DailyMed Label: Increlex

DailyMed Label: Increlex

2024

DailyMed Prescription

Increlex

mecasermin

Ipsen Biopharmaceuticals, Inc.

NDC: 15054-1040

NDC: 15054-1040

NDC: 15054-1040

NDC: 15054-1040

NDC: 15054-1040

NDC: 15054-1040

NDC: 15054-1040

Mecasermin is a human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 Da. The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesized in bacteria ( E. coli ) that have been modified by the addition of the gene for human IGF-1. INCRELEX (mecasermin) injection is a sterile, aqueous, clear and colorless solution intended for subcutaneous injection. Each multiple-dose vial of INCRELEX contains 40 mg of mecasermin in 4 mL solution, and each mL contains 10 mg mecasermin, 9 mg benzyl alcohol, 0.43 mg glacial acetic acid, 2 mg polysorbate 20, 3.51 mg sodium acetate, and 5.84 mg sodium chloride in Water for Injection, USP at a pH of approximately 5.4.

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.

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 ) 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. 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.

Injection: 40 mg/4 mL (10 mg/mL) clear and colorless solution in a multiple-dose glass vial. Injection: 40 mg/4 mL (10 mg/mL) solution supplied in a multiple-dose glass vial ( 3 )

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 (6.3) ]. 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 (6.3) ].

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. ( 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 ) Severe hypolgycemia leading to hypolycemic 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. 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 (6.3) ] 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 (6.3) ]. 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 (6.3) ]. Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during INCRELEX therapy should be carefully evaluated. 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. There have been postmarketing reports of malignant neoplasms in pediatric patients who have received treatment with INCRELEX [see Adverse Reactions (6.3) ] . 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) ] . 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) ] .

Pediatric Use: Safety and effectiveness has not been established in children less than 2 years of age. ( 8.4 ) 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). Risk Summary There is no information available on the presence of mecasermin in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for INCRELEX and any potential adverse effects on the breast-fed child from INCRELEX or from the underlying maternal condition. Toxicity (Gasping Syndrome) with Benzyl Alcohol Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). INCRELEX contains 9 mg/mL benzyl alcohol as a preservative. Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. Use of INCRELEX in infants is not recommended [see Warnings and Precautions (5.8) ] . Safety and effectiveness in pediatric patients below the age of 2 years of age have not been established. The safety and effectiveness of INCRELEX in patients aged 65 and over has not been established.

How Supplied INCRELEX injection is supplied as a 40 mg/4 mL (10 mg/mL) sterile, clear, and colorless solution in multiple-dose glass vials (NDC-15054-1040-5). Storage and Handling Before Opening – Vials of INCRELEX are stable when refrigerated at 2º to 8ºC (36º to 46ºF). Avoid freezing the vials of INCRELEX. Protect from direct light. Expiration dates are stated on the labels. After Opening – Vials of INCRELEX are stable for 30 days after initial vial entry when stored refrigerated at 2º to 8ºC (36º to 46ºF). Avoid freezing the vials of INCRELEX. Protect from direct light. INCRELEX should not be used after its expiration date. Keep refrigerated and use within 30 days of initial vial entry. Remaining unused material should be discarded.

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. The following actions have been demonstrated for endogenous human IGF-1: Tissue Growth – 1) Skeletal growth occurs at the cartilage growth plates of the epiphyses of bones where stem cells divide to produce new cartilage cells or chondrocytes. The growth of chondrocytes is under the control of IGF-1 and GH. The chondrocytes become calcified so that new bone is formed allowing the length of the bones to increase. This results in skeletal growth until the cartilage growth plates fuse at the end of puberty. 2) Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activities that lead to an increased number of cells in the body. 3) Organ growth: Treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth. Carbohydrate Metabolism –IGF-1 suppresses hepatic glucose production and stimulates peripheral glucose utilization and therefore has a hypoglycemic potential. IGF-1 has inhibitory effects on insulin secretion. Absorption – The absolute bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects is estimated to be close to 100%. However, the absolute bioavailability of INCRELEX given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined. Distribution – In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is greatly reduced in subjects with severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to healthy subjects. The total IGF-1 volume of distribution after subcutaneous administration in subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) L/kg at an INCRELEX dose of 0.045 mg/kg and is estimated to increase as the dose of INCRELEX increases. Elimination – IGF-1 is metabolized by both liver and kidney. The mean terminal t 1/2 after single subcutaneous administration of 0.12 mg/kg INCRELEX in pediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of INCRELEX is inversely proportional to IGF binding protein-3 (IGFBP-3) levels. CL/F is estimated to be 0.04 L/hr/kg at 0.5 micrograms/mL of IGFBP-3, and 0.01 L/hr/kg at 3 micrograms/mL IGFBP-3; the latter is the median IGFBP-3 in subjects with normal IGF-1 serum levels. Gender – In children with Primary IGFD there were no apparent differences between males and females in the pharmacokinetics of INCRELEX. Race –The effect of race on pharmacokinetics of INCRELEX has not been studied. Table 1. Summary of INCRELEX Single-Dose Pharmacokinetic Parameters in Children with Severe Primary IGFD (0.12 mg/kg, SC) C max (ng/mL) T max (hr) AUC 0-8 (hr*ng/mL) t 1/2 (hr) Vd/F (L/kg) CL/F (L/hr/kg) n 3 3 3 3 12 Data represents 3 subjects each at doses 0.015, 0.03, 0.06, and 0.12 mg/kg SC. 12 C max = maximum concentration; T max = time of maximum concentration; AUC 0-8 = area under the curve; t 1/2 = half-life; Vd/F = apparent volume of distribution; CL/F = apparent systemic clearance; SC = subcutaneous injection; CV% = coefficient of variation in %. Male/female data combined, ages 12 to 22 years. PK parameters based on baseline adjusted plasma concentrations. Mean 234 2 2932 5.8 0.257 0.0424 CV% 23 0 50 64 28 38 Figure 1. Mean Total IGF-1 Concentration after a Single Subcutaneous Dose of INCRELEX in Children with Severe Primary IGFD (0.06 mg/kg and 0.12 mg/kg, n=3 per group) Figure 1 Renal impairment – No studies have been conducted in Primary IGFD children with renal impairment. Hepatic impairment – No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of rhIGF-1 in Primary IGFD children with hepatic impairment. The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of INCRELEX or other growth hormones. Anti-IGF-1 antibodies were present at one or more of the periodic assessments in 14 of 23 children with Primary IGFD treated for 2 years. However, no clinical consequences of these antibodies were observed (e.g., attenuation of growth).

Carcinogenesis : INCRELEX was tumorigenic in rats in a study using doses of 0, 0.25, 1, 4, and 10 mg/kg/day by subcutaneous injection for up to 2 years. The incidence of adrenal medullary hyperplasia and pheochromocytoma increased in male rats given ≥1 mg/kg/day (below clinical exposure at the maximum recommended human dose [MRHD] based on AUC) and in female rats at all dose levels (below clinical exposure at the MRHD based on AUC). The incidence of keratoacanthoma in the skin increased in male rats given 4 and 10 mg/kg/day (approximately the clinical exposure at the MRHD based on AUC). The incidence of mammary gland carcinoma in male rats increased in animals treated with 10 mg/kg/day (3 times the MRHD based on AUC). Only doses that exceeded the maximum tolerated dose (MTD) (based on excess mortality secondary to IGF-1 induced hypoglycemia) caused skin and mammary tumors. Mutagenesis : INCRELEX was not clastogenic in the in vitro chromosome aberration assay and the in vivo mouse micronucleus assay. Impairment of fertility : INCRELEX had no effects on fertility in rats using intravenous doses 0.25, 1, and 4 mg/kg/day (up to 3 times the clinical exposure at the MRHD based on BSA).

Five clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of INCRELEX generally ranging from 0.06 to 0.12 mg/kg (60 to 120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/mL): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were pre-pubertal at baseline. Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 2. Pre-treatment height velocity data were available for 58 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year. Table 2: Annual Height Results by Number of Years Treated with INCRELEX Pre-Tx Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS = Standard Deviation Score Height Velocity (cm/yr) N 58 58 48 38 23 21 20 16 13 Mean (SD) 2.8 (1.8) 8.0 (2.2) 5.8 (1.5) 5.5 (1.8) 4.7 (1.6) 4.7 (1.6) 4.8 (1.5) 4.6 (1.5) 4.3 (1.1) Mean (SD) for change from pre-treatment +5.2 (2.6) +2.9 (2.4) +2.3 (2.4) +1.5 (2.2) +1.5 (1.8) +1.5 (1.7) +1.0 (2.1) +0.7 (2.5) P-value for change from pre-treatment P-values for comparison versus pre-treatment values are computed using paired t-tests. <0.0001 <0.0001 <0.0001 0.0045 0.0015 0.0009 0.0897 0.3059 Height Velocity SDS N 58 58 47 37 22 19 18 15 11 Mean (SD) -3.3 (1.7) 1.9 (3.0) -0.2 (1.6) -0.2 (2.0) -0.7 (2.1) -0.6 (2.1) -0.4 (1.4) -0.4 (1.9) -0.4 (1.9) Mean (SD) for change from pre-treatment +5.2 (3.1) +3.1 (2.3) +2.9 (2.3) +2.2 (2.2) +2.5 (2.2) +2.7 (1.7) +2.5 (2.1) +2.7 (2.8) Height SDS N 61 61 51 40 24 21 20 16 13 Mean (SD) -6.7 (1.8) -5.9 (1.8) -5.6 (1.8) -5.4 (1.8) -5.5 (1.9) -5.6 (1.8) -5.4 (1.8) -5.2 (2.0) -5.2 (2.0) Mean (SD) for change from pre-treatment +0.8 (0.5) +1.2 (0.8) +1.4 (1.1) +1.3 (1.2) +1.4 (1.3) +1.4 (1.2) +1.4 (1.1) +1.5 (1.1) Forty-nine subjects were included in an analysis of the effects of INCRELEX on bone age advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean ± SD change in bone age was 5.3 ± 3.4 years.

This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 10/2023 PATIENT INFORMATION INCRELEX ® (EENK-RUH-LEX) (mecasermin) injection for subcutaneous use Read the Patient Information that comes with INCRELEX before your child starts receiving INCRELEX and each time your child gets a refill. There may be new information. This Patient Information leaflet does not take the place of talking with your child's doctor about your child's medical condition or treatment. What is INCRELEX? INCRELEX is a liquid that contains man-made insulin-like growth factor-1 (IGF-1). INCRELEX is used to treat children who are very short for their age because their bodies do not make enough IGF-1. This condition is called primary IGF-1 deficiency. IGF-1 should not be used instead of growth hormone. It is not known if INCRELEX is safe and effective in children under 2 years of age. Who should not receive INCRELEX? Your child should not receive INCRELEX if your child: is allergic to mecasermin or any of the ingredients in INCRELEX. See the end of this Patient Information leaflet for a complete list of ingredients in INCRELEX. Check with your child's doctor if you are not sure. has finished growing (the bone growth plates are closed). has any cancerous tumors or growths; or has a history of cancer or a condition that increases the risk of cancer. Your child should never receive INCRELEX through a vein. What should I tell my child's doctor before my child starts receiving INCRELEX? Tell your child's doctor about all of your child's medical conditions, including if your child: has diabetes. has a curved spine (scoliosis). is pregnant or you think your child might be pregnant. It is not known if INCRELEX can harm an unborn baby. is breastfeeding or plans to breastfeed. Talk to your child's doctor about the best way for your child to feed her baby if she receives INCRELEX. Tell your child's doctor about all the medicines your child takes, including prescription and over-the-counter medicines, vitamins, and herbal supplements . Especially tell your child's doctor if your child takes insulin or other anti-diabetes medicines. A change in dose may be needed for these medicines. How should my child receive INCRELEX? Use INCRELEX exactly as prescribed for your child. Your child's doctor or nurse should teach you how to inject INCRELEX. Do not give your child INCRELEX unless you understand all of the instructions. See the " Instructions for Use " at the end of this Patient Information leaflet. Inject INCRELEX under your child's skin 20 minutes before or 20 minutes after a meal or snack. Skip your child's dose of INCRELEX if your child cannot eat for any reason. Do not give your child an extra dose of INCRELEX or increase the amount of your child's dose to make up for a missed dose. What are the possible side effects of INCRELEX? INCRELEX may cause serious side effects, including: Low blood sugar (hypoglycemia) . INCRELEX may lower blood sugar levels. It is important to only give your child INCRELEX 20 minutes before or 20 minutes after a meal or snack to reduce the chances of low blood sugar. Do not give your child INCRELEX if your child cannot eat. Signs of low blood sugar include: dizziness tiredness restlessness hunger irritability trouble concentrating sweating nausea fast or irregular heartbeat Severe hypoglycemia may cause unconsciousness, seizures, or death. If your child receives INCRELEX, they should avoid participating in high risk activities (e.g. driving, exercise, etc.) within 2 to 3 hours after the INCRELEX injection, especially at the beginning of INCRELEX treatment. Before beginning treatment with INCRELEX your child's doctor or nurse will explain to you how to treat hypoglycemia. Your child should always have a source of sugar such as orange juice, glucose gel, candy, or milk available in case symptoms of hypoglycemia happen. For severe hypoglycemia, if your child is not responsive and cannot drink sugar-containing fluids, you should get emergency medical help for your child right away. Your doctor or nurse will show you how to give the injection. Allergic reactions . See " Who should not receive INCRELEX? " Allergic reactions are a serious but common side effect of INCRELEX. Your child may have a mild or serious allergic reaction with INCRELEX. Call your child's doctor right away if your child gets a rash or hives. Hives, also known as urticaria, appear as a raised, itchy skin reaction. Hives appear pale in the middle with a red rim around it. Hives generally appear minutes to hours after the injection and may sometimes occur at many places on the skin. Stop taking INCRELEX and get medical help right away if your child has trouble breathing or goes into shock, with symptoms like dizziness, pale, clammy skin or passing out . INCRELEX can also cause reactions at the injection site including: loss of fat (lipoatrophy) increase of fat (lipohypertrophy) pain, redness, or bruising Injection site reactions can be avoided by changing (rotating) the injection site at each injection. Increased pressure in the brain (intracranial hypertension). INCRELEX, like growth hormone, can sometimes cause a temporary increase in pressure within the brain. The symptoms of intracranial hypertension can include headache, nausea and vomiting. Tell your doctor if your child has a headache with vomiting. Your doctor can then check to see if intracranial hypertension is present. If it is present, your child's doctor may decide to temporarily reduce or stop INCRELEX therapy. Enlarged tonsils. Some signs of enlarged tonsils include: snoring, difficulty breathing, sleep apnea (a condition where breathing stops briefly during sleep), or fluid in the middle-ear. Sleep apnea can cause excessive daytime sleepiness. Call your child's doctor if these symptoms bother your child. Your child's doctor should do regular exams to check your child's tonsils. A bone problem called slipped capital femoral epiphysis. This happens when the top of the upper leg (femur) slips apart. Get medical help for your child right away if your child develops a limp or has hip or knee pain. Worsened scoliosis (caused by rapid growth) . If your child has scoliosis, your child will need to be checked often for an increase in the curve of the spine. Tumor Growths . Several cases of cancerous tumors have been observed in pediatric patients who received treatment with INCRELEX. Tell your doctor immediately if your child develops any new growths or symptoms of cancer. Benzyl alcohol toxicity. Benzyl alcohol is a preservative in INCRELEX. Benzyl alcohol can cause serious side effects, including death in infants who have received medicines that contain the benzyl alcohol preservative. The most common side effects of INCRELEX include: hypoglycemia (low blood sugar), injection site reactions, allergic reactions and enlarged tonsils. Call your child's doctor if your child has any side effects that bothers them or that does not go away. These are not all the possible side effects of INCRELEX. For more information, ask your child's doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 . How should I store INCRELEX? Before Opening : Store new, unopened vials of INCRELEX in the refrigerator between 36°F to 46°F (2°C to 8°C). After Opening : Store opened vials of INCRELEX in the refrigerator between 36°F to 46°F (2°C to 8°C) for 30 days after you start using the vial. Throw away any unused INCRELEX after 30 days. Do not freeze INCRELEX. If a vial freezes, throw it away. Keep INCRELEX out of direct light. Do not use INCRELEX after the expiration date printed on the label. Keep INCRELEX and all medicines out of the reach of children . General information about the safe and effective use of INCRELEX. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not give INCRELEX to your child for a condition for which it was not prescribed. Do not give INCRELEX to a person other than your child. It may harm them. This Patient Information leaflet summarizes the most important information about INCRELEX. If you would like more information, talk to your child's doctor. You can also ask your child's doctor or pharmacist for information about INCRELEX that is written for health professionals. What are the ingredients in INCRELEX? Active ingredient : mecasermin Inactive ingredients : benzyl alcohol, glacial acetic acid, polysorbate 20, sodium acetate, sodium chloride, and Water for Injection, USP. Manufactured by: Ipsen Biopharmaceuticals, Inc. INCRELEX is a registered trademark of Ipsen Biopharmaceuticals, Inc. Cambridge, MA 02142 USA. U.S. License No. 2194 © 2023. All rights reserved. For more information, go to www.Increlex.com or call 855-463-5127.

IPSEN Rx only increlex ® (mecasermin) injection 40 mg/4 mL (10 mg/mL) For subcutaneous use only 4 mL multiple-dose vial PRINCIPAL DISPLAY PANEL - 4 mL Vial Carton