Data from FDA - Curated by Toby Galbraith - Last updated 14 May 2017
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, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients [see Warnings and Precautions (5.2)]. • Active Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting 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. • Hypersensitivity GENOTROPIN is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. The 5 mg and 12 mg presentations of GENOTROPIN lyophilized powder contain m-cresol as a preservative. Systemic hypersensitivity reactions have been reported with post-marketing 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.
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)] Otitis media and cardiovascular disorders in patients with Turner syndrome [see Warnings and Precautions (5.12)] Lipoatrophy [see Warnings and Precautions (5.13)] Pancreatitis [see Warnings and Precautions (5.15)] Other common somatropin-related adverse reactions include injection site reactions/rashes and lipoatrophy (6.1) and headaches (6.3). To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 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. Clinical Trials in children with GHD In clinical studies with GENOTROPIN in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild hyperglycemia. Clinical Trials in PWS In two clinical studies with GENOTROPIN in pediatric patients with Prader-Willi syndrome, the following drug-related events were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia. Clinical Trials in children with SGA In clinical studies of 273 pediatric patients born small for gestational age treated with GENOTROPIN, the following clinically significant events were reported: mild transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Anti-hGH antibodies were not detected in any of the patients treated with GENOTROPIN. Clinical Trials in children with Turner Syndrome In two clinical studies with GENOTROPIN in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses (influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint pain. Clinical Trials in children with Idiopathic Short Stature In two open-label clinical studies with GENOTROPIN in pediatric patients with ISS, the most commonly encountered adverse events include upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies, during GENOTROPIN treatment, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0. 23 and the 0.47 mg/kg/week groups, respectively, had at least one measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD. Clinical Trials in adults with GHD In clinical trials with GENOTROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction. Table 1 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN. Also presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials. Table 1 Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of GENOTROPIN and Placebo, Grouped by Duration of Treatment Double Blind Phase Open Label Phase GENOTROPIN Adverse Event Placebo 0–6 mo. n = 572 % Patients GENOTROPIN 0–6 mo. n = 573 % Patients 6–12 mo. n = 504 % Patients 12–18 mo. n = 63 % Patients 18–24 mo. n = 60 % Patients n = number of patients receiving treatment during the indicated period. % = percentage of patients who reported the event during the indicated period. Swelling, peripheral 5.1 17.5Increased significantly when compared to placebo, P≤.025: Fisher´s Exact Test (one-sided) 5.6 0 1.7 Arthralgia 4.2 17.3 6.9 6.3 3.3 Upper respiratory infection 14.5 15.5 13.1 15.9 13.3 Pain, extremities 5.9 14.7 6.7 1.6 3.3 Edema, peripheral 2.6 10.8 3.0 0 0 Paresthesia 1.9 9.6 2.2 3.2 0 Headache 7.7 9.9 6.2 0 0 Stiffness of extremities 1.6 7.9 2.4 1.6 0 Fatigue 3.8 5.8 4.6 6.3 1.7 Myalgia 1.6 4.9 2.0 4.8 6.7 Back pain 4.4 2.8 3.4 4.8 5.0 Post-Trial Extension Studies in Adults In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN. Of the 3,031 patients receiving GENOTROPIN, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia. Anti-hGH Antibodies 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 GENOTROPIN 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. In 419 pediatric patients evaluated in clinical studies with GENOTROPIN lyophilized powder, 244 had been treated previously with GENOTROPIN or other growth hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously treated patients at baseline. Three of the six became negative for anti-hGH antibodies during 6 to 12 months of treatment with GENOTROPIN. Of the remaining 413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients. Periplasmic Escherichia coli Peptides Preparations of GENOTROPIN contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients treated with GENOTROPIN, but these appear to be of no clinical significance. 6.2 Post-Marketing Experience Because these adverse events 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 post-marketing use of somatropin products [see Warnings and Precautions (5.6)]. Leukemia has been reported in a small number of GHD children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any, remains to be established [see Contraindications (4) and Warnings and Precautions (5.3)]. The following serious adverse reactions have been observed with use of somatropin (including events observed in patients who received brands of somatropin other than GENOTROPIN): acute critical illness [see Warnings and Precautions (5.1)], sudden death [see Warnings and Precautions (5.2)], intracranial tumors [see Warnings and Precautions (5.3)], central hypothyroidism [see Warnings and Precautions (5.9)], cardiovascular disorders, and pancreatitis [see Warnings and Precautions (5.15)]. Slipped capital femoral epiphysis and Legg-Calve-Perthes disease (osteonecrosis/avascular necrosis; occasionally associated with slipped capital femoral epiphysis) have been reported in children treated with growth hormone [see Warnings and Precautions (5.10)]. Cases have been reported with GENOTROPIN. The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and significant diabetic retinopathy. New-onset type 2 diabetes mellitus has been reported.
Dosing and administration
2 DOSAGE AND ADMINISTRATION The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN must not be injected intravenously. Therapy with GENOTROPIN should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure associated with growth hormone deficiency (GHD), Prader-Willi syndrome (PWS), Turner syndrome (TS), those who were born small for gestational age (SGA) or Idiopathic Short Stature (ISS), and adult patients with either childhood onset or adult onset GHD. GENOTROPIN should be administered subcutaneously (2) Pediatric GHD: 0.16 to 0.24 mg/kg/week (2.1) Prader-Willi Syndrome: 0.24 mg/kg/week (2.1) Small for Gestational Age: Up to 0.48 mg/kg/week (2.1) Turner Syndrome: 0.33 mg/kg/week (2.1) Idiopathic Short Stature: up to 0.47 mg/kg/week (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-I concentrations (2.2) Non-weight based dosing: A starting dose of approximately 0.2mg/day (range, 0.15–0.30 mg/day) may be used without consideration of body weight, and increased gradually every 1–2 months by increments of approximately 0.1–0.2 mg/day. (2.2) Weight based dosing: The recommended initial dose is not more than 0.04 mg/kg/week; the dose may be increased as tolerated to not more than 0.08 mg/kg/week at 4–8 week intervals. (2.2) GENOTROPIN cartridges are color-coded to correspond to a specific GENOTROPIN PEN delivery device (2.3) Injection sites should always be rotated to avoid lipoatrophy (2.3) 2.1 Dosing of Pediatric Patients General Pediatric Dosing Information The GENOTROPIN dosage and administration schedule should be individualized based on the growth response of each patient. 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 GH (rhGH). Treatment with GENOTROPIN for short stature should be discontinued when the epiphyses are fused. Pediatric Growth Hormone Deficiency (GHD) Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended. Prader-Willi Syndrome Generally, a dose of 0.24 mg/kg body weight/week is recommended. Turner Syndrome Generally, a dose of 0.33 mg/kg body weight/week is recommended. Idiopathic Short Stature Generally, a dose up to 0.47 mg/kg body weight/week is recommended. Small for Gestational Age Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.48 mg/kg/week), especially in very short children (i.e., height SDS <–3), and/or older/ pubertal children, and that a reduction in dosage (e.g., gradually towards 0.24 mg/kg/week) should be considered if substantial catch-up growth is observed during the first few years of therapy. On the other hand, in younger SGA children (e.g., approximately <4 years) (who respond the best in general) with less severe short stature (i.e., baseline height SDS values between -2 and -3), consideration should be given to initiating treatment at a lower dose (e.g., 0.24 mg/kg/week), and titrating the dose as needed over time. In all children, clinicians should carefully monitor the growth response, and adjust the somatropin dose as necessary. Generally, a dose of up to 0.48 mg/kg body weight/week is recommended. 2.2 Dosing of Adult Patients Adult Growth Hormone Deficiency (GHD) Either of two approaches to GENOTROPIN dosing may be followed: a non-weight based regimen or a weight based regimen. Non-weight based — based on published consensus guidelines, 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 1–2 months by increments of approximately 0.1–0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor I (IGF-I) concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person, and between male and female patients. Weight based — based on the dosing regimen used in the original adult GHD registration trials, the recommended dosage at the start of treatment is not more than 0.04 mg/kg/week. The dose may be increased according to individual patient requirements to not more than 0.08 mg/kg/week at 4–8 week intervals. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I concentrations should be used as guidance in dose titration. 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 The GENOTROPIN 5 and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN Pen delivery device. The 5 mg cartridge has a green tip to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. GENOTROPIN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. GENOTROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. Reproduction studies carried out with GENOTROPIN at doses of 0.3, 1, and 3.3 mg/kg/day administered SC in the rat and 0.08, 0.3, and 1.3 mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic. In rats receiving SC doses during gametogenesis and up to 7 days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day (approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted. In perinatal and postnatal studies in rats, GENOTROPIN doses of 0.3, 1, and 3.3 mg/kg/day produced growth-promoting effects in the dams but not in the fetuses. Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offsprings due to GENOTROPIN. 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 There have been no studies conducted with GENOTROPIN in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GENOTROPIN is administered to a nursing woman. 8.5 Geriatric Use The safety and effectiveness of GENOTROPIN in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of GENOTROPIN, 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)].
Pregnancy and lactation
8.3 Nursing Mothers There have been no studies conducted with GENOTROPIN in nursing mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GENOTROPIN is administered to a nursing woman.
|Date Last Revised||26-04-2017|
|Type||HUMAN PRESCRIPTION DRUG|
|Storage and handling||Storage and Handling Except as noted below, store GENOTROPIN lyophilized powder under refrigeration at 36°F to 46°F (2°C to 8°C).Do not freeze. Protect from light. The 5 mg and 12 mg cartridges of GENOTROPIN contain a diluent with a preservative. Thus, after reconstitution, they may be stored under refrigeration for up to 28 days. The GENOTROPIN MINIQUICK Growth Hormone Delivery Device should be refrigerated prior to dispensing, but may be stored at or below 77°F (25°C) for up to three months after dispensing. The diluent has no preservative. After reconstitution, the GENOTROPIN MINIQUICK may be stored under refrigeration for up to 24 hours before use. The GENOTROPIN MINIQUICK should be used only once and then discarded.|
|Marketing authorisation holder||Pharmacia and Upjohn Company LLC|