Increlex

1 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.

2 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.

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) ].

5 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) ] .

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions (5.1) ]. Hypersensitivity and Allergic Reactions, including Anaphylaxis [see Warnings and Precautions (5.2) ] Intracranial hypertension (IH) [see Warnings and Precautions (5.3) ] Tonsillar and Adenoidal Hypertrophy and related complications [see Warnings and Precautions (5.4) ] Slipped Capital Femoral Epiphysis [see Warnings and Precautions (5.5) ] Progression of Preexisting Scoliosis [see Warnings and Precautions (5.6) ] Malignant Neoplasia [see Warnings and Precautions (5.7) ] Benzyl Alcohol [see Warnings and Precautions (5.8) ] Common INCRELEX-related adverse reactions in clinical trials include: hypoglycemia, local and systemic hypersensitivity, tonsillar hypertrophy ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Ipsen Biopharmaceuticals, Inc. at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical studies of 71 subjects with Primary IGFD treated for a mean duration of 3.9 years and representing 274 subject-years, no subjects withdrew from any clinical study because of adverse reactions. Adverse reactions to INCRELEX treatment that occurred in 5% or more of these study participants are listed below by organ class. Metabolism and Nutrition Disorders: hypoglycemia General Disorders and Administrative Site Conditions: lipohypertrophy, bruising Infections and Infestations: otitis media, serous otitis media Respiratory, Thoracic and Mediastinal Disorders: snoring, tonsillar hypertrophy Nervous System Disorders: headache, dizziness, convulsions Gastrointestinal Disorders: vomiting Ear and Labyrinth Disorders: hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry Investigations: cardiac murmur Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity Blood and Lymphatic System Disorders: thymus hypertrophy Surgical and Medical Procedures: ear tube insertion Hypoglycemia was reported by 30 subjects (42%) at least once during their course of therapy. Most cases of hypoglycemia were mild or moderate in severity. Five subjects had severe hypoglycemia (requiring assistance and treatment) on one or more occasions and 4 subjects experienced hypoglycemic seizures/loss of consciousness on one or more occasions. Of the 30 subjects reporting hypoglycemia, 14 (47%) had a history of hypoglycemia prior to treatment. The frequency of hypoglycemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly (i.e., 20 minutes) before or after the administration of INCRELEX. Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years. Tonsillectomy or tonsillectomy/adenoidectomy was performed in 7 subjects; 3 of these had obstructive sleep apnea, which resolved after the procedure in all three cases. Intracranial hypertension occurred in three subjects. In two subjects the events resolved without interruption of INCRELEX treatment. INCRELEX treatment was discontinued in the third subject and resumed later at a lower dose without recurrence. Mild elevations in the serum AST and LDH were found in a significant proportion of patients before and during treatment. Rise in levels of these serum enzymes did not lead to treatment discontinuation. ALT elevations were occasionally noted during treatment. Renal and splenic lengths (measured by ultrasound) increased rapidly on INCRELEX treatment during the first years of therapy. This lengthening slowed down subsequently; though in some patients, renal and/or splenic length reached or surpassed the 95 th percentile. Renal function (as defined by serum creatinine and calculated creatinine clearance) was normal in all patients, irrespective of renal growth. Elevations in cholesterol and triglycerides to above the upper limit of normal were observed before and during treatment. Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals without associated clinical symptoms. The relation of these cardiac changes to drug treatment cannot be assessed due to underlying disease and the lack of a control group. Thickening of the soft tissues of the face was observed in several patients and should be monitored during INCRELEX treatment. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of INCRELEX. 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. Systemic hypersensitivity: anaphylaxis, generalized urticaria, angioedema, dyspnea In the post-marketing setting, the frequency of cases indicative of anaphylaxis was estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnea, and some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients. Local allergic reactions at the injection site: pruritus, urticaria Skin and Subcutaneous Tissue Disorders: alopecia, hair texture abnormal General Disorders and Administrative Site Conditions: injection site reactions (e.g. erythema, pain, hematoma, hemorrhage, induration, rash, swelling) Musculoskeletal and Connective Tissue Disorders: osteonecrosis/avascular necrosis (occasionally associated with slipped capital femoral epiphysis) Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)

8.1 Pregnancy Risk Summary There are no available data on INCRELEX use in pregnant women. Exposure to INCRELEX during pregnancy is unlikely because the drug is not indicated for use after epiphyseal closure. In animal reproduction studies, there were no observed embryo-fetal development abnormalities with intravenous administration of INCRELEX to pregnant rats and rabbits during fetal organogenesis given at exposures up to 11 and 3 times the maximum recommended human dose (MRHD) of 0.24 mg/kg/day based on body surface area (BSA), respectively (see Data ) . The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Studies to assess embryo-fetal toxicity evaluated the effects of INCRELEX during organogenesis in Sprague Dawley rats given 1, 4, and 16 mg/kg/day and in New Zealand White rabbits given 0.125, 0.5, and 2 mg/kg/day, administered intravenously. There were no observed embryo-fetal developmental abnormalities in rats given up to 16 mg/kg/day (11 times the MRHD based on BSA comparison). In the rabbit study, the NOAEL for fetal toxicity was 0.5 mg/kg/day (approximately equivalent to the MRHD based on BSA) due to an increase in fetal death at 2 mg/kg. INCRELEX displayed no teratogenicity or maternal toxicity in rabbits given up to 2 mg/kg (3 times the MRHD based on BSA).