INCRELEX

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 ) 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.

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) ].

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 Eton Pharmaceuticals, Inc. at 1-855-224-0233 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)

Storage and Handling Before Opening – Vials of INCRELEX are stable when refrigerated at 2° to 8°C (36° to 46°F). 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 2° to 8°C (36° to 46°F). 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.