Increlex

Description for Increlex

INCRELEX® (mecasermin [rDNA origin] injection) contains 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 daltons. 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® is a sterile, aqueous, clear and colorless solution intended for subcutaneous injection. Each multi-dose vial of INCRELEX® contains 10 mg per mL mecasermin, 9 mg per mL benzyl alcohol, 5.84 mg per mL sodium chloride, 2 mg per mL polysorbate 20, and 0.05M acetate at a pH of approximately 5.4.

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)]

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 95th 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.

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)

Drug Interactions for Increlex

No information provided

Warnings for Increlex

Included as part of the PRECAUTIONS section.

Precautions for Increlex

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 highrisk 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.

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)]

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)]

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)].

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.

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.

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)].

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)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

OVERDOSAGE

Treatment of acute overdose should be directed at reversing hypoglycemia. Oral glucose or food should be consumed. If the overdose results in loss of consciousness, intravenous glucose or parenteral glucagon may be required to reverse the hypoglycemic effects.

A small number of overdose cases have been reported in the post-marketing experience. In one case of acute overdose, a 3-year old patient experienced hypoglycemia after receiving one 4 mg dose of INCRELEX (a 10-fold increase beyond the prescribed dose). The event resolved following treatment with IV glucose.

Long term overdosage with INCRELEX may result in signs and symptoms of acromegaly.

Contraindications for Increlex

• 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)].

Clinical Pharmacology for Increlex

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.

Pharmacodynamics

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.

Pharmacokinetics

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 t1/2 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)

	Cmax (ng/mL)	Tmax (hr)	AUC0-8 (hr*ng/mL)	t1/2 (hr)	Vd/F (L/kg)	CL/F (L/hr/kg)
n	3	3	3	3	12a	12a
Mean	234	2	2932	5.8	0.257	0.0424
CV%	23	0	50	64	28	38
Cmax = maximum concentration; Tmax = time of maximum concentration; AUC0-8 = area under the curve; t1/2 = 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. a Data represents 3 subjects each at doses 0.015, 0.03, 0.06, and 0.12 mg/kg SC. PK parameters based on baseline adjusted plasma concentrations.

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)

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.

Immunogenicity

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).

PATIENT COUNSELING INFORMATION

Advise patients and/or caregivers to read the FDA-approved patient labeling (Patient Information) and Instructions for Use.

Counsel patients and/or parents that there have been occurrences of malignant neoplasia observed among pediatric patients who received treatment with INCRELEX. Instruct patients and/or parents to monitor for development of any new growth or symptoms of cancer and to report it immediately.

Instruct patients and/or caregivers in the proper administration of INCRELEX. Give INCRELEX shortly before or after (20 minutes on either side of) a meal or snack. Do not give INCRELEX when the meal or snack is omitted. Do not increase the dose of INCRELEX to make up for one or more omitted doses. INCRELEX therapy will be initiated at a low dose and the dose should be increased only if no hypoglycemia episodes have occurred after at least 7 days of dosing. Educate patients and caregivers on how to recognize the signs and symptoms of hypoglycemia.

Educate patients and caregivers on the identification of signs and symptoms of serious allergic reactions to INCRELEX and the need to seek prompt medical contact should such a reaction occur. Instruct patients and caregivers to discontinue INCRELEX if a reaction occurs.