Increlex

Generic Name: Mecasermin
Class: Somatotropin Agonists
Chemical Name: Insulin-like growth factor I (human)
Molecular Formula: C331H512N94O101S7
CAS Number: 68562-41-4

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 Increlex

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.1 3 13 25

Designated an orphan drug by FDA for the treatment of GH insensitivity syndrome4 11 (i.e., various genetic and acquired conditions with action of GH absent or attenuated).3

Mecasermin rinfabate (Iplex) previously was approved for treatment of growth failure in children with IGF-I deficiency or GH deletion,22 but no longer is commercially available after litigation regarding patent infringement.23 24 28 (See Amyotrophic Lateral Sclerosis under Uses.)

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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.1 3 7 25 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;1 2 25 exogenously administered GH not expected to elicit an adequate response in these patients.1 3 25

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).1 3 13 21

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 Correct thyroid and nutritional deficiencies prior to initiation of mecasermin therapy.1 Not a substitute for GH therapy.1

Safety and efficacy not established in adults.1

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 in a limited number of patients.26 27 29

Currently available under a limited-access investigational new drug (IND) protocol.28

Limited evidence with the drug suggests a slower rate of progression of amyotrophic lateral sclerosis, but such findings remain to be confirmed.26 27 29

Increlex Dosage and Administration

General

  • Administer under supervision of clinicians experienced in diagnosis and management of growth disorders.1

  • Consider monitoring preprandial blood glucose concentrations at treatment initiation and until a well-tolerated dosage is established.1 25 If hypoglycemia occurs with recommended dosages despite adequate food intake, reduce dosage.1 25 If frequent or severe symptoms of hypoglycemia occur, continue monitoring preprandial blood glucose concentrations.1 (See Hypoglycemia under Cautions.)

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 5 Use low-volume syringe to ensure accuracy of dosing.1 5

Do not administer IV or IM.1 5

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 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 Increlex

Contraindications

  • Children with closed epiphyses.1

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

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

Warnings/Precautions

Warnings

Benzyl Alcohol in Neonates

Mecasermin contains benzyl alcohol as a preservative, which has been associated with toxicity (fatalities) in neonates.1 12 17 18 19 20 (See Pediatric Use under Cautions.)

Sensitivity Reactions

Local or systemic allergic reactions reported.1 If allergic reaction occurs, discontinue mecasermin therapy.1 (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.1 11 13 25 (See Actions.)

Increased risk of hypoglycemia with insufficient caloric intake or concurrent drug use (e.g., antidiabetic agents).1 5 (See Specific Drugs under Interactions.)

Consider monitoring preprandial blood glucose concentrations at treatment initiation and until a well-tolerated dosage is established.1 (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.5 Severe hypoglycemia (associated with altered states of consciousness) may require use of IV glucagon.5

Lymphoid Tissue Hypertrophy

Lymphoid tissue hypertrophy may occur.1 3 13 25 Tonsillar hypertrophy reported more frequently in the first 1–2 years of therapy.1 25

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.1 5 (See Advice to Patients.)

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 (See Advice to Patients.)

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 GH treatment.1 5 (See Advice to Patients.)

Progression of 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 GH treatment.1 5 (See Advice to Patients.)

Effects on Facial Growth

Facial effects (e.g., thickening and overgrowth of soft tissues) reported.1 3 11 25 Monitor patients for signs and symptoms of this condition.1

Specific Populations

Pregnancy

Category C.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

Hypoglycemia,1 11 13 16 25 injection site lipohypertrophy,1 2 3 11 13 25 headache,1 11 hypoacusis,1 11 13 25 vomiting,1 11 otitis media,1 11 tonsillar/adenoidal hypertrophy,1 11 13 16 25 thymus hypertrophy,1 11 13 25 fluid in middle ear,1 11 13 arthralgia,1 11 25 extremity pain,1 11 cardiac murmur,1 11 dizziness,1 11 ear pain,1 11 injection site bruising,1 11 abnormal tympanometry,1 11 seizures.1 11

Interactions for Increlex

Specific Drugs

Drug

Interaction

Comments

Antidiabetic agents

Potential risk of hypoglycemia5 21

Dosage adjustments of antidiabetic agents may be necessary5

Increlex 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 IGFD 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 IGFD1 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 IGFD have increased clearance and shorter half-life of IGF-I compared with healthy individuals.1 3 11 14 (See Plasma Protein Binding under Pharmacokinetics.)

Stability

Storage

Parenteral

Solution for Sub-Q Injection

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

Opened vials stable at 2–8°C for 30 days.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 (See Lymphoid Tissue Hypertrophy under Cautions.)

  • 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 (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.5

  • 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.1 5

  • Importance of administering the drug ≤20 minutes before or after a meal or snack.1 5 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.1 5

  • Importance of proper glucose monitoring and how to recognize signs and symptoms of hypoglycemia.1 5 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.1 5 For severe cases, advise patient and/or patient’s parent or guardian on the proper use of glucagon injection.1 5

  • 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.1 5

  • Importance of advising patients and/or patient’s parent or guardian of possible allergic reactions.1 5 Importance of discontinuing therapy and contacting 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 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.1 5

  • 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.1 5

  • Importance of informing clinicians if signs and symptoms of increased pressure in the brain (e.g., headache, nausea, vomiting, vision disorders) occur.1 5 Advise patient that funduscopic examination is recommended at treatment initiation and periodically thereafter.1

  • 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).5

  • Risk of worsening scoliosis caused by rapid growth.1 5 Importance of clinicians evaluating patients with scoliosis for increased curvature of the spine during therapy.1 5

  • Importance of patients informing clinicians if they are or plan to become pregnant or plan to breast-feed.5

  • 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).1 5

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

Preparations

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

Mecasermin (Recombinant DNA Origin)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use

10 mg/mL (40 mg)

Increlex

Tercica

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Tercica. Increlex (mecasermin) injection prescribing information. Brisbane, CA; 2007 Aug.

2. Laron Z. The essential role of IGF-I: lessons from the long-term study and treatment of children and adults with Laron syndrome. J Clin Endocrinol Metab. 1999; 84:4397-404. [PubMed 10599694]

3. Backeljauw PF, Underwood LE, GHIS Collaborative Group. Therapy for 6.5–7.5 years with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome: a clinical research center study. J Clin Endocrinol Metab. 2001; 86:1504-10. [PubMed 11297575]

4. Food and Drug Administration. List of all orphan products designated and approved. From FDA web site . 2006 Jan 24.

5. Tercica. Increlex (mecasermin) injection patient information. Brisbane, CA; 2007 Oct.

7. Klinger B, Jensen LT, Sibergeld A et al. Insulin-like growth factor-I raises serum procollagen levels in children and adults with Laron syndrome. Clin Endocrinol. 1996; 45:423-9.

8. Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. J Clin Pathol: Mol Pathol. 2001; 54:311-6.

9. Reiter ED, Rosenfeld RG. Normal and aberrant growth. In: Larsen PR, Kronenberg HM, Melmed S et al., eds. Williams textbook of endocrinology. 10th ed. Philadelphia, PA: Saunders; 2003:1003-114.

11. Meyer RJ. Mecasermin injection, Increlex: medical review, FDA approval package. NDA number: 21-839. Rockville, MD: US Food and Drug Administration; 2005 Aug 30.

12. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041]

13. Chernausek SD, Backeljauw PF, Frane J et al. Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007; 92:902-10. [PubMed 17192294]

14. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG et al. Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab. 1999; 84:4436-43. [PubMed 10599699]

15. Guevara-Aguirre J, Vasconez O, Martinez V et al. A randomized, double-blind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency. J Clin Endocrinol Metab. 1995; 80:1393-8.

16. Chung S, Ahn HY. Mecasermin injection, Increlex: clinical pharmacology and biopharmaceutics review(s), FDA approval package. NDA number: 21-839. Rockville, MD: US Food and Drug Administration; 2005 Aug 30.

17. Centers for Disease Control. Neonatal deaths associated with use of benzyl alcohol. MMWR. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084]

18. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

19. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

20. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

21. Tercica, Brisbane, CA: Personal communication.

22. Insmed. IPLEX (mecasermin rinfabate) prescribing information. Glen Allen, VA; 2005 Dec 8.

23. Insmed. IPLEX press release. Available at . Accessed Mar 4, 2009.

24. Life Sciences Law & Industry. Insmed settles all litigation over Iplex, will stop selling drug for growth treatment. Mar 16, 2007.

25. Keating GM. Mecasermin. Biodrugs. 2008; 22:177-88. [PubMed 18481900]

26. Lai EC, Felice KJ, Festoff BW et al. Effect of recombinant human insulin-like growth factor-I on progression of ALS. A placebo-controlled study. The North America ALS/IGF-I Study Group. Neurology. 1997; 49:1621-30. [PubMed 9409357]

27. Department of Health and Human Services, Food and Drug Administration. FDA summary of controlled clinical data for human IGF-1 in treatment of patients with amyotrophic lateral sclerosis. 2009 Mar 10. Available at: . Accessed 2009 Mar 27.

28. Food and Drug Administration, Center for Drug Evaluation and Research. FDA position on allowing patients with ALS access to Iplex under an IND. 2009 Mar 10. Available at: . Accessed 2009 Mar 27.

29. Mitchell JD, Wokke JH, Borasio GD. Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2007; :CD002064. [PubMed 17943766]

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