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 Jul 22, 2022. Written by ASHP.

Introduction

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

Uses for Mecasermin

Insulin-Like Growth Factor I Deficiency

Long-term replacement therapy for treatment of growth failure in children with severe primary insulin-like growth factor I (IGF-I) deficiency (primary IGFD) or growth hormone (GH) gene deletion.

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

Mecasermin rinfabate (Iplex) previously was approved for treatment of growth failure in children with IGF-I deficiency or GH deletion, but no longer is commercially available after litigation regarding patent infringement. (See Amyotrophic Lateral Sclerosis under Uses.)

Patients with severe primary IGFD have extremely short stature (defined as height standard deviation score not exceeding −3), low serum concentrations of IGF-I (defined as standard deviation score not exceeding −3), and normal or elevated GH secretion. Primary IGFD may be associated with abnormalities of the GH receptor, post-GH-receptor signaling pathway, or the IGF-I gene resulting in GH insensitivity; exogenously administered GH not expected to elicit an adequate response in these patients.

Patients with GH gene deletion are likely to develop GH-neutralizing antibodies following exposure to exogenous GH preparations (secondary GH insensitivity syndrome, isolated GH deficiency type IA).

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). Correct thyroid and nutritional deficiencies prior to initiation of mecasermin therapy. Not a substitute for GH therapy.

Safety and efficacy not established in adults.

Amyotrophic Lateral Sclerosis

Mecasermin rinfabate (Iplex), a combination of IGF-I and IGF binding protein-3, has been used in the management of amyotrophic lateral sclerosis^{† [off-label]} in a limited number of patients.

Currently available under a limited-access investigational new drug (IND) protocol.

Limited evidence with the drug suggests a slower rate of progression of amyotrophic lateral sclerosis, but such findings remain to be confirmed.

Mecasermin Dosage and Administration

General

• Administer under supervision of clinicians experienced in diagnosis and management of growth disorders.

• Consider monitoring preprandial blood glucose concentrations at treatment initiation and until a well-tolerated dosage is established. If hypoglycemia occurs with recommended dosages despite adequate food intake, reduce dosage. If frequent or severe symptoms of hypoglycemia occur, continue monitoring preprandial blood glucose concentrations. (See Hypoglycemia under Cautions.)

Administration

Sub-Q Administration

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

Do not administer IV or IM.

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

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. 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. Continue therapy until closure of epiphyses.

Prescribing Limits

Pediatric Patients

Insulin-Like Growth Factor I Deficiency

Sub-Q

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

Special Populations

No special population dosage recommendations at this time.

Cautions for Mecasermin

Contraindications

• Children with closed epiphyses.

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

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

Warnings/Precautions

Warnings

Benzyl Alcohol in Neonates

Mecasermin contains benzyl alcohol as a preservative, which has been associated with toxicity (fatalities) in neonates. (See Pediatric Use under Cautions.)

Sensitivity Reactions

Local or systemic allergic reactions reported. If allergic reaction occurs, discontinue mecasermin therapy. (See Advice to Patients.)

General 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. (See Actions.)

Increased risk of hypoglycemia with insufficient caloric intake or concurrent drug use (e.g., antidiabetic agents). (See Specific Drugs under Interactions.)

Consider monitoring preprandial blood glucose concentrations at treatment initiation and until a well-tolerated dosage is established. (See General under Dosage and Administration and also see Advice to Patients.)

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

Lymphoid Tissue Hypertrophy

Lymphoid tissue hypertrophy may occur. Tonsillar hypertrophy reported more frequently in the first 1–2 years of therapy.

Examine patients periodically to rule out potential complications (e.g., snoring, sleep apnea, chronic middle ear effusions, dyspnea, dysphagia) and administer appropriate treatment, if necessary. (See Advice to Patients.)

Intracranial Hypertension

Intracranial hypertension with papilledema, visual changes, headache, nausea and/or vomiting reported. Such effects may resolve spontaneously during continued therapy or after interruption of therapy. 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.

Funduscopic examination recommended at treatment initiation and periodically thereafter (e.g., at each follow-up visit, if headache is present). (See Advice to Patients.)

Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Monitor patient for hip or knee pain or limping and other signs and symptoms generally known to be associated with GH treatment. (See Advice to Patients.)

Progression of Scoliosis

Progression of scoliosis can occur in patients who experience rapid growth. Monitor patient for increased curvature of the spine and other signs and symptoms generally known to be associated with GH treatment. (See Advice to Patients.)

Effects on Facial Growth

Facial effects (e.g., thickening and overgrowth of soft tissues) reported. Monitor patients for signs and symptoms of this condition.

Specific Populations

Pregnancy

Category C.

Not indicated for use in adults, including pregnant women.

Lactation

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

Not indicated for use in adults, including nursing women.

Pediatric Use

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

Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) associated with toxicity in neonates; each mL of mecasermin contains 9 mg of benzyl alcohol. Not indicated for use in neonates.

Geriatric Use

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

Not indicated for use in adults, including geriatric patients.

Hepatic Impairment

Not studied in patients with hepatic impairment.

Renal Impairment

Not studied in patients with renal impairment.

Common Adverse Effects

Hypoglycemia, injection site lipohypertrophy, headache, hypoacusis, vomiting, otitis media, tonsillar/adenoidal hypertrophy, thymus hypertrophy, fluid in middle ear, arthralgia, extremity pain, cardiac murmur, dizziness, ear pain, injection site bruising, abnormal tympanometry, seizures.

Interactions for Mecasermin

Specific Drugs

Mecasermin Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration in healthy individuals, bioavailability is approximately 100%. Bioavailability in individuals with IGF-I deficiency not determined.

In individuals with severe IGF-I deficiency, serum concentrations of IGF-I were very low prior to mecasermin administration. 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.

Distribution

Extent

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

Not known whether mecasermin is distributed into milk.

Plasma Protein Binding

>99% of circulating IGF-I bound to IGFBPs, with >80% bound as a complex with IGFBP-3 and an acid labile subunit. Plasma concentrations of IGFBP-3 and acid labile subunit are reduced in patients with severe primary IGFD compared with healthy individuals, resulting in greater drug clearance. (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.

Elimination Route

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

Half-life

Terminal half-life averages 5.8 hours in children with severe primary IGFD and 19.2 hours in healthy individuals.

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

Stability

Storage

Parenteral

Solution for Sub-Q Injection

2–8°C; protect from light and freezing. If freezing occurs, do not use.

Opened vials stable at 2–8°C for 30 days. Discard any remaining solution if not used within 30 days.

Actions

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

• GH binds to GH receptors in the liver and other tissues and stimulates the synthesis/secretion of IGF-I. IGF-I activates IGF-I receptors, leading to intracellular signals that stimulate growth.

• Many actions of GH mediated through IGF-I; however, the precise roles of GH and IGF-I not fully elucidated.

• Stimulates mitogenesis in many tissues.

• 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.

• 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).

• Promotes growth of various organs, including spleen, kidneys, brain, and lymphoid tissues. (See Lymphoid Tissue Hypertrophy under Cautions.)

• Stimulates uptake of fatty acids and amino acids to support growing tissues.

• Structurally similar to insulin; binds with low affinity to insulin receptors and suppresses hepatic glucose production and stimulates peripheral glucose utilization. These effects may result in hypoglycemia particularly during the first month of treatment. Exogenous IGF-I inhibits insulin secretion resulting in reduced likelihood of hypoglycemia during long-term administration. (See Hypoglycemia under Cautions.)

Advice to Patients

• Provide copy of manufacturer’s patient information to the patient and/or patient’s parent or guardian and advise of the importance of reading this information each time a new or refill prescription is dispensed.

• Importance of advising patients and/or patient’s parent or guardian about safe administration of the drug and proper disposal of used needles and syringes.

• Importance of administering the drug ≤20 minutes before or after a meal or snack. Advise patient and/or patient’s parent or guardian not to administer the drug if the meal or snack is omitted prior to administration and not to make up the missed dose.

• Importance of proper glucose monitoring and how to recognize signs and symptoms of hypoglycemia. Advise patient and/or patient’s parent or guardian to always keep a source of carbohydrates (e.g., orange juice, candy) available in case hypoglycemia occurs. For severe cases, advise patient and/or patient’s parent or guardian on the proper use of glucagon injection.

• Importance of avoiding high-risk activities (e.g., driving) within 2–3 hours following drug administration, particularly after therapy initiation, until a well-tolerated dosage established.

• Importance of advising patients and/or patient’s parent or guardian of possible allergic reactions. Importance of discontinuing therapy and contacting a clinician promptly if allergic reactions (e.g., rash, hives, breathing problems, shock) occur.

• Advise patient and/or patient’s parent or guardian that the drug should not be used if the child has finished growing (i.e., bone growth plates are closed), has cancer, or has causes of growth failure other than primary IGF-I deficiency.

• Importance of informing clinicians if signs and symptoms of enlarged tonsils (e.g., snoring, breathing or swallowing problems, sleep disorders, hearing disorders, fluid in middle ear) occur.

• Importance of informing clinicians if signs and symptoms of increased pressure in the brain (e.g., headache, nausea, vomiting, vision disorders) occur. Advise patient that funduscopic examination is recommended at treatment initiation and periodically thereafter.

• Importance of informing clinicians immediately if the patient develops a limp or hip or knee pain, since these may be signs of a slipped capital femoral epiphysis (a condition that occurs when the top of the femur slips apart from the ball of the hip joint).

• Risk of worsening scoliosis caused by rapid growth. Importance of clinicians evaluating patients with scoliosis for increased curvature of the spine during therapy.

• Importance of patients informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., insulin, other antidiabetic agents), vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., diabetes mellitus, kidney or liver disease, curved spine).

• Importance of informing patients and/or patient’s parent or guardian of other important precautionary information. (See Cautions.)

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.

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