Drug Criteria & Outcomes

Iplex® and Increlex® Formulary Evaluation

By Spencer H. Durham, PharmD Candidate
Auburn (AL) University Harrison School of Pharmacy

Iplex® (mecasermin rinfabate) and Increlex® (mecasermine) are two recently approved agents for the treatment of short stature in pediatric patients. Mecasermin rinfabate is composed of human insulin-like growth factor-1 (IGF-1) and human insulin-like growth factor-binding protein-3 (IGFBP-3). Mecasermine is an aqueous preparation containing human insulin-like growth factor-1 (IGF-1).

Indication

Mecasermin rinfabate and mecasermine are indicated for treatment of growth failure in children with severe primary IGF-1 deficiency (also known as primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to growth hormone. Mecasermine is approved for long-term treatment but mecasermin rinfabate is not.

Mechanism of Action

The main role of IGF-1 in the body is to promote linear growth, and it also suppresses hepatic glucose production as well as stimulates peripheral glucose utilization. IGFBP-3 has no direct effect on growth promotion. It aids in the modulation of IGF-1 by binding to IGF-1 and circulating throughout the body; thus, it is thought to increase distribution of IGF-1 in the body.

Pharmacokinetics

The pharmacokinetic profiles of mecasermin rinfabate and mecasermine are presented in Table 1.

Dosage and Administration

Mecasermin rinfabate is supplied as a 36 mg/0.6 mL preservative-free sterile solution in single-dose glass vials. The initial dose is 0.5 mg/kg administered via subcutaneous injection. The maximum dose per day is 2 mg/kg, but the normal therapeutic dosing range is 1-2 mg/kg per day.

Mecasermine is supplied as a 10 mg/mL sterile solution in multiple-dose glass vials (40 mg/vial). The recommended starting dose is 0.04-0.08 mg/kg administered twice per day via subcutaneous injection. The dose may be increased by 0.04 mg/kg per dose up to a maximum dose of 0.12 mg/kg given twice per day.

Contraindications

Mecasermin rinfabate and mecasermine are contraindicated in patients with closed epiphyses, patients who are allergic to any portion of the product formulation, and patients who have active or suspected neoplasia (mecasermine should also be discontinued if a patient develops neoplasia). In addition, intravenous administration is contraindicated.

Warnings and Precautions

Mecasermin rinfabate has not been studied in patients younger than 3 years of age; use caution in this population.

Mecasermine contains benzyl alcohol, so it should not be used in neonates due to possible neurological toxicity.

Both agents must be administered only via subcutaneous injections.

Adverse Drug Effects

Adverse drug effects reported for mecasermin rinfabate include hypoglycemia (31%), arthralgia, injection site reactions, headaches (22%), lymphadenopathy, iron deficiency anemia, thyromegaly, hyperglycemia, arthralgia, bone pain, muscular atrophy, increased transaminases, papilledema, hematuria, and ovarian cysts.

Hypoglycemia (42%), arthralgia, injection site reactions, lipohypertrophy, bruising, otitis media, snoring, tonsillar hypertrophy, headache, dizziness, convulsions, vomiting, hypoacusis, ear pain, abnormal tympanometry, cardiac murmur, pain in extremities, thymus hypertrophy, and intracranial hypertension have been reported with mecasermine use.

Special Considerations

Studies have not been conducted in patients with renal or hepatic impairment; caution should be used in these patients.

Patients always should take mecasermin rinfabate and mecasermine with food to avoid hypoglycemia. Do not administer if patient cannot take with food.

Clinical Trials

The only information available about these drugs come from the package inserts, so critical evaluation is not possible.

Mecasermin rinfabate

Study Design and Treatment Regimen

  • Prospective, open-label multicenter study involving 36 pediatric patients.
  • Inclusion criteria: extremely short stature, low IGF-1, low IGFBP-3, and normal GH secretion.
  • Patients were started on 0.5 mg/kg/day and titrated up to 2 mg/kg/day based on tolerability and serum IGF-1 levels.

Results

  • There was a statistically significant increase in height velocity (P < 0.0001) from baseline at both six months and 1 year.
  • Patients had a significant increase in height from baseline; for children receiving ≤ 1 mg/kg/day, P < 0.0001 at six months and P < 0.002 at 1 year; for children receiving ≤ 2 mg/kg/day, P < 0.001.

Mecasermine

Study Design and Treatment Regimen

  • Five clinical trials (one randomized, double-blind, controlled trial and four open-label trials) were conducted involving 71 pediatric patients. Data from these trials were combined to assess safety and efficacy.
  • Inclusion criteria: extremely short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth secretions.
  • Patients were administered doses ranging from 0.06 mg/kg bid to 0.12 mg/kg bid for up to eight years.

Results

  • Height velocity was significantly increased in years 1-6 of the study (P < 0.0001 in years 1-3, P < 0.0045 in year 4, P < 0.0015 in year 5, and P < 0.0009 in year 6).
  • No significant increases in height in years 7 and 8.

Cost Comparison

In general, mecasermine is a cheaper option than mecasermin rinfabate, though both drugs cost thousands of dollars annually. Table 2 compares the annual cost of both drugs. These numbers are based on mecasermine's multiuse 40 mg vial and an average wholesale price per vial of $562.50 and mecasermin rinfabate's single-use 36 mg vial and an average wholesale price per vial of $90.

Formulary Recommendation

At this time, neither mecasermin rinfabate nor mecasermine should be placed on formulary. It is unlikely that these agents would be used to any significant extent in the hospital setting. If a case should arise that requires use of one of these agents, evaluate on a case-by-case basis.

Resources

  • Iplex™. Package Insert. Glen Allen, VA: Insmed Inc.; 2006.
  • Increlex™. Package Insert. Brisbane, CA: Tercica Inc.; 2005.
  • Tercica Inc. Tercica's increlex pricing provides a significant competitive advantage, June 5, 2006. Available at: www.tercica.com. Accessed Oct. 4, 2006.