis and disturbances in fluid balance. Growth Hormone Deficient Adult Patients For a description of the clinical trials refer to section 14. During the 6-month placebo-controlled study, adverse reactions were reported in 56 patients (93.3%) in the somatropin-treated group and 42 patients (76.4%) in the placebo-treated group. Adverse reactions with an incidence of ≥5% in SAIZEN-treated patients which were more frequent in SAIZEN-treated patients compared with placebo-treated patients are listed in Table 1. Arthralgia, myalgia, peripheral edema, other types of edema, carpal tunnel syndrome, paraesthesia and hypoaesthesia were common in the somatropin-treated patients and reported more frequently than in the placebo group. These types of adverse reactions are thought to be related to the fluid accumulating effects of somatropin. During the placebo-controlled portion of the study, approximately 10% of patients without preexisting diabetes mellitus or impaired glucose tolerance treated with somatropin manifested mild, but persistent, abnormalities of glucose tolerance, compared with none in the placebo group. During the open label phase of the study, approximately 10% of patients treated with somatropin required a small upward adjustment of thyroid hormone replacement therapy for preexisting central hypothyroidism and 1 patient was newly diagnosed with central hypothyroidism. In addition, during the open label phase of the study, when all patients were being treated with somatropin, two patients with preexisting central hypoadrenalism required upward titration of hydrocortisone maintenance therapy which was considered to be suboptimal (unrelated to intercurrent stress, surgery or disease), and 1 patient was diagnosed de novo with central adrenal insufficiency after six months of somatropin treatment. Anti-GH antibodies were not detected. Table 1 Adverse Reactions with ≥5% Overall Incidence in SAIZEN-Treated Patients Which Were More Frequent in SAIZEN-Treated Patients Compared with Placebo-Treated Patients During a 6 Month Study Adverse Reaction SAIZEN-Treated (N=60) Placebo (N=55) N = number of patients Arthralgia 14(23.3%) 7(12.7%) Headache 11(18.3%) 8(14.5%) Edema peripheral 9(15.0%) 2(3.7%) Myalgia 5(8.3%) 2(3.6%) Paraesthesia 4(6.7%) 1(1.8%) Hypoaesthesia 4(6.7%) 0 Edema dependent 3(5.0%) 2(3.6%) Skeletal Pain 3(5.0%) 1(1.8%) Carpal tunnel syndrome 3(5.0%) 1(1.8%) Edema generalized 3(5.0%) 0 Chest pain 3(5.0%) 0 Depression 3(5.0%) 0 Hypothyroidism 3(5.0%) 0 Insomnia 3(5.0%) 0 The adverse reaction pattern observed during the open label phase of the study was similar to the one presented above. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SAIZEN with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed. 6.3 Post-Marketing Experience The following adverse reactions have been identified during post approval use of SAIZEN. 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. Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [See Warnings and Precautions (5.6)]. Leukemia has been reported in a small number of growth hormone deficient patients treated with growth hormone. It is uncertain whether this increased risk is related to the pathology of growth hormone deficiency itself, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. So far, epidemiological data fail to confirm the hypothesis of a relationship between growth hormone therapy and leukemia. The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults) (see Warnings and Precautions [5.14]).

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For subcutaneous injection. SAIZEN therapy should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth hormone deficiency or adult patients with either childhoodonset or adult-onset growth hormone deficiency. Pediatric GHD: 0.18 mg/kg/week, divided into equal doses given either on 3 alternate days, 6 times per week or daily (2.1) Adult GHD: Either a non-weight based or a weight based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-1 concentrations (2.2) Non-weight-based dosing: A starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight, and increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day (2.2) Weight-based dosing: The recommended initial dose is not more than 0.005 mg/kg/day; the dose may be increased as tolerated to not more than 0.01 mg/kg/day after 4 weeks (2.2) Injection sites should always be rotated to avoid lipoatrophy (2.3) 2.1 Pediatric Growth Hormone Deficiency (GHD) SAIZEN dosage and administration schedule should be individualized for each patient. The recommended weekly dosage is 0.18 mg/kg of body weight by subcutaneous injection. It should be divided into equal doses given either on 3 alternate days, 6 times per week or daily. Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age and antibodies to recombinant human growth hormone. Treatment with SAIZEN of growth failure due to growth hormone deficiency should be discontinued when the epiphyses are fused. 2.2 Adult Growth Hormone Deficiency (GHD) Either of two approaches to SAIZEN dosing may be followed: a weight-based regimen or a non-weight-based regimen. Weight-based Based on the dosing utilized in the original pivotal study described herein, the recommended dosage at the start of therapy is not more than 0.005 mg/kg given as a daily subcutaneous injection. The dosage may be increased to not more than 0.01 mg/kg/day after 4 weeks according to individual patient requirements. Clinical response, side effects, and determination of age-and gender-adjusted serum insulin-like growth factor (IGF-1) levels may be used as guidance in dose titration. Non-weight-based Alternatively, taking into account more recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-1 concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse reactions and/or serum IGF-1 levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person. A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women. 2.3 Preparation and Administration Vials To prevent possible contamination, wipe the rubber vial stopper with an antiseptic solution before puncturing it with the needle. It is recommended that SAIZEN be administered using sterile, disposable syringes and needles. The syringes should be of small enough volume that the prescribed dose can be drawn from the vial with reasonable accuracy. After determining the appropriate patient dose, reconstitute each vial of SAIZEN as follows: 5 mg vial with 1 to 3 mL of Bacteriostatic Water for Injection, USP (Benzyl Alcohol preserved); 8.8 mg vial with 2-3 mL of Bacteriostatic Water for Injection, USP (Benzyl Alcohol preserved). Approximately 10% mechanical loss can be associated with reconstitution and multidose administration. If sensitivity to the diluent occurs, SAIZEN may be reconstituted with Sterile Water for Injection, USP. When SAIZEN is reconstituted in this manner, the reconstituted solution should be used immediately and any unused solution should be discarded [see Warnings and Precautions (5.15)]. To reconstitute SAIZEN, inject the diluent into the vial of SAIZEN aiming the liquid against the glass vial wall. Swirl the vial with a GENTLE rotary motion until contents are dissolved completely. DO NOT SHAKE. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. SAIZEN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. click.easy® cartridges For drug preparation instructions for SAIZEN click.easy® cartridges, please refer to the instructions for use provided with click.easy® reconstitution device. Injection sites should always be rotated to avoid lipoatrophy.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 31 and 62 times, respectively, the human (child) weekly dose based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to SAIZEN. 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. 8.3 Nursing Mothers It is not known whether SAIZEN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SAIZEN is administered to a nursing woman. 8.5 Geriatric Use The safety and effectiveness of SAIZEN in patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of SAIZEN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration (2.2)]. 8.6 Hepatic Impairment A reduction in somatropin clearance has been noted in patients with hepatic dysfunction as compared with normal controls. However, no studies have been conducted for SAIZEN in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Subjects with chronic renal failure tend to have decreased clearance of somatropin compared to those with normal renal function. However, no studies have been conducted for SAIZEN in patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.8 Gender Effect In adults, the clearance of somatropin in both men and women tends to be similar. No gender studies have been performed in children.
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether SAIZEN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SAIZEN is administered to a nursing woman.

Interactions

7 DRUG INTERACTIONS Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses (7.1) Glucocorticoid Replacement: Should be carefully adjusted (7.2) Cytochrome P450-Metabolized Drugs: Monitor carefully if used with somatropin (7.3) Oral Estrogen: Larger doses of somatropin may be required in women (7.4) Insulin and/or Oral/Injectable Hypoglycemic Agents: May require adjustment (7.5) 7.1 Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1) The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; 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 11βHSD-1 [see Warnings and Precautions (5.8)]. 7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. 7.3 Cytochrome P450-Metabolized Drugs Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450) mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted. 7.4 Oral Estrogen Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see Dosage and Administration (2.2)]. 7.5 Insulin and/or Oral/Injectable Hypoglycemic Agents In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable agent may require adjustment when somatropin therapy is initiated [see Warnings and Precautions (5.4)].

More information

Category Value
Authorisation number NDA019764
Orphan designation No
Product NDC 44087-1088,44087-1005,44087-1080
Date Last Revised 19-12-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 542438
Storage and handling 16.2 Storage and Handling Before Reconstitution - SAIZEN should be stored at room temperature (15°-30°C/59°-86°F). Expiration dates are stated on the labels. After Reconstitution - SAIZEN 5 mg and 8.8 mg vials reconstituted with the Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) provided should be stored under refrigeration (2°–8°C/36°–46°F) for up to 14 days. SAIZEN 8.8 mg click.easy® cartridge reconstituted with the Sterile Water for Injection, 0.3% (w/v) metacresol provided should be stored under refrigeration (2°–8°C/36°–46°F) for up to 21 days. Avoid freezing reconstituted vials or cartridges of SAIZEN.
Marketing authorisation holder EMD Serono, Inc.