Iplex

Description

IPLEX™ (mecasermin rinfabate rdna origin injection) (mecasermin rinfabate [rDNA origin] injection) is an aqueous solution for injection containing a binary protein complex of human insulin-like growth factor-1 (rhIGF-1) and human insulin-like growth factor-binding protein-3 (rhIGFBP-3), both produced by recombinant DNA technology.

rhIGF-1 and rhIGFBP-3 are produced by two separate E. coli strains: one containing the human gene for insulin-like growth factor-1 (IGF-1), the other containing the human gene for insulin-like growth factor-binding protein-3 (IGFBP-3). IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons. The amino acid sequence of the rhIGF-1 protein is identical to that of endogenous human IGF-1. IGFBP-3 consists of 264 amino acid residues with a molecular weight of 28,732 daltons. The amino acid sequence of the rhIGFBP-3 protein is identical to that of endogenous human IGFBP-3. Endogenous IGFBP-3 contains 18 cysteine residues that are all paired in disulfide bonds to form the biologically active molecule, but the pairings have not been fully elucidated. The rhIGF-1 and rhIGFBP-3 proteins are complexed in a 1:1 molar ratio for formation of mecasermin rinfabate with a molecular weight of 36,381 daltons. IGFBP-3 from human plasma is glycosylated, whereas rhIGFBP-3 produced in E. coli is non-glycosylated. Glycosylated and non-glycosylated IGFBP-3 bind IGF-1 with similar affinities.

Primary structures for rhIGF-1/rhIGFBP-3:

Recombinant human insulin growth factor-1 ( rhIGF-1)

Recombinant human insulin growth factor binding protein-3 (rhIGFBP-3)

IPLEX (mecasermin rinfabate rdna origin injection) is prepared to a final concentration of 36 mg/0.6 mL in 50 mM sodium acetate and 105 mM sodium chloride with a final pH of 5.5. IPLEX (mecasermin rinfabate rdna origin injection) is for subcutaneous injection only and is a preservative-free, sterile, clear, colorless-to-slightly-yellow liquid.

IPLEX (mecasermin rinfabate [rDNA origin] injection) is indicated for the treatment of growth failure in children with severe primary IGF-1 deficiency (Primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Severe primary IGFD is defined by:

• height standard deviation score ≤ -3 and
• basal IGF-1 standard deviation score ≤ -3 and
• normal or elevated growth hormone

Severe primary IGFD includes patients with mutations in the GH receptor (GHR), post-GHR signaling pathway, and IGF-1 gene defects; they are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.

IPLEX (mecasermin rinfabate [rdna origin] injection) is not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating IPLEX (mecasermin rinfabate [rdna origin] injection) treatment.

IPLEX (mecasermin rinfabate [rdna origin] injection) is not a substitute for GH treatment.

Dosage And Administration

IPLEX (mecasermin rinfabate [rdna origin] injection) dosage and administration should be individualized for each patient. IPLEX (mecasermin rinfabate [rdna origin] injection) should be administered via subcutaneous injection at an initial dose of 0.5 mg/kg, to be increased into the therapeutic dose range of 1 to 2 mg/kg, given once daily. IPLEX (mecasermin rinfabate [rdna origin] injection) can be given in the morning or in the evening but should be administered at approximately the same time every day and the patient should maintain a regular, balanced diet. IPLEX (mecasermin rinfabate [rdna origin] injection) should not be administered if the patient cannot or will not eat or if they skip a meal. Subsequent doses of IPLEX (mecasermin rinfabate [rdna origin] injection) should not be increased to make up for a missed dose.

In order to establish tolerability to IPLEX (mecasermin rinfabate [rdna origin] injection) , glucose monitoring should be considered at treatment initiation or when a dose has been increased. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. Glucose monitoring is also advised for patients with recent occurrences of asymptomatic or symptomatic hypoglycemia. If evidence of hypoglycemia is present at the time of dosing, the dose should be withheld.

Dosage can be titrated up to a maximum of 2 mg/kg daily based on measurement of IGF-1 levels obtained 8-18 hours after the previous dose. Treating physicians should target on-treatment IGF-1 levels of 0 to +2 SD score for age. Dosage should be adjusted downward in the event of adverse effects (including hypoglycemia) and/or IGF-1 levels that are greater than or equal to 3 standard deviations above the normal reference range for IGF-1.

Growth response to IPLEX (mecasermin rinfabate [rdna origin] injection) is expected to decrease with time, as seen with other growth-promoting agents. However, failure to increase height velocity during the first year of therapy by at least 2 cm/year suggests the need for assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, and advanced bone age. Patients with undetectable ALS levels at baseline may require higher doses of IPLEX (mecasermin rinfabate [rdna origin] injection) .

Rotate sites for injection (thigh, abdomen, upper outer buttock, or upper arm). New injections should be given at least one inch from previous injection site(s) and never into areas where the skin is tender, bruised, red, hard, or lipodystrophic.

IPLEX (mecasermin rinfabate [rdna origin] injection) should be administered using sterile disposable syringes and needles. The syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy.

For use, remove a vial of IPLEX (mecasermin rinfabate [rdna origin] injection) from the freezer. Thaw the contents by warming the vial in your hand for approximately 2 minutes. When the vial is at room temperature, gently swirl the vial in a rotary motion to ensure content uniformity. DO NOT SHAKE. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. DO NOT inject the contents if the solution is cloudy or discolored; discard the vial. Use IPLEX (mecasermin rinfabate [rdna origin] injection) within 12 hours after the vial is removed from the freezer. After removing the dose of IPLEX (mecasermin rinfabate [rdna origin] injection) , discard the vial with any unused portion.

Storage Conditions

IPLEX (mecasermin rinfabate [rDNA origin] injection) is temperature sensitive and should remain frozen at -15. 5°C to -1. 5°C (4.1 °F to 29.3°F ) until time of use. IPLEX (mecasermin rinfabate [rdna origin] injection) can be stored in a home freezer for up to 3 months.

When a freezer is unavailable, a vial of IPLEX (mecasermin rinfabate [rdna origin] injection) (stored for up to 3 months in a home freezer) can be stored at refrigerator temperature for up to 5 days. Use IPLEX (mecasermin rinfabate [rdna origin] injection) within 2 hours after the vial is removed from the refrigerator.

How Supplied

IPLEX (mecasermin rinfabate [rDNA origin] injection) is supplied as a 36 mg/0.6 mL preservative-free sterile solution in single dose glass vials.

Box containing 35 vials

NDC– 16249-001-01

Single vial

NDC– 16249-001-02

IPLEX (mecasermin rinfabate [rDNA origin] injection) is temperature sensitive and must be transported and stored frozen.

Manufactured for: Insmed Incorporated, Glen Allen, Virginia 23058. www.insmed.com. Manufactured by: Insmed Therapeutic Proteins Boulder, Colorado 80301. Revision Date: September 19, 2006

Treatment-emergent adverse events were assessed in the clinical study of IPLEX (mecasermin rinfabate [rDNA origin] injection) in children with Primary IGFD. In this study, 36 patients had an average exposure of 10.4 months (range: 27 days – 22.5 months), for a total of 374 patient-months. Safety information beyond one year of treatment is limited and safety beyond 21 months of treatment has not been established.

The most common treatment-related adverse events occurring in 2 or more ( ≥ 5%) subjects were iron deficiency anemia, lymphadenopathy, thyromegaly, injection site conditions, increased transaminases, hyperglycemia, hypoglycemia, arthralgia, bone pain, muscular atrophy, pain in an extremity, headache, papilledema, hematuria, ovarian cysts, and tonsillar hypertrophy.

Common injection site conditions included erythema, lipohypertrophy, and hair growth at the injection sites.

Hypoglycemia was reported in 11/36 (31%) patients in the study generally rated as mild and asymptomatic. Four hypoglycemic episodes were characterized as symptomatic including two cases that required acute intervention.

Headaches were reported in 8/36 (22%) patients in the study. One adverse event of asymptomatic papilledema was reported. An adverse event of increased intracranial pressure and papilledema (possible intracranial hypertension) was also reported, which resolved with revision of a blocked existing ventriculo-peritoneal shunt.

Seven of 36 (19%) patients in the study, reported an adverse event of tonsillar and/or adenoid hypertrophy and 2 patients underwent tonsillectomy and/or adenoidectomy.

Increases in liver, spleen, and kidney size were noted in several patients on abdominal ultrasound assessments; occasional measurements near the upper-limit-of-normal were noted. Renal function (as defined by serum creatinine and calculated creatinine clearance) was normal. Two patients had ovarian cysts on pelvic ultrasound and one patient had sonographic evidence of hepatomegaly.

Mild elevations in the serum AST and LDH were found in a significant proportion of patients before and during treatment without treatment discontinuations. Two patients had AST elevations that required temporary interruption of treatment. Echocardiographic evidence of valvulopathy was observed in a few individuals without associated clinical symptoms. Because of the underlying disease and the lack of a control group, the relationship of the valvular changes to drug treatment cannot be assessed.

Since IGF-1 is the main mediator of GH effects and GH may produce acromegalic changes, such changes should be monitored during IPLEX (mecasermin rinfabate [rdna origin] injection) treatment.

By 9 months of treatment, a proportion of patients developed antibodies to the protein complex (90%), rhIGFBP-3 (50%), and/or rhIGF-1 (20%), using assays with varying degrees of sensitivity. No evidence of neutralization of biological activity, such as reduced height velocity, was noted in antibody-positive patients during the first year of IPLEX (mecasermin rinfabate [rdna origin] injection) treatment.

Drug Interactions

No information provided.

IPLEX (mecasermin rinfabate [rDNA origin] injection) is supplied as a single use, preservative-free solution for subcutaneous injection. Aseptic technique must be followed for administration. Discard any unused portion.

If sensitivity to IPLEX (mecasermin rinfabate [rdna origin] injection) occurs, treatment should be discontinued.

Precautions

General

Therapy with IPLEX (mecasermin rinfabate [rDNA origin] injection) should be directed by physicians experienced in the diagnosis and management of patients with growth disorders.

IPLEX (mecasermin rinfabate [rdna origin] injection) has not been studied in children less than 3 years of age or adults with Primary IGFD.

IPLEX (mecasermin rinfabate [rdna origin] injection) should be administered at approximately the same time every day. Because it has insulin-like hypoglycemic effects, patients should avoid missing meals and should have a balanced diet. IPLEX (mecasermin rinfabate [rdna origin] injection) should not be administered on days when the patient cannot or will not eat. Special attention should be paid to small children because their oral intake may be inconsistent. At the time of initiation of IPLEX (mecasermin rinfabate [rdna origin] injection) therapy and any upward adjustment of dose patients should avoid engaging in any high-risk activities until tolerability has been established (e.g., 3 – 5 days).

Lymphoid tissue hypertrophy (e.g., tonsillar and adenoidal) has been associated with IPLEX (mecasermin rinfabate [rdna origin] injection) . Patients should have periodic examinations to detect potential complications of adenotonsillar enlargement (such as excessive snoring, sleep apnea, chronic middle ear effusions, hearing loss) and receive appropriate treatment if necessary.

The syndrome of intracranial hypertension, with papilledema, visual changes, headache, and nausea and/or vomiting, may occur during treatment with IPLEX (mecasermin rinfabate [rdna origin] injection) and has been reported in children with growth failure treated with related products (growth hormone, rhIGF-1). Fundoscopic examination is recommended at the initiation of and periodically during the course of IPLEX (mecasermin rinfabate [rdna origin] injection) therapy.

Slipped capital femoral epiphysis and progression of scoliosis can occur in patients who experience rapid growth. These conditions and other symptoms and signs known to be associated with GH treatment in general should be monitored during IPLEX (mecasermin rinfabate [rdna origin] injection) treatment.

As with any exogenous protein administration, local or systemic allergic reactions may occur. Parents and patients should be informed that such reactions are possible and that if an allergic reaction occurs, treatment should be interrupted and prompt medical attention should be sought.

Information for Patients

Patients and/or their caregivers should be instructed in the safe administration of IPLEX (mecasermin rinfabate [rdna origin] injection) . Because of the possibility of hypoglycemia, patients using IPLEX (mecasermin rinfabate [rdna origin] injection) should be on a regular, balanced diet. IPLEX (mecasermin rinfabate [rdna origin] injection) should be administered at the same time every day. IPLEX (mecasermin rinfabate [rdna origin] injection) should not be administered if the patient cannot or will not eat or when a meal is omitted. Therapy should be instituted in accordance with the prescribing physician’s instructions. The dose of IPLEX (mecasermin rinfabate [rdna origin] injection) should not be increased to make up for a missed dose. If severe or persistent hypoglycemia occurs on treatment despite adequate food intake, IPLEX (mecasermin rinfabate [rdna origin] injection) dose reduction should be considered. Providers should educate patients and caregivers on how to recognize the signs and symptoms of adverse reactions, particularly hypoglycemia.

Patients and/or caregivers should be thoroughly instructed in the importance of proper needle disposal. A puncture-resistant container should be used for the disposal of used needles and/or syringes (consistent with applicable state requirements). Needles and syringes must not be reused.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies for the evaluation of carcinogenicity with mecasermin rinfabate (rhIGF-1/rhIGFBP-3) have not been performed.

The genotoxic potential of mecasermin rinfabate has not been assessed. rhIGF-1 tested negative for genotoxic potential in the Ames test and in chromosomal aberration assays conducted with human lymphocytes or rat peripheral lymphocytes.

Animal fertility studies have not been performed with mecasermin rinfabate. Effects of rhIGF-1 on fertility and reproductive performance were assessed in male and female rats administered 0.4, 2, and 10 mg/kg/day subcutaneously (0.2, 1, and 7 times clinical exposures with the maximum recommended human dose [MRHD] based on body surface area). rhIGF-1 had no effects on mating, fertility, or reproductive performance in rats.

Pregnancy – Pregnancy Category C

Animal reproduction studies have not been conducted with mecasermin rinfabate. Effects of rhIGF-1 on embryofetal development were assessed in rats and rabbits.

Subcutaneous administration of 0.4, 2, or 10 mg/kg/day rhIGF-1 to pregnant rats during organogenesis had no effects on embryofetal development (0.5, 1.5, and 4 times therapeutic exposures with MRHD based on body surface area).

Subcutaneous administration of 0.2, 0.5, or 1.25 mg/kg/day rhIGF-1 to rabbits during organogenesis resulted in an increased incidence of fetal loss but no fetal anomalies. Increased early resorptions were observed in rabbits treated with 1.25 mg/kg and increased preimplantation loss was observed (exposure equivalent to ≥ 0.3 times MRHD based on body surface area).

A second rabbit embryofetal development study was conducted to determine the role of hypoglycemia in rhIGF-1 mediated fetal loss. Rabbits were administered subcutaneous doses of 0, 0.5, and 1.25 mg/kg/day rhIGF-1; 1.25 or 2.5 mg/kg rhIGF-1 plus glucose supplementation; or 2.5 IU/kg/day insulin. A comparable degree of hypoglycemia was observed in rabbits treated with 1.25 mg/kg rhIGF-1 alone or 2.5 IU/kg insulin. Animals treated with 0.5 mg/kg rhIGF-1 or rhIGF-1 plus glucose maintained normal glucose levels.

Similar to the initial rabbit study, an increase in early fetal resorptions was observed in rabbits treated with 1.25 mg/kg/day rhIGF-1 (2 times MRHD based on body surface area). This finding was not observed in insulin-treated rabbits despite a comparable degree of drug-induced hypoglycemia. A dose-related increase in postimplantation loss was observed in all rhIGF-1 treated groups ( ≥ 0.5 times MRHD based on body surface area). While the incidence of fetal loss was somewhat reduced in glucose-supplemented rabbits, it was not clearly attributable to drug-induced hypoglycemia since significant fetal loss was still observed in normoglycemic rhIGF-1 treated rabbits.

The effects of IPLEX (mecasermin rinfabate [rdna origin] injection) on an unborn child have not been studied. Therefore, there is insufficient medical information to determine whether there are significant risks to a fetus.

Nursing Mothers

It is not known whether this drug is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when IPLEX (mecasermin rinfabate [rdna origin] injection) is administered to a nursing woman.

Geriatric Use

The safety and effectiveness of IPLEX (mecasermin rinfabate [rdna origin] injection) in patients aged 65 and over has not been established.

There were no instances of overdosage with IPLEX (mecasermin rinfabate [rdna origin] injection) in the Primary IGFD clinical trial. Based on the known pharmacological effects of IGF-1, acute overdosage could lead to hypoglycemia. Treatment of acute overdosage of IPLEX (mecasermin rinfabate [rdna origin] injection) should be directed at reversing hypoglycemia. Mild hypoglycemia can usually be treated with oral glucose or food. If the overdose results in loss of consciousness, treatment with parenteral glucagon or intravenous glucose may be required.

Long-term overdosage could result in signs and/or symptoms of acromegaly.

Contraindications

IPLEX (mecasermin rinfabate [rDNA origin] injection) should not be used for growth promotion in patients with closed epiphyses.

IPLEX (mecasermin rinfabate [rdna origin] injection) is contraindicated in the presence of active or suspected neoplasia, and therapy should be discontinued when there is any evidence of active neoplasia.

IPLEX (mecasermin rinfabate [rdna origin] injection) is contraindicated in patients allergic to mecasermin rinfabate (rhIGF-1/rhIGFBP-3) or any of the excipients in IPLEX (mecasermin rinfabate [rdna origin] injection) .

Intravenous administration of IPLEX (mecasermin rinfabate [rdna origin] injection) is contraindicated.

The primary pharmacologic effect of IGF-1 in children is the promotion of linear growth. Secondary pharmacologic actions of IGF-1 include other anabolic effects, insulin sensitization, and insulin-like effects. There are no known direct growth-promoting effects of IGFBP-3. The primary effect of IGFBP-3 in the mecasermin rinfabate complex is the modulation of IGF-1 action.

In normal human circulation, less than 2% of total IGF-1 exists in the free form. Most circulating IGF-1 is found in association with the growth hormone (GH)-dependent binding protein IGFBP-3, and this binary complex further associates with a third serum protein, the GH-dependent acid-labile subunit (ALS), to form a non-covalent ternary complex of ~150 kD, which represents the natural physiologic reservoir of IGF-1. The ternary complex consists of one molecule each of IGF-1, IGFBP-3, and ALS.

The half-life of IGF-1 in the ternary complex is > 12 hr. Proteolytic cleavage of IGFBP-3 and interaction of the ternary complex with proteoglycans have been shown to release IGF-1 from the ternary complex.

Pharmacokinetics

In pediatric patients with severe primary IGF-1 deficiency (Primary IGFD), 1 mg/kg was administered by subcutaneous injection to 4 patients in a pharmacokinetic sub-study of the clinical trial. A summary of the pharmacokinetic parameters for IGF-1 and IGFBP-3, uncorrected for baseline values, is presented in Table 1 and Figure 1. The assays employed do not distinguish between exogenous and endogenous IGF-1 or IGFBP-3.

Table 1. Mean (±SD) Pharmacokinetic Parameters in Patients with Primary IGFD Treated with IPLEX (mecasermin rinfabate [rdna origin] injection) 1 mg/kg (n= 4)

Figure 1. Mean (±SD) Uncorrected IGF-1 (Panel A) and IGFBP-3 (Panel B) (ng/mL) Concentrations in Patients with Primary IGFD Treated with IPLEX (mecasermin rinfabate [rdna origin] injection) 1 mg/kg (n=4)

Special Populations

Geriatric

The pharmacokinetics of IPLEX (mecasermin rinfabate [rdna origin] injection) have not been studied in subjects greater than 65 years of age.

Gender

No information is available.

Race

No information is available.

Renal insufficiency

No studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of IPLEX (mecasermin rinfabate [rdna origin] injection) .

Hepatic insufficiency

No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of IPLEX (mecasermin rinfabate [rdna origin] injection) .

Clinical Studies

A prospective, open-label multicenter study was conducted to evaluate the safety and efficacy of IPLEX (mecasermin rinfabate [rDNA origin] injection) in children and adolescents with primary IGF-1 deficiency (Primary IGFD). Subjects were enrolled in the clinical trial on the basis of extreme short stature, low IGF-1 and IGFBP-3 serum concentrations, and normal GH secretion. Thirty-six prepubertal subjects received up to 2 mg/kg mecasermin rinfabate administered once daily by subcutaneous injection for a mean duration of 10.4 months (range: 27 days – 22.5 months). Baseline characteristics at enrollment were (mean ± standard deviation [SD]): chronological age (years): 8.7± 3.1; bone age (years): 5.9 ± 3.2 (n=27); height standard deviation score (SDS): -6.9 ± 1.7; height velocity (cm/yr): 3.0 ± 1.8. Thirty-two (89%) had Primary IGFD due to GH receptor deficiency (Laron syndrome), 3 (8%) had GH gene deletion with neutralizing antibodies to GH, and one (3%) had Primary IGFD due to unknown etiology. Twenty (56%) of the subjects were male and 28 (78%) were Caucasian. All subjects were prepubertal at baseline.

Subjects were divided into two cohorts treated sequentially: Cohort # 1 (n=19) and Cohort # 2 (n=17). Treatment was initiated at a dose of 0.5 mg/kg daily and titrated upward to a maximum dose of 2 mg/kg/day based on clinical tolerability and serum IGF-1 levels. In Cohort #1, subjects were treated with a dose of up to 1 mg/kg daily for the first 12 months; 16 subjects were evaluable for efficacy at Month 6 and Month 12. Subjects in Cohort # 2 were titrated up to 2 mg/kg daily; 9 subjects were evaluable for efficacy at Month 6. Primary and secondary efficacy endpoints are summarized in Table 2. Efficacy beyond one year of treatment has not been established.

Table 2. Mean (± SD) Efficacy Results for Patients with Primary IGFD Treated with Mecasermin Rinfabate

In the Cohort #1 evaluable population, there were 10 subjects with detectable acid-labile subunit (ALS) levels and 6 subjects with undetectable ALS. The mean height velocity for Months 0-6 was 8.1 ± 2.2 cm/yr for Cohort #1 subjects with detectable ALS and 6.3 ± 1.0 cm/yr for Cohort #1 subjects with undetectable ALS levels. In the Cohort #2 evaluable population, 8/9 subjects had undetectable ALS, and had a mean height velocity for Months 0-6 of 9.1 ± 1.9 cm/yr on the higher dose. In Cohort #1, height velocity correlated with IGF-1 SDS at Month 1 (r=0.71, p=0.005, n=14). The mean height velocity for Month 0-6 was 8.5 ± 2.1 cm/yr for subjects with IGF-1 SDS at Month ≥ 1 -2 (n=8), and 6.7 ± 1.2 cm/yr for subjects with IGF-1 SDS at Month 1 < -2 (n=6).