Mecasermin

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# Overview
Mecasermin is an endocrine-metabolic agent that is FDA approved for the treatment of growth failure in children with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.   Common adverse reactions include hypoglycemia, local and systemic hypersensitivity, tonsillar hypertrophy.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- 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. The dosage of INCRELEX should be individualized for each patient. The recommended starting dose of INCRELEX is 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. 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. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not be used. 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. Subsequent doses of INCRELEX should never be increased to make up for one or more omitted dose.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecasermin in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Mecasermin in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- 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. The dosage of INCRELEX should be individualized for each patient. The recommended starting dose of INCRELEX is 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. 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. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not be used. 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. Subsequent doses of INCRELEX should never be increased to make up for one or more omitted dose.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Mecasermin in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Mecasermin in pediatric patients.

# Contraindications
- Active or Suspected Neoplasia
- INCRELEX is contraindicated in the presence of active or suspected malignancy, and therapy should be discontinued if evidence of malignancy develops.
- 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.
- Intravenous Administration
- Intravenous administration of INCRELEX is contraindicated.
- Closed Epiphyses
- INCRELEX should not be used for growth promotion in patients with closed epiphyses.

# Warnings

### Precautions
- Hypoglycemia
- 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 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, etc.) within 2 to 3 hours after dosing, particularly during the initiation of INCRELEX treatment until tolerability and a stable dose have been established. 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.
- 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.
- 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.
- Slipped Capital Femoral Epiphysis
- 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 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.
- Benzyl Alcohol
- Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

# Adverse Reactions

## 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.
Hypoglycemia
Lipohypertrophy, bruising
Otitis media, serous otitis media
Snoring, tonsillar hypertrophy
Headache, dizziness, convulsions
Vomiting
Hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry
Cardiac murmur
Arthralgia, pain in extremity
Thymus hypertrophy
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 occasion and 4 subjects experienced hypoglycemic seizures/loss of consciousness on one or more occasion. 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.
- As with all therapeutic proteins, there is potential for immunogenicity. 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). The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to INCRELEX with the incidence of antibodies to other products may be misleading.

## 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.
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.
Pruritus, urticaria.
Alopecia, hair texture abnormal.
Injection site reactions (e.g. erythema, pain, haematoma, haemorrhage, induration, rash, swelling).
Osteonecrosis/avascular necrosis (occasionally associated with slipped capital femoral epiphysis)

# Drug Interactions
There is limited information regarding Mecasermin Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- 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 (20 times the maximum recommended human dose  based on body surface area  comparison). In the rabbit study, the NOAEL for fetal toxicity was 0.5 mg/kg (2 times 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 (8 times the MRHD based on BSA).
The effects of INCRELEX on an unborn child have not been studied. Therefore, there is insufficient medical information to determine whether there are significant risks to a fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Mecasermin in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Mecasermin during labor and delivery.

### Nursing Mothers
- Excretion of INCRELEX in human milk has not been studied. Caution should be exercised when INCRELEX is administered to a nursing woman.

### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 2 years of age have not been established.

### Geriatic Use
- The safety and effectiveness of INCRELEX in patients aged 65 and over have not been established.

### Gender
There is no FDA guidance on the use of Mecasermin with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Mecasermin with respect to specific racial populations.

### Renal Impairment
- No studies have been conducted in Primary IGFD children or adult subjects with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Mecasermin in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Mecasermin in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Mecasermin in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Subcutaneous

### Monitoring
There is limited information regarding Monitoring of Mecasermin in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Mecasermin in the drug label.

# Overdosage

## Acute Overdose
- 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.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Mecasermin in the drug label.

# Pharmacology

## 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.

## Structure
- INCRELEX (mecasermin  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.

## 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.
- 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.

## Nonclinical Toxicology
- 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 ( 1 times the clinical exposure with the maximum recommended human dose  based on AUC) and in female rats at all dose levels ( 30% of the clinical exposure with the MRHD based on AUC). The incidence of keratoacanthoma in the skin increased in male rats given 4 and 10 mg/kg/day ( 4 times the MRHD). The incidence of mammary gland carcinoma in male rats increased in animals treated with 10 mg/kg/day (7 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/day (up to 4 times the clinical exposure with the MRHD based on AUC.)

# Clinical Studies
- 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 1. 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.
- 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.

# How Supplied
- NDC-15054-1040-5     INCRELEX is supplied as a 10 mg per mL sterile solution in multiple dose glass vials (40 mg per vial).
- Before Opening  Vials of INCRELEX are stable when refrigerated . 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 at 2 to 8C (35 to 46F). Avoid freezing the vials of INCRELEX. Protect from direct light.
- Vial contents should be clear without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected. 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.

## Storage
There is limited information regarding Mecasermin Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients and/or their parents should be instructed in the proper administration of INCRELEX. INCRELEX should be given shortly before or after (20 minutes on either side of) a meal or snack. 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. INCRELEX therapy should 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. If severe hypoglycemia or persistent hypoglycemia occurs on treatment despite adequate food intake, INCRELEX dose reduction should be considered. Providers should educate patients and caregivers on how to recognize the signs and symptoms of hypoglycemia.
- Providers should 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. They should be informed that if an allergic reaction occurs, INCRELEX treatment should be discontinued.
- Patients and/or parents should be thoroughly instructed in the importance of proper needle disposal. A puncture-resistant container should be used for the disposal of used needles and/or syringes (consistent with applicable state requirements). Needles and syringes must not be reused.

# Precautions with Alcohol
- Alcohol-Mecasermin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- INCRELEX

# Look-Alike Drug Names
There is limited information regarding Mecasermin Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price