Mecasermin (Monograph)

Brand name: Increlex
Drug class: Somatotropin Agonists
Chemical name: Insulin-like growth factor I (human)
Molecular formula: C₃₃₁H₅₁₂N₉₄O₁₀₁S₇
CAS number: 68562-41-4

Medically reviewed by Drugs.com on Apr 24, 2023. Written by ASHP.

Introduction

Somatotropin agonist (a somatomedin); biosynthetic (recombinant DNA origin) form of human insulin-like growth factor I (IGF-1; IGF-I).^{1 8 21}

Uses for Mecasermin

Insulin-Like Growth Factor I Deficiency

Treatment of growth failure in pediatric patients ≥2 years of age with severe primary insulin-like growth factor I (IGF-I) deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH following exposure to exogenous GH preparations.^{1 3 13 25}

Severe primary IGF-I deficiency is defined as extremely short stature (height standard deviation score not exceeding -3), low serum concentrations of IGF-I (standard deviation score not exceeding -3), and normal or elevated GH.^{1 3 7 25} Primary IGF-I deficiency may be associated with abnormalities of the GH receptor, post-GH-receptor signaling pathway, or the IGF-I gene resulting in GH insensitivity;^{1 2 25} exogenously administered GH not expected to elicit an adequate response in these patients.^{1 3 25}

Designated an orphan drug by FDA for the treatment of GH insensitivity syndrome^{4 11} (i.e., various genetic and acquired conditions with action of GH absent or attenuated).³

Guidelines generally support use of mecasermin in patients with severe primary IGF-I deficiency who have unexplained deficiency or hormone signaling defects that are unresponsive to GH treatment.¹⁰¹

Not intended for use in children with secondary forms of IGF-I deficiency (e.g., GH deficiency [not including those with GH gene deletion], malnutrition, hypothyroidism, corticosteroid-induced growth failure).^{1 21 25} Not a substitute for GH therapy.¹

Mecasermin Dosage and Administration

General

Pretreatment Screening

• Perform funduscopic examination at initiation of treatment with mecasermin and periodically thereafter (e.g., at each follow-up visit, if headache is present).^{1 21}

Patient Monitoring

• Monitor preprandial blood glucose at treatment initiation until a well-tolerated dose is established.¹ Continue preprandial blood glucose monitoring if severe hypoglycemia or frequent hypoglycemia occur.¹

• Examine patients periodically to rule out potential complications of lymphoid tissue hypertrophy (e.g., snoring, sleep apnea, chronic middle-ear effusions, dyspnea, dysphagia).^{1 5}

• Monitor patients for signs of slipped capital femoral epiphysis (e.g., hip or knee pain or limping).¹

• Monitor patients with a history of scoliosis for disease progression.¹

• Monitor for development of neoplasms.¹

Dispensing and Administration Precautions

• Administer mecasermin shortly (20 minutes or less) before or after a meal or snack to reduce the risk of hypoglycemia.¹

• Withhold doses if the child is unable to eat shortly before or after drug administration.^{1 13}

Other General Considerations

• Supervise treatment with mecasermin by a physician experienced in the diagnosis and management of pediatric patients with short stature associated with severe primary IGF-1 deficiency or with GH gene deletion and who have developed neutralizing antibodies to GH.¹

Administration

Sub-Q Administration

Administer by sub-Q injection into abdomen, buttock, thigh, or upper arm.^{1 25} Rotate injection sites with each injection.¹ Use low-volume syringe to ensure accuracy of dosing.¹

Do not administer IV.¹

Give shortly (≤20 minutes) before or after meal or snack to reduce risk of hypoglycemia.^{1 5 25} If child is unable to eat shortly before or after drug administration, withhold dose.^{1 5 13} Do not increase dosage of mecasermin to replace one or more missed doses.^{1 5} Take particular care with young children, whose oral intake may not be consistent.¹

Dosage

Pediatric Patients

Insulin-Like Growth Factor I Deficiency

Sub-Q

Children ≥2 years of age: Initially, 0.04–0.08 mg/kg twice daily.^{1 25} If well tolerated for ≥1 week (e.g., no hypoglycemic episodes), increase dosage by 0.04 mg/kg per dose to a maximum dosage of 0.12 mg/kg twice daily.^{1 25} Reduce dosage if hypoglycemia occurs with recommended dosages despite adequate food intake.¹

Continue therapy until closure of epiphyses.^{11 21}

Prescribing Limits

Pediatric Patients

Insulin-Like Growth Factor I Deficiency

Sub-Q

Children ≥2 years of age: Maximum 0.12 mg/kg twice daily.^{1 25} Dosages of mecasermin >0.12 mg/kg twice daily not evaluated and not recommended for use in children.¹

Special Populations

No special population dosage recommendations at this time.¹

Cautions for Mecasermin

Contraindications

• Known hypersensitivity to mecasermin or any ingredient (e.g., benzyl alcohol) in the formulation.¹ (See Pediatric Use under Cautions.)

• Children with closed epiphyses.¹

• Active or suspected neoplasm; discontinue therapy if evidence of neoplasm develops.¹

Warnings/Precautions

Hypoglycemia

Hypoglycemia (generally mild to moderate) reported, particularly during the first month of treatment; young children and those with a history of hypoglycemia are at higher risk.^{1 11 13 25}

Increased risk of hypoglycemia with insufficient caloric intake or concurrent drug use (e.g., antidiabetic agents).^{1 5}

Consider monitoring preprandial blood glucose concentrations at treatment initiation and until a well-tolerated dosage is established.¹

Advise patients to avoid engaging in high-risk activities (e.g., driving, exercise) within 2–3 hours after dosing, particularly during treatment initiation phase.¹

Use a rapidly absorbed carbohydrate (e.g., orange juice, candy, glucose gel, milk) for treatment of mild to moderate hypoglycemia.⁵ Severe hypoglycemia (associated with altered states of consciousness) may require use of IV glucagon.⁵

Hypersensitivity and Allergic Reactions

Local or systemic allergic reactions, including anaphylaxis, reported.¹ If an allergic reaction occurs, interrupt therapy and seek immediate medical attention.¹

Intracranial Hypertension

Intracranial hypertension with papilledema, visual changes, headache, nausea and/or vomiting reported.^{1 2 13 15 25} Such effects may resolve spontaneously during continued therapy or after interruption of therapy.^{1 5 13 25} Upon resolution, therapy may be resumed at the lowest previously tolerated dosage; the maximum recommended dosage (0.12 mg/kg twice daily) may eventually be reinitiated in some of these patients without recurrence of intracranial hypertension.²¹

Funduscopic examination recommended at treatment initiation and periodically thereafter (e.g., at each follow-up visit, if headache is present).^{1 21}

Lymphoid Tissue Hypertrophy

Lymphoid tissue hypertrophy may occur with therapy; tonsillar hypertrophy reported more frequently during the initial 1–2 years of treatment.¹ Examine patients periodically to rule out potential complications and administer appropriate treatment, if needed.¹

Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis can occur in patients who experience rapid growth.¹ Monitor patient for hip or knee pain or limping and other signs and symptoms generally known to be associated with treatment.^{1 5}

Progression of Preexisting Scoliosis

Progression of scoliosis can occur in patients who experience rapid growth.¹ Monitor patient for increased curvature of the spine and other signs and symptoms generally known to be associated with treatment.^{1 5}

Malignant Neoplasia

Malignant neoplasms reported, predominantly in patients with rare genetic conditions or other conditions that increase risk of cancer, and in patients treated with doses of mecasermin higher than recommended doses, or at doses that produced serum IGF-1 levels above the normal reference ranges for age and sex.¹ Monitor carefully for development of neoplasms.¹ Advise patients/caregivers to report development of new neoplasms.¹ Discontinue mecasermin if malignant neoplasia develops.¹

Benzyl Alcohol in Neonates

Mecasermin contains benzyl alcohol as a preservative, which has been associated with toxicity in neonates.^{1 12 17 18 19 20} Serious and fatal adverse reactions including “gasping syndrome,” CNS depression, and metabolic acidosis can occur in neonates and infants treated with benzyl-alcohol preserved drugs.¹

Immunogenicity

Formation of anti-mecasermin antibodies reported; antibodies were not associated with loss of efficacy.^{1 1}

Specific Populations

Pregnancy

No available data on mecasermin use in pregnant women.¹ Not indicated for use in adults, including pregnant women.¹

Lactation

Not known whether mecasermin is distributed into milk.¹ Use caution.¹

Not indicated for use in adults, including nursing women.¹

Pediatric Use

Safety and efficacy not established in children <2 years of age.¹

Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) associated with toxicity in neonates;^{12 17 18 19 20} each mL of mecasermin contains 9 mg of benzyl alcohol.¹ Not indicated for use in neonates.¹

Geriatric Use

Safety and efficacy not established in patients ≥65 years of age.¹

Not indicated for use in adults, including geriatric patients.¹

Hepatic Impairment

Not studied in patients with hepatic impairment.^{1 11}

Renal Impairment

Not studied in patients with renal impairment.^{1 11}

Common Adverse Effects

Common adverse effects include hypoglycemia, local and systemic hypersensitivity, and tonsillar hypertrophy.¹

Drug Interactions

Specific Drugs

Mecasermin Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration in healthy individuals, bioavailability is approximately 100%.^{1 16 25} Bioavailability in individuals with IGF-I deficiency not determined.^{1 25}

In individuals with severe IGF-I deficiency, serum concentrations of IGF-I were very low prior to mecasermin administration.¹¹ Following administration of a single dose (0.12 mg/kg) in these individuals, average peak plasma concentrations attained at 2 hours were below normal or in the low-normal range.^{1 11 13 16 25}

Distribution

Extent

Tissue availability of free IGF-I determined by presence of 6 IGF binding proteins (IGFBPs) in the blood.^{1 8 11} IGFBPs, particularly IGFBP-3, limit the extent of distribution.¹¹

Not known whether mecasermin is distributed into milk.¹

Plasma Protein Binding

>99% of circulating IGF-I bound to IGFBPs,^{1 8} with >80% bound as a complex with IGFBP-3 and an acid labile subunit.^{1 8 25} Plasma concentrations of IGFBP-3 and acid labile subunit are reduced in patients with severe primary IGF-I deficiency compared with healthy individuals, resulting in greater drug clearance.^{1 3 14 15} (See Half-life under Pharmacokinetics.)

Elimination

Metabolism

Mecasermin and endogenous IGF-I are metabolized by lysosomal enzymes principally in the liver and kidneys to amino acids.^{1 11 16 21 25}

Elimination Route

Excreted principally in urine.^{16 21} Presumably less than 0.1% is excreted in urine as unchanged drug based on studies with endogenous IGF-I.²¹

Half-life

Terminal half-life averages 5.8 hours in children with severe primary IGF-I deficiency^{1 11 16 25} and 19.2 hours in healthy individuals.^{1 11 16}

Clearance of free IGF-I occurs at a faster rate than IGF-I bound to IGFBPs; therefore, patients with severe primary IGF-I deficiency have increased clearance and shorter half-life of IGF-I compared with healthy individuals.^{1 3 11 14} (See Plasma Protein Binding under Pharmacokinetics.)

Special Populations

Pharmacokinetics unaffected by gender.¹ Effect of race not established.¹

Stability

Storage

Parenteral

Solution for Sub-Q Injection

2–8°C; protect from direct light and freezing.^{1 5} If freezing occurs, do not use.⁵

Opened vials stable at 2–8°C for 30 days; protect from direct light and freezing.^{1 5} Discard any remaining solution if not used within 30 days.^{1 5}

Actions

• Mecasermin is a biosynthetic (recombinant DNA origin) form of human IGF-I and the principal mediator of somatotropic effects of human GH (somatotropin).¹

• GH binds to GH receptors in the liver and other tissues and stimulates the synthesis/secretion of IGF-I.^{1 8 9 13 25} IGF-I activates IGF-I receptors, leading to intracellular signals that stimulate growth.^{1 9 25}

• Many actions of GH mediated through IGF-I; however, the precise roles of GH and IGF-I not fully elucidated.^{8 9 13}

• Stimulates mitogenesis in many tissues.^{1 9}

• Bypasses blockade of GH action and stimulates growth in the presence of GH receptor mutations, abnormalities of the post-GH-receptor signaling pathway, or defects in the IGF-I or GH gene.^{3 7 9 13}

• Promotes linear growth by stimulating proliferation of chondrocytes in epiphyseal cartilage, proliferation of osteoblasts, and formation of soft connective tissue (as evidenced by increased production of procollagen).^{1 2 7 8}

• Promotes growth of various organs, including spleen, kidneys, brain, and lymphoid tissues.^{1 2 3 11 13 25}

• Stimulates uptake of fatty acids and amino acids to support growing tissues.^{1 25}

• Structurally similar to insulin; binds with low affinity to insulin receptors and suppresses hepatic glucose production and stimulates peripheral glucose utilization.^{1 8} These effects may result in hypoglycemia particularly during the first month of treatment.^{1 2} Exogenous IGF-I inhibits insulin secretion resulting in reduced likelihood of hypoglycemia during long-term administration.^{1 2}

Advice to Patients

• Advise patients and/or caregivers to read the FDA-approved patient labeling (Patient Information) and Instructions for Use.¹

• Inform patients and/or patient's parent or guardian that there have been occurrences of malignant neoplasia observed among pediatric patients who received treatment with mecasermin.¹ Instruct patients and/or patient's parent or guardian to monitor for development of any new growth or symptoms of cancer and to report it to a clinician immediately.¹

• Inform patients and/or patient's parent or guardian to administer the drug within 20 minutes before or after a meal or snack.^{1 5} Also advise not to administer the drug if the meal or snack is omitted prior to administration and not to make up the missed dose.^{1 5}

• Instruct patient and/or patient's parent or guardian on how to recognize signs and symptoms of hypoglycemia.^{1 5}

• Advise patient and/or patient's parent or guardian that 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.¹

• Advise patients and/or patient's parent or guardian of possible allergic reactions and the need to discontinue therapy and contact a clinician promptly if allergic reactions (e.g., rash, hives, breathing problems, shock) occur.^{1 5}

• Advise patient and/or patient's parent or guardian to inform clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses.^{1 5}

• Inform patients and/or patient's parent or guardian of other important precautionary information.¹ (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Mecasermin can only be obtained through select designated specialty pharmacies.⁶

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