INCRELEX: Uses, Dosage & Side Effects

What Is INCRELEX and What Is It Used For?

INCRELEX contains the active substance mecasermin, which is recombinant human insulin-like growth factor 1 (rhIGF-1) produced by recombinant DNA technology in Escherichia coli. Mecasermin is a 70-amino acid polypeptide that is structurally identical to endogenous human IGF-1, a naturally occurring hormone that plays a fundamental role in postnatal growth and development. IGF-1 is the primary mediator of the growth-promoting effects of growth hormone (GH), acting as the key downstream effector in what is known as the GH-IGF-1 axis. Understanding this hormonal axis is essential to appreciating why INCRELEX exists and for whom it is intended.

Under normal physiological conditions, growth hormone is secreted by the anterior pituitary gland in a pulsatile fashion, primarily during sleep and in response to various stimuli including exercise, fasting, and stress. Growth hormone travels through the bloodstream to the liver, where it binds to growth hormone receptors and stimulates the production and secretion of IGF-1. The liver is the primary source of circulating IGF-1, although IGF-1 is also produced locally in many other tissues. Once released into the circulation, IGF-1 binds to IGF binding proteins (primarily IGFBP-3 and the acid-labile subunit, ALS), which form a ternary complex that extends the half-life of IGF-1 and regulates its bioavailability to target tissues.

IGF-1 exerts its growth-promoting effects by binding to the IGF-1 receptor (IGF-1R), a transmembrane tyrosine kinase receptor expressed on virtually all cell types. Activation of the IGF-1R triggers intracellular signaling cascades, most notably the PI3K/AKT and RAS/MAPK pathways, which promote cellular proliferation, differentiation, and survival while inhibiting apoptosis (programmed cell death). In the growth plate of long bones, IGF-1 stimulates the proliferation and hypertrophy of chondrocytes (cartilage cells), leading to longitudinal bone growth. IGF-1 also promotes growth of internal organs, muscle development, and has important metabolic effects including stimulation of glucose uptake in peripheral tissues, protein synthesis, and lipid metabolism.

Severe primary IGF-1 deficiency (Primary IGFD) is a rare condition in which the body fails to produce adequate levels of IGF-1 despite normal or even elevated levels of growth hormone. This distinguishes it from secondary IGF-1 deficiency, where low IGF-1 levels are caused by insufficient growth hormone production (i.e., growth hormone deficiency). In primary IGFD, the defect lies at or downstream of the growth hormone receptor, meaning that the body's tissues are unable to respond properly to growth hormone signaling. Causes of severe primary IGFD include:

• Growth hormone receptor deficiency (Laron syndrome): An autosomal recessive condition caused by mutations in the growth hormone receptor (GHR) gene, rendering cells insensitive to growth hormone. This is the most well-characterized cause of severe primary IGFD.
• Post-receptor signaling defects: Mutations in the intracellular signaling molecules downstream of the growth hormone receptor, such as STAT5b deficiency, which disrupt the transduction of GH signals needed for IGF-1 gene transcription.
• IGF-1 gene deletions or mutations: Rare genetic defects in the IGF-1 gene itself that prevent the production of functional IGF-1 protein.
• GH gene deletion with neutralizing antibodies: Children born with complete absence of the growth hormone gene who develop neutralizing antibodies against exogenous growth hormone during GH replacement therapy, rendering it ineffective.

Children with severe primary IGFD present with marked short stature, typically well below the third percentile for age and sex, despite normal or elevated serum growth hormone levels. Their IGF-1 levels are significantly reduced (below the 2.5th percentile for age and sex), and they do not show an adequate growth response to exogenous growth hormone therapy. Additional clinical features may include characteristic facial features (frontal bossing, midface hypoplasia), delayed skeletal maturation, and in some forms, additional metabolic abnormalities such as fasting hypoglycemia.

INCRELEX was developed to address this specific unmet medical need. By providing exogenous rhIGF-1, INCRELEX bypasses the defective GH-IGF-1 axis and delivers the growth-promoting factor directly to target tissues. Clinical trials have demonstrated that mecasermin treatment significantly improves height velocity (growth rate) in children with severe primary IGFD. In the pivotal clinical studies, children treated with INCRELEX showed mean height velocity increases from approximately 2–3 cm/year at baseline to 8–9 cm/year during the first year of treatment, with sustained growth improvements over multiple years of therapy. Long-term data from registries such as the European INCRELEX Growth Forum Database (Eu-IGFD) have confirmed the sustained efficacy and characterized the long-term safety profile of mecasermin treatment.

INCRELEX was first approved by the U.S. Food and Drug Administration (FDA) in 2005 and by the European Medicines Agency (EMA) in 2007. It is currently marketed by Ipsen and remains the only approved IGF-1 replacement therapy for severe primary IGFD. INCRELEX is classified as an orphan drug, reflecting the rarity of the condition it treats. It is important to emphasize that INCRELEX is not intended for use in children with growth hormone deficiency, short stature from other causes, or as a performance-enhancing substance; its use is strictly limited to confirmed severe primary IGF-1 deficiency under specialist supervision.

What Should You Know Before Taking INCRELEX?

Contraindications

INCRELEX must not be used in the following circumstances:

• Active or suspected malignancy (cancer): Because IGF-1 promotes cell growth and proliferation, INCRELEX is contraindicated in patients with any active neoplasm (tumor) or suspected malignancy. IGF-1 can stimulate the growth of both normal and abnormal cells. Treatment with INCRELEX should be discontinued if a malignancy develops during therapy. If previous malignancy existed, a thorough assessment and a period of cancer-free remission should be documented before considering INCRELEX therapy.
• Closed epiphyses (growth plates): INCRELEX should not be used in patients whose growth plates have fused, as linear growth is no longer possible after epiphyseal closure. Treatment would provide no growth benefit and could expose the patient to unnecessary side effects. Growth plate status should be confirmed by bone age X-ray before initiating and periodically during treatment.
• Hypersensitivity: INCRELEX is contraindicated in patients with known hypersensitivity to mecasermin or any of the excipients in the formulation. Serious allergic reactions, though rare, have been reported. The excipients include benzyl alcohol, sodium chloride, polysorbate 20, glacial acetic acid, sodium acetate trihydrate, and water for injections.
• Intravenous administration: INCRELEX must not be given intravenously. It is designed exclusively for subcutaneous injection. Intravenous administration could cause severe and potentially life-threatening hypoglycemia.

Warnings and Precautions

Before starting INCRELEX and throughout treatment, the following precautions should be carefully considered:

• Intracranial hypertension (benign intracranial hypertension/pseudotumor cerebri): Cases of intracranial hypertension with papilledema, visual changes, headache, nausea, and vomiting have been reported during treatment with INCRELEX. Regular fundoscopic examinations are recommended, especially at the start of treatment and periodically thereafter. If intracranial hypertension is confirmed, treatment should be interrupted and only resumed after resolution of signs and symptoms, at a reduced dose. Parents should be alert for persistent headaches, visual disturbances, or unexplained vomiting.
• Lymphoid tissue hypertrophy: IGF-1 stimulates the growth of lymphoid tissues. Tonsillar hypertrophy (enlargement of the tonsils) and adenoidal hypertrophy are commonly reported in patients treated with INCRELEX. These can lead to snoring, sleep apnea, and chronic ear infections (otitis media with effusion). Patients should have regular ear, nose, and throat examinations. In some cases, tonsillectomy or adenoidectomy may be necessary to address obstructive symptoms.
• Slipped capital femoral epiphysis: Patients receiving growth-promoting therapies, including INCRELEX, are at increased risk of slipped capital femoral epiphysis (SCFE). This is a condition where the head of the femur (thigh bone) slips off the neck of the bone at the growth plate. Clinicians and parents should be alert for the development of a limp, hip pain, or knee pain in children receiving INCRELEX, and these symptoms should be promptly evaluated.
• Progression of scoliosis: Scoliosis (abnormal curvature of the spine) may progress during periods of rapid growth. Children with pre-existing scoliosis should be monitored for progression during INCRELEX treatment.
• Allergic reactions: Both local (injection site) and systemic allergic reactions have been reported. Systemic reactions including anaphylaxis are rare but possible. The INCRELEX formulation contains benzyl alcohol as a preservative, which has been associated with serious adverse reactions and death in neonates and premature infants. INCRELEX should not be used in neonates.
• Malignancy risk: While INCRELEX is contraindicated in patients with active malignancy, there is a theoretical concern that long-term supraphysiological IGF-1 levels could promote neoplastic growth. Physicians should monitor IGF-1 levels and adjust dosing to avoid sustained supraphysiological concentrations. Any suspicious findings should be promptly investigated.

Pregnancy and Breastfeeding

INCRELEX is intended for use in children and adolescents, and pregnancy is not a typical clinical scenario. However, for completeness: there are no adequate and well-controlled studies of mecasermin in pregnant women. Animal reproductive studies have shown that IGF-1 can cross the placenta. INCRELEX should not be used during pregnancy unless clearly necessary and the potential benefits justify the potential risks to the fetus. Women of childbearing age receiving INCRELEX should be counseled about the potential risks and advised to use effective contraception.

It is not known whether mecasermin is excreted in human breast milk. Because many hormones are secreted in breast milk and because of the potential for adverse effects in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the treatment to the mother.

Effects on Ability to Drive and Operate Machinery

Due to the risk of hypoglycemia, INCRELEX may impair the ability to drive or operate machinery. Patients who experience hypoglycemic episodes should avoid potentially hazardous activities until blood sugar levels have stabilized. Since INCRELEX is primarily used in children, this consideration is most relevant for adolescents who may be of driving age. Parents and caregivers should be aware of the hypoglycemia risk when supervising children during physical activities.

How Does INCRELEX Interact with Other Drugs?

INCRELEX (mecasermin) has a distinct drug interaction profile compared to many other medications. As a protein-based therapeutic (a polypeptide), mecasermin is not metabolized by hepatic cytochrome P450 (CYP) enzymes and therefore does not interact with other drugs through classical pharmacokinetic mechanisms of enzyme inhibition or induction. However, there are important pharmacodynamic interactions that must be considered, primarily related to the insulin-like metabolic effects of IGF-1.

IGF-1 shares structural homology with insulin and can activate the insulin receptor (though with much lower affinity than insulin itself). This means that IGF-1 has hypoglycemic properties: it promotes glucose uptake by skeletal muscle and adipose tissue and suppresses hepatic glucose production. The clinical consequence is that INCRELEX can lower blood glucose levels, particularly when administered without food or in combination with other agents that lower blood sugar. Understanding these interactions is essential for safe treatment.

Major Interactions

Insulin and oral hypoglycemic agents: This is the most clinically significant interaction. Because IGF-1 has insulin-like hypoglycemic effects, combining INCRELEX with insulin or oral hypoglycemic agents such as sulfonylureas (e.g., glibenclamide) or meglitinides can result in additive or synergistic lowering of blood glucose, potentially leading to severe hypoglycemia. Some children with severe primary IGFD, particularly those with Laron syndrome, may also have fasting hypoglycemia as part of their condition. When INCRELEX is added to the treatment regimen of a child who is also receiving insulin (for example, in the rare scenario of concurrent diabetes), the insulin dose should be carefully reduced and blood glucose monitored very frequently during dose titration. Close collaboration between the treating endocrinologist and a diabetes specialist is recommended.

Growth hormone (somatotropin): INCRELEX should not be used concurrently with growth hormone. The entire rationale for INCRELEX therapy is that growth hormone is ineffective in severe primary IGFD. Combining the two would not provide additional benefit and could increase the risk of adverse effects. If a patient was previously on growth hormone therapy and is being transitioned to INCRELEX, growth hormone should be discontinued before starting mecasermin. Additionally, growth hormone has diabetogenic effects (it raises blood glucose), which could unpredictably alter the metabolic and glucose-lowering effects of INCRELEX.

Minor and Theoretical Interactions

Systemic corticosteroids: Chronic systemic corticosteroid use (e.g., prednisolone, dexamethasone) can inhibit linear growth and may attenuate the growth-promoting effects of INCRELEX. While short courses of corticosteroids (e.g., for asthma exacerbations) are unlikely to have a significant impact, prolonged use should be avoided where possible in children receiving INCRELEX. If chronic corticosteroid therapy is medically necessary, the treating physician should be aware that the growth response to INCRELEX may be diminished.

Beta-blockers: Beta-adrenergic blocking agents (e.g., propranolol, atenolol) can mask the sympathetic symptoms of hypoglycemia, such as tremor and tachycardia (rapid heartbeat). While this interaction is well-documented with insulin, it is also relevant to INCRELEX because of its hypoglycemic potential. If a child is receiving both INCRELEX and a beta-blocker, parents and caregivers should be counseled about the altered presentation of hypoglycemia and the importance of regular blood glucose monitoring.

Anticonvulsants and other CNS-active medications: There is no direct pharmacokinetic interaction between INCRELEX and anticonvulsant medications. However, since some anticonvulsants can affect glucose metabolism and since hypoglycemia can lower the seizure threshold, children on anticonvulsant therapy who also receive INCRELEX should have their blood glucose monitored carefully, particularly during dose titration.

What Is the Correct Dosage of INCRELEX?

INCRELEX dosing requires careful individualization under the supervision of a pediatric endocrinologist experienced in managing growth disorders. The dose is based on the child's body weight and is gradually titrated upward to achieve optimal growth response while minimizing side effects, particularly hypoglycemia. All dosing should follow the prescribing physician's instructions precisely.

Children and Adolescents (Primary Population)

INCRELEX is indicated for children and adolescents aged 2 years and older with confirmed severe primary IGF-1 deficiency. The recommended dosing schedule is as follows:

The recommended starting dose of INCRELEX is 0.04 mg/kg body weight administered by subcutaneous injection twice daily. If well tolerated for at least one week, the dose may be increased by increments of 0.04 mg/kg per injection to the maximum recommended dose of 0.12 mg/kg administered twice daily. Doses higher than 0.12 mg/kg twice daily should not be used due to the increased risk of hypoglycemia and other adverse effects without proportionally greater growth benefit.

Each injection should be given subcutaneously (under the skin) in the upper arm (deltoid region), upper leg (thigh), abdomen, or buttock. Injection sites should be rotated with each dose to reduce the risk of lipohypertrophy (thickening of fat tissue). The two daily doses should be approximately 12 hours apart, and each dose must be administered shortly before or after a meal or snack containing adequate calories and carbohydrates.

Adults

INCRELEX is not approved for use in adults. The safety and efficacy of mecasermin in adult patients have not been established in adequate and well-controlled clinical trials. Adults with conditions potentially related to IGF-1 deficiency should consult with an endocrinologist to discuss alternative management strategies.

Elderly Patients

INCRELEX is a pediatric medication not indicated for use in elderly patients. There are no clinical data supporting the use of mecasermin in the geriatric population.

Missed Dose

If a dose of INCRELEX is missed, the patient should not take a double dose to make up for the missed one. The missed dose should be skipped and the next dose administered at the regular scheduled time with a meal. If a child cannot eat (due to illness, vomiting, or other reasons), the corresponding dose of INCRELEX must also be skipped to avoid the risk of hypoglycemia. Parents and caregivers should be clearly instructed on this critical safety measure. Keeping a treatment diary can help track doses and meals.

Overdose

Overdose with INCRELEX would be expected to cause hypoglycemia, which is the most significant acute risk. Acute single overdose may produce hypoglycemia followed by a potential hyperglycemic rebound. The first and most important step in managing INCRELEX overdose is immediate treatment of hypoglycemia with oral glucose or, if the patient is unconscious, intravenous dextrose (glucose) solution. Long-term overdosage could cause acromegalic features (enlargement of hands, feet, and facial features), organomegaly (enlargement of internal organs), and other signs of excessive IGF-1 action.

There is no specific antidote for mecasermin overdose. Treatment is symptomatic and supportive, with close monitoring of blood glucose levels. Given the relatively short half-life of mecasermin (approximately 5.8 hours), symptoms of overdose should resolve within hours, but monitoring should continue for at least 24 hours. In case of suspected overdose, contact a poison control center or emergency medical services immediately.

What Are the Side Effects of INCRELEX?

Like all medicines, INCRELEX can cause side effects, although not everybody gets them. The safety profile of INCRELEX has been characterized through clinical trials, post-marketing surveillance, and long-term registry data (including the European INCRELEX Growth Forum Database). The side effect profile reflects the pharmacological actions of IGF-1, which include growth promotion of various tissues and insulin-like metabolic effects. Understanding these side effects is essential for parents, caregivers, and healthcare providers to ensure safe and effective treatment.

Side effects are classified below by frequency according to the following convention:

Hypoglycemia deserves special attention as it is the most common and potentially most dangerous side effect. In clinical trials, hypoglycemic events were reported in approximately 30–50% of patients. Most episodes were mild to moderate, characterized by sweating, hunger, tremor, dizziness, drowsiness, or irritability, and could be treated with oral glucose or carbohydrate-containing food or drink. However, severe hypoglycemia (requiring third-party assistance, loss of consciousness, or seizures) has also been reported, particularly in young children, during the initial dose-titration period, or when INCRELEX is administered without adequate food intake.

Parents and caregivers should be thoroughly trained to recognize the signs of hypoglycemia, which may be subtle in young children (irritability, pallor, excessive sleepiness, refusal to eat). A source of rapid-acting glucose (glucose tablets, fruit juice, or sugar-containing drinks) should always be readily available. Blood glucose monitoring should be performed regularly, especially during dose changes and during intercurrent illness. If severe hypoglycemia occurs despite adequate food intake and appropriate dosing, the dose should be reduced and the treating physician consulted.

Tonsillar and adenoidal hypertrophy is the second most notable side effect category. IGF-1 stimulates growth of lymphoid tissue, and the tonsils and adenoids are particularly responsive. Enlarged tonsils and adenoids can cause upper airway obstruction, leading to snoring, mouth breathing, obstructive sleep apnea, and recurrent ear infections. Parents should be advised to report any new snoring, sleep disturbances, or recurrent ear problems to the treating physician. Sleep studies (polysomnography) may be indicated if obstructive sleep apnea is suspected. Tonsillectomy and/or adenoidectomy may be necessary in some cases.

Intracranial hypertension is uncommon but requires vigilance. Signs include persistent or worsening headache, visual disturbances (blurred vision, double vision, visual field deficits), nausea, and vomiting. Fundoscopic examination should be performed before starting treatment, periodically during treatment, and whenever symptoms suggestive of raised intracranial pressure develop. If papilledema is confirmed, INCRELEX should be stopped and only restarted at a lower dose after complete resolution of symptoms, if clinically appropriate.

How Should You Store INCRELEX?

Proper storage of INCRELEX is essential to maintain the stability and potency of the medication. Mecasermin is a protein-based drug that is sensitive to temperature extremes, light, and physical agitation. Incorrect storage can lead to degradation of the protein, loss of efficacy, or formation of potentially immunogenic aggregates. Follow these storage instructions carefully:

• Before first use: Store unopened vials of INCRELEX in a refrigerator at 2–8 °C (36–46 °F). Do not freeze. If the solution has been accidentally frozen, it must be discarded, as freezing can damage the protein structure and render the medication ineffective or potentially harmful.
• After first opening: Once the rubber stopper has been punctured for the first dose, the vial should be returned to the refrigerator and can be used for up to 30 days. After 30 days, any remaining solution must be discarded, even if the vial still contains medication. Record the date of first use on the vial label to help track the 30-day expiration window.
• Protect from light: Keep the vial in its original outer carton when not in use to protect the solution from light exposure, which can accelerate protein degradation.
• Do not shake vigorously: Gentle mixing is acceptable if needed, but do not shake the vial vigorously. Excessive agitation can cause foaming and protein aggregation, which may reduce the potency of the medication and increase the risk of immunogenic reactions.
• Inspect before each use: Before drawing each dose, visually inspect the solution. INCRELEX should be a clear, colorless to slightly opalescent solution. Do not use if the solution is cloudy, discolored, or contains visible particulate matter. Small bubbles may be present and are not a concern.
• Keep out of reach of children: Store INCRELEX out of the sight and reach of children when not being administered. Used needles and syringes should be disposed of immediately in a sharps container.
• Do not use after the expiry date: Check the expiry date on the vial and outer carton before each use. Do not use INCRELEX after the stated expiry date (EXP). The expiry date refers to the last day of that month.

When traveling with INCRELEX, use an insulated cooling bag or travel cooler with ice packs to maintain the required temperature range (2–8 °C). Do not place the vial directly against ice packs, as direct contact may cause localized freezing. If the cold chain is interrupted for an extended period, consult your pharmacist about whether the medication is still usable.

What Does INCRELEX Contain?

Each milliliter of INCRELEX solution for injection contains:

INCRELEX is supplied as a clear, colorless to slightly opalescent sterile solution in a 4 mL glass vial containing 40 mg of mecasermin (10 mg/mL). The vial is closed with a rubber stopper and an aluminum seal with a plastic flip-off cap. Each vial is for multiple-dose use. INCRELEX does not contain latex in the stopper.

Mecasermin is recombinant human insulin-like growth factor 1 (rhIGF-1), a 70-amino acid single-chain polypeptide with a molecular weight of approximately 7,649 Daltons. It is produced in Escherichia coli using recombinant DNA technology and is structurally and biologically identical to endogenous human IGF-1. The three-dimensional structure is maintained by three disulfide bonds. Mecasermin is the International Nonproprietary Name (INN) for this substance.

Benzyl alcohol is included as a preservative to allow multi-dose use of the vial. As noted in the warnings section, benzyl alcohol can be harmful to neonates and premature infants. The concentration of 9 mg/mL is within the range commonly used in injectable pharmaceutical products. Patients or parents with concerns about benzyl alcohol should discuss them with the prescribing physician.

The solution has a pH of approximately 5.4. It is isotonic and suitable for subcutaneous injection without further dilution. No reconstitution or preparation is required before administration. Simply withdraw the prescribed dose using an appropriate insulin syringe and inject subcutaneously.