Omnitrope Drug Information

Dosing of Adult Patients Adult Growth Hormone Deficiency (GHD) Weight-Based Dosing Based on the weight-based dosing utilized in clinical studies with another somatropin product, the recommended dosage at the start of therapy is not more than 0.04 mg/kg/week given as a daily subcutaneous injection. The dose may be increased at 4- to 8-week intervals according to individual patient requirements to not more than 0.08 mg/kg/week. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-1 levels may be used as guidance in dose titration.

Non-Weight Dosing Alternatively, taking into account 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 1-2 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 events 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.

Preparation and Administration OMNITROPE Cartridge 5 mg/1.5 mL and Cartridge 10 mg/1.5 mL Each cartridge of OMNITROPE must be inserted into its corresponding OMNITROPE Pen 5 or OMNITROPE Pen 10 delivery system. Instructions for delivering the dosage are provided in the OMNITROPE INSTRUCTIONS FOR USE booklet enclosed with the OMNITROPE drug and the OMNITROPE Pens. OMNITROPE for injection 5.8 mg/vial Instructions for delivering the dosage are provided in the INSTRUCTIONS FOR USE leaflets enclosed with the OMNITROPE drug.

Once the diluent is added to the lyophilized powder, swirl gently; do not shake. Shaking may cause denaturation of the active ingredient. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

OMNITROPE MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. OMNITROPE must be refrigerated at 2° to 8°C (36° to 46°F).

Patients and caregivers who will administer OMNITROPE in medically unsupervised situations should receive appropriate training and instruction on the proper use of OMNITROPE from the physician or other suitably qualified health professional. The dosage of OMNITROPE must be adjusted for the individual patient. The dose should be given daily by subcutaneous injections (administered preferably in the evening).

OMNITROPE may be given in the thigh, buttocks, or abdomen. Injection sites should always be rotated to avoid lipoatrophy.

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 Pediatric GHD Patients The following events were observed during clinical studies with OMNITROPE Cartridge conducted in children with GHD: Table 1. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with OMNITROPE for Injection (N=44) Clinical Trials in PWS In two clinical studies in pediatric patients with Prader-Willi Syndrome carried out with another somatropin product, 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 another somatropin product, 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. Clinical Trials in Children with Idiopathic Short Stature In two open-label clinical studies conducted with another somatropin product in pediatric patients with ISS, the most commonly encountered adverse events were upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies during treatment with this other somatropin product, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range.

Clinical Trials in Children with Turner Syndrome In two clinical studies with another somatropin product 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 Adults with GHD In clinical trials with another somatropin product 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 3 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with another somatropin product. 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 3. Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of Another Somatropin Product and Placebo, Grouped by Duration of Treatment 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 another somatropin product. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving this other somatropin product.

Of the 3,031 patients receiving this other somatropin product, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption or surgery. Other adverse events that have been reported include generalized edema and hypoesthesia.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of somatropin or OMNITROPE. 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. The adverse events reported during postmarketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. Leukemia has been reported in a small number of GH deficient 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. The following additional adverse reactions have been observed during the use of somatropin: headaches (children and adults), gynecomastia (children), osteonecrosis (children), and pancreatitis (children and adults).

New-onset type 2 diabetes mellitus has been reported.

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.

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.

Oral Estrogen

In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal.

Insulin and/or Oral Hypoglycemic Agents

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated.

Pregnancy Risk Summary OMNITROPE contains the preservative benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs.

Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. In animal studies (rats and rabbits), there was no evidence of embryo‑fetal or neonatal harm following somatropin administration during organogenesis at doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area ( see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is respectively. In perinatal and postnatal studies in rats, doses of 0.3, 1, and 3.3 mg/kg/day somatropin 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 offspring due to somatropin.

• OMNITROPE is contraindicated in patients with:
• 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.
• 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.
• 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 GHD 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 OMNITROPE 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 somatropins.
• 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.
• Acute Critical Illness
• Children with Prader-Willi Syndrome who are severely obese or have severe respiratory impairment - reports of sudden death
• Active Malignancy
• Hypersensitivity to somatropin or its excipients
• Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy
• Children with closed epiphyses

Short-Term Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention. Long-Term Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone.