mecasermin 10 MG/ML Injectable Solution

INDICATIONS AND USAGE INCRELEX (mecasermin) injection is indicated for the treatment of growth failure in pediatric patients 2 years of age and older with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. ( 1 ) Limitations of use: INCRELEX is not a substitute to GH for approved GH indications. Severe Primary IGF-1 Deficiency (Primary IGFD) INCRELEX is indicated for the treatment of growth failure in pediatric patients 2 years of age and older with: severe primary IGF-1 deficiency or growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Severe Primary IGF-1 deficiency (IGFD) is defined by: height standard deviation score ≤ –3.0 and basal IGF-1 standard deviation score ≤ –3.0 and normal or elevated growth hormone (GH). Limitations of use: INCRELEX is not a substitute to GH for approved GH indications. INCRELEX is not indicated for use in patients with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory corticosteroids.

DOSAGE AND ADMINISTRATION INCRELEX should be administered subcutaneously. ( 2.2 ) Injection sites should be rotated to avoid lipohypertrophy. ( 2.2 ) Recommended starting dosage: 0.04 mg/kg to 0.08 mg/kg twice daily. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. ( 2.1 ) 2.1 Recommended Dosage Treatment with INCRELEX should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with severe primary IGF-1 deficiency or with growth hormone gene deletion and who have developed neutralizing antibodies to growth hormone. The dosage of INCRELEX should be individualized for each patient. The recommended starting dose of INCRELEX is 0.04 mg/kg to 0.08 mg/kg of body weight twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg of body weight per dose, to the maximum dose of 0.12 mg/kg of body weight given twice daily [see Warnings and Precautions (5.1 and 5.7) ]. Preprandial glucose monitoring is recommended at treatment initiation and until a well-tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue, and glucose monitoring should also occur at the time of event if possible. If hypoglycemia occurs with recommended doses despite adequate food intake, the dose should be reduced. INCRELEX should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of INCRELEX should be withheld. If one or more doses of INCRELEX is missed, do not increase the subsequent doses to make up for omitted doses. 2.2 Administration Instructions INCRELEX is administered by subcutaneous injection only. Do not administer intravenously. INCRELEX injection sites should be rotated to a different site (upper arm, thigh, buttock or abdomen) with each injection to help prevent lipohypertrophy. INCRELEX should be administered using sterile disposable syringes and needles. The syringes should be of small enough volume so that the prescribed dose can be withdrawn from the vial with accuracy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy or contains particulate matter. If using syringes that measure dose in units, doses in mg/kg must be converted to units using the following formula: Weight (kg) × Dose (mg/kg) × 1 mL/10 mg × 100 units/1 mL = units/injection.

WARNINGS AND PRECAUTIONS Hypoglycemia: Severe hypoglycemia leading to hypoglycemic seizures has been observed with INCRELEX treatment. Administer INCRELEX shortly before or after a meal or snack, because it has insulin-like hypoglycemic effects. ( 5.1 ) Hypersensitivity and Allergic Reactions, including Anaphylaxis: A low number of cases indicative of anaphylaxis requiring hospitalization have been reported. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought. ( 5.2 ) Intracranial Hypertension : Funduscopic examination is recommended at the initiation and periodically during the course of INCRELEX therapy. ( 5.3 ) Lymphoid Tissue Hypertrophy (tonsillar/adenoidal hypertrophy): Patients should have periodic examinations to rule out potential complications and receive appropriate treatment if necessary. ( 5.4 ) Slipped Capital Femoral Epiphysis (SCFE): Evaluate any child with onset of a limp or hip/knee pain for possible SCFE and osteonecrosis. ( 5.5 ) Progression of Scoliosis: Monitor any child with scoliosis for progression of the spine curve. ( 5.6 ) Malignant Neoplasia: Several cases of malignant neoplasia have been observed in pediatric patients treated with INCRELEX. Therapy should be discontinued if evidence of malignant neoplasia develops and appropriate expert medical care sought. ( 5.7 ) Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preserved Solution: Benzyl alcohol, a preservative in INCRELEX, has been associated with serious adverse reactions, including death, in neonates and infants. Use of INCRELEX in infants is not recommended. ( 5.8 ) 5.1 Hypoglycemia Severe hypoglycemia leading to hypoglycemic seizures has been observed with INCRELEX treatment [see Adverse Reactions (6.1) ]. Because INCRELEX has insulin-like hypoglycemic effects it should be administered shortly before or after (± 20 minutes) a meal or snack. Glucose monitoring and INCRELEX dose titration are recommended until a well-tolerated dose is established [see Dosage and Administration (2.1) ] and subsequently as medically indicated. Special attention should be paid to small children because their oral intake may not be consistent. Patients should avoid engaging in any high-risk activities (e.g., driving, exercise, etc.) within 2 to 3 hours after dosing, particularly during the initiation of INCRELEX treatment until tolerability and a stable dose have been established [see Adverse Reactions (6.1) ] . INCRELEX should not be administered when the meal or snack is omitted. The dose of INCRELEX should never be increased to make up for one or more omitted doses. 5.2 Hypersensitivity and Allergic Reactions, including Anaphylaxis Allergic reactions to INCRELEX have been reported post-marketing. They range from localized (injection site) reactions to systemic reactions, including anaphylaxis requiring hospitalization. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought. [see Contraindications (4) and Adverse Reactions (6) ] 5.3 Intracranial Hypertension Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting have occurred in patients treated with INCRELEX. IH-associated signs and symptoms resolved after interruption of dosing. Funduscopic examination is recommended at the initiation and periodically during the course of INCRELEX therapy. [see Adverse Reactions (6) ]. 5.4 Lymphoid Tissue Hypertrophy Lymphoid tissue (e.g., tonsillar and adenoidal) hypertrophy associated with complications, such as snoring, sleep apnea, and chronic middle-ear effusions have been reported with the use of INCRELEX. Patients should have periodic examinations to rule out such potential complications and receive appropriate treatment if necessary [see Adverse Reactions (6) ]. 5.5 Slipped Capital Femoral Epiphysis Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients receiving products indicated to treat growth failure and/or short stature, including INCRELEX. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during INCRELEX therapy should be evaluated for slipped capital femoral epiphysis and osteonecrosis and managed accordingly. 5.6 Progression of Preexisting Scoliosis Progression of scoliosis may occur in patients who experience rapid growth. Because INCRELEX increases growth rate, patients with a history of scoliosis who are treated with INCRELEX should be monitored for progression of scoliosis. 5.7 Malignant Neoplasia There have been postmarketing reports of malignant neoplasms in pediatric patients who have received treatment with INCRELEX [see Adverse Reactions (6) ] . The cases of malignant neoplasms represented a variety of different malignancies. It is unknown whether there is any relationship between INCRELEX therapy and new occurrence of neoplasia. The occurrence of neoplasia was mostly reported in patients with rare genetic conditions of short stature associated with an increased risk of cancer, or in patients with other cancer predisposing conditions. The tumors were observed also more frequently in patients who received INCRELEX at higher than recommended doses, or at doses that produced serum IGF-1 levels above the normal reference ranges for age and sex. Monitor all patients receiving INCRELEX carefully for development of neoplasms. Advise patients/caregivers to report development of new neoplasms. If malignant neoplasia develops, discontinue INCRELEX treatment [see Contraindications (4) ] . 5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preserved Solution Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including INCRELEX. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. Use of INCRELEX in infants is not recommended [see Use in Specific Populations 8.4) ] .

CONTRAINDICATIONS Known Hypersensitivity to mecasermin ( 4 ) Closed Epiphyses ( 4 ) Malignant Neoplasia ( 4 ) Known Hypersensitivity INCRELEX should not be used by patients who are allergic to mecasermin (rhIGF-1) or any of the inactive ingredients in INCRELEX, or who have experienced a severe hypersensitivity to INCRELEX [see Warnings and Precautions (5.2) and Adverse Reactions (6) ]. Closed Epiphyses INCRELEX should not be used for growth promotion in patients with closed epiphyses. Malignant Neoplasia INCRELEX is contraindicated in pediatric patients with malignant neoplasia or a history of malignancy [see Warnings and Precautions (5.7) and Adverse Reactions (6) ].

Mechanism of Action Insulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.