Mecasermin

Trade Names:
Increlex
- Injection 10 mg/mL

Trade Names:
Iplex
- Injection 36 mg per 0.6 mL

Mechanism of Action

Pharmacology

Mimics actions of insulin-like growth factor-1 (IGF-1), which is the principal hormonal mediator of statural growth. Binds to and activates type 1 IGF-1 receptors that stimulate multiple processes leading to statural growth. Metabolic actions are in part directed at stimulating uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.

Mecasermin rinfabate contains human IGF-1, which provides the pharmacologic effects, and human insulin-like growth factor-binding protein-3 (IGFBP-3), which modulates IGF-1 action but has no known growth-promoting effects of its own.

IGF-1 can produce hypoglycemia by suppressing hepatic glucose production and stimulating peripheral glucose utilization.

Pharmacokinetics

Absorption

Bioavailability close to 100% (subcutaneous dosing). T _max is 2 h.

C _max , T _max , and AUC for IGF-1 are 133 ng/mL, 11.3 h, and 3,654 ng•h/mL, respectively. The corresponding values for IGFBP-3 are 1,574 ng/mL, 19.5 h, and 62,525 ng•h/mL, respectively.

Distribution

More than 80% protein bound. Vd estimated to be 0.257 L/kg, but increases as dose increases.

Metabolism

Metabolized by liver and kidney.

Elimination

The t _½ is about 5.8 h (subcutaneous dosing). Cl is about 0.04 L/h/kg.

The t _½ of IGF-1 and IGFBP-3 are 13.4 h and 54.1 h, respectively.

Indications and Usage

Long-term 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.

Contraindications

Patients with closed epiphyses; presence of active or suspected neoplasia; IV administration; hypersensitivity to any component of the product.

Dosage and Administration

Subcutaneous 0.04 to 0.08 mg/kg (40 to 80 mcg/kg) twice daily initially. If well tolerated for at least 7 days, the dose may be increased by 0.04 mg/kg/dose, to the max dose of 0.12 mg/kg twice daily. Reduce dose if hypoglycemia occurs despite adequate food intake.

Subcutaneous Dosage is individualized. 0.5 mg/kg/day initially, to be increased into therapeutic dose range of 1 to 2 mg/kg/day based on measurement of IGF-1 levels obtained 8 to 18 h after previous dose. Target IGF-1 levels of treatment are 0 to +2 standard deviation (SD)score for age. Adjust dosage downward in event of adverse reactions, including hypoglycemia and/or IGF-1 levels that are at least 3 SD above normal reference range.

General Advice

• For subcutaneous administration only. Not for intradermal, IM, IV, or intra-arterial administration.
• Do not administer if solution is discolored, cloudy, or contains particulate matter.
• Rotate injection sites (abdomen, buttocks, thigh, or upper arm). Give new injections at least 1 inch from previous injection. Do not inject into skin areas that are tender, bruised, red, hard, or lipodystrophic.

• Mecasermin
• Administer prescribed dose 20 min before or after a meal or snack. Do not administer when meal or snack is omitted.

• Mecasermin Rinfabate
• Administer prescribed dose in the morning or evening, but at approximately the same time each day.
• Do not administer if patient cannot or will not eat, or if a meal is skipped. Do not increase subsequent doses to make up for a missed dose.
• Do not administer dose if evidence of hypoglycemia is present at time of scheduled dose.
• Remove vial from freezer and allow to thaw at room temperature (66° to 77°F) for 45 min prior to use. After thawing, allow vial to reach room temperature (approximately 45 min).
• Gently swirl vial in a rotary motion to ensure content uniformity. Do not shake vial.
• Use within 1 h after vial reaches room temperature. Discard solution if it has been at room temperature for more than 2 h.
• Discard vial and any unused solution.

Storage/Stability

Store unopened and opened vials in refrigerator (36° to 46°F). Protect from freezing and direct light. Discard any unused solution remaining after 30 days following initial vial entry.

Must be stored frozen at −94°F while in distribution chain. Patient must be instructed to keep medication frozen (transport on dry ice) while transferring it to a home freezer (−4°F) where it must be stored until time of use. Can be stored frozen for up to 2 months. Do not store in home freezer that allows contents to thaw during defrost cycle. Do not use if medication thaws during transfer or storage.

Drug Interactions

None well documented.

Adverse Reactions

Cardiovascular

Cardiac murmur (at least 5%).

CNS

Convulsions, dizziness, headache (at least 5%).

Headache (at least 5%).

Dermatologic

Thickening of soft tissue of the face.

EENT

Abnormal tympanometry, ear pain, ear tube insertion, fluid in middle ear, hypoacusis, otitis media, serous otitis media (at least 5%).

Papilledema, tonsillar hypertrophy (at least 5%).

Endocrine

Thyromegaly (at least 5%).

GI

Vomiting (at least 5%).

Genitourinary

Hematuria, ovarian cysts (at least 5%); increased kidney size.

Hematologic-Lymphatic

Thymus hypertrophy (at least 5%).

Iron deficiency anemia, lymphadenopathy (at least 5%).

Hepatic

Increased liver size.

Lab Tests

Mild elevations in AST and LDH, elevations in cholesterol and triglycerides.

Increased transaminases (at least 5%).

Local

Bruising, lipohypertrophy (at least 5%).

Injection-site reactions (at least 5%); erythema, hair growth, lipohypertrophy.

Metabolic-Nutritional

Hypoglycemia (at least 5%).

Hyperglycemia, hypoglycemia (at least 5%).

Musculoskeletal

Arthralgia, pain in extremity (at least 5%).

Arthralgia, bone pain, muscular atrophy (at least 5%).

Miscellaneous

Snoring, tonsillar hypertrophy (at least 5%); intracranial hypertension (4%), thickening of the soft tissues of the face.

Pain in the extremities (at least 5%); acromegalic changes, increased kidney size, increased spleen size.

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Mecasermin has not been studied in children younger than 2 yr of age. Mecasermin rinfabate has not been studied in patients younger than 3 yr of age.

Hazardous Tasks

Because of risk of hypoglycemia, avoid high-risk activities (eg, driving) within 2 to 3 h after mecasermin dosing until a well-tolerated mecasermin dose has been established. Avoid high-risk activities at time of initiation of mecasermin rinfabate and any upward adjustment of dose until tolerability has been established (eg, 3 to 5 days).

Adults

Mecasermin and mecasermin rinfabate have not been studied in adults.

Allergic reaction

May occur.

Benzyl alcohol

Mecasermin contains benzyl alcohol, which has been associated with neurologic toxicity in neonates.

Insulin-like hypoglycemic effects

Administer mecasermin shortly before or after a meal or snack to reduce risk of hypoglycemic reactions. Administer mecasermin rinfabate at about the same time each day; do not administer on days when patient cannot or will not eat. Pay special attention to small children because oral intake may be inconsistent.

Intracranial hypertension

Intracranial hypertension, with papilledema, visual changes, headache, nausea and/or vomiting has been reported.

Lymphoid tissue hypertrophy

Lymphoid tissue (eg, tonsillar and adenoidal) hypertrophy associated with complications such as snoring, sleep apnea, and chronic middle-ear effusions has been reported.

Scoliosis

Progression of scoliosis can occur in patients who experience rapid growth.

Slipped capital femoral epiphysis

Can occur in patients who experience rapid growth.

Thyroid/Nutritional deficiencies

Should be corrected before initiating therapy.

Overdosage

Symptoms

No experience; expected signs and symptoms include hypoglycemia with an acute overdosage and acromegaly with long-term overdosage.

Patient Information

• Ensure patient or caregiver understands how to store, prepare, and administer the dose, and dispose of used equipment and supplies. Advise patient or caregiver to review the patient information leaflet before starting therapy and to read and check for new information each time the medication is refilled.
• Advise patient or caregiver that therapy will be started at a low dose and then gradually increased as tolerated to max effective dose. Caution patient or caregiver not to stop taking or change the dose unless advised by health care provider.
• Instruct patient or caregiver to rotate injection sites and to give new injections at least 1 inch from previous injection site(s). Caution patient to never inject into areas where the skin is tender, bruised, red, hard, or shows signs of lipodystrophy.
• Review symptoms of hypoglycemia (low blood sugar) and action plan to undertake if hypoglycemia occurs. Instruct patient or caregiver to notify health care provider if severe or frequent hypoglycemic reactions occur despite adequate food intake.
• Advise patient or caregiver to notify health care provider if any of the following occur: frequent or persistent nausea and/or vomiting, persistent headache, snoring, visual changes.
• Advise patient or caregiver to discontinue therapy and notify health care provider if signs or symptoms of an allergic reaction are noted.

• Mecasermin
• Caution patient or caregiver that each dose must be administered within 20 min before or after a snack or meal and to skip the dose if the meal or snack is omitted. Caution patient or caregiver not to double the dose to catch up if a dose is missed.
• Caution patient to avoid engaging in any high-risk activity within 2 to 3 h after dosing until a well-tolerated dose (no hypoglycemic reactions in 7 days) has been established.

• Mecasermin Rinfabate
• Advise patient or caregiver to administer prescribed dose once daily in the morning or evening, and at approximately the same time each day.
• Instruct patient or caregiver not to administer dose if patient cannot or will not eat, or if a meal is skipped. Caution patient or caregiver not to increase subsequent doses to make up for a missed dose.
• Ensure patient or caregiver understands the blood glucose monitoring schedule required for safe use of the medication.
• Instruct patient or caregiver not to administer dose if evidence of hypoglycemia is present at time of scheduled dose.
• Caution patient to avoid high-risk activities at time of initiation of mecasermin rinfabate and any upward adjustment of dose until tolerability has been established (eg, 3 to 5 days).