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Increlex▼ (mecasermin) - patient safety update

Increlex ▼, for Growth delay due to insulin-like growth factor type 1 deficiency from Ipsen

The Medicines and Healthcare products Regulatory Agency (MHRA) have announced that cases of benign and malignant neoplasms have been identified in patients being treated with Ipsen's treatment for primary insulin-like growth factor type 1 deficiency mecasermin, brand name Increlex▼.

The syndrome is extremely rare and only four cases have been reported in the literature so far.

The MHRA state that:
'An EU review identified an increased incidence of benign and malignant tumours in patients receiving mecasermin in the post-marketing setting compared with the background incidence in this patient population. These cases represented a variety of different malignancies and included rare cancers not usually seen in children. Most cases occurred in patients treated outside the authorised indication or exceeding the maximum dose, however some were reported within the authorised indication and posology for mecasermin.'

Neoplasms are defined as unusual growth or formation of tissue in the body.

The MHRA advice to healthcare professionals is:
  • cases of benign and malignant neoplasms have been observed among children and adolescents who received treatment with mecasermin
  • permanently discontinue mecasermin if a benign or malignant neoplasm develops
  • mecasermin is contraindicated in children and adolescents with active or suspected neoplasia and in any condition or medical history that increases the risk of benign or malignant neoplasia
  • mecasermin is licensed only for the treatment of severe primary insulin-like growth factor 1 (IGF-1) deficiency and the recommended maximum dose is 0.12 mg/kg given twice daily – data suggest the risk of neoplasia is higher when used outside of the licensed indication or dose

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About primary insulin-like growth factor type 1 deficiency (source National Institute for Health)
Growth delay due to insulin-like growth factor I (IGF-1) deficiency is characterised by the association of intrauterine and postnatal growth retardation with sensorineural deafness and intellectual deficit.

The syndrome is extremely rare and only four cases have been reported in the literature so far.

Addition clinical features include microcephaly, adiposity, and insulin resistance. Partial gonadal dysfunction and osteoporosis may also be present. A case of partial IGF-I deficiency has also been described and was associated with pre- and postnatal growth retardation and microcephaly but the developmental delay was mild and hearing tests were normal.

IGF-I deficiency is caused by homozygous mutations in the insulin-like growth factor 1 gene (IGFI; 12q22-q24.1). IGF-I is essential for foetal and postnatal growth, brain development and metabolism.

Diagnosis relies on direct sequencing of the five IGF1 exons and of the intron-exon junctions. Measurement of IGF-I levels can be used for diagnosis but the circulating levels of IGF-I vary between patients (ranging from undetectable, low to very high) depending on the molecular defect present and on the immunoassay used.

The differential diagnosis should include growth hormone deficiency and growth hormone resistance (caused by GH receptor or STAT5b anomalies), growth delay due to insulin-like growth factor I resistance and primary acid-labile subunit (ALS) deficiency syndrome (see these terms), as well as secondary IGF-I deficiency due to nutritional problems.

Prenatal diagnosis is feasible for families with an identified IGF1 mutation proven to be responsible for the disease phenotype of intrauterine and postnatal growth delay associated with intellectual deficit.

IGF-I deficiency is transmitted as an autosomal recessive trait. Affected families should be offered genetic counselling and informed of a 25% risk of recurrence.

About Increlex (source EMA)
Increlex is used for the long-term treatment of patients aged two to 18 years who are short for their age due to a condition known as ‘severe primary insulin-like-growth-factor-1 deficiency’. Patients with this condition have low levels of the hormone insulin-like growth factor-1 or IGF-1, which is required for normal growth.

Because the number of patients with primary IGF-1 deficiency is low, the disease is considered ‘rare’, and Increlex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 22 May 2006.

The medicine can only be obtained with a prescription.

How Increlex works (source EMA)
The active substance in Increlex, mecasermin, is a copy of the hormone IGF-1. IGF-1 is important in determining how tall a child grows. It does this by stimulating cells to divide and grow and to absorb nutrients, supporting the growth of body tissues. Increlex works in the same way as natural IGF-1, replacing the missing hormone and helping the child to grow taller.

Increlex was first made available in the EU in 2007. It is manufactured by Ipsen.

Sources
European Medicines Agency website page for Increlex
National Institute for Health website for primary insulin-like growth factor type 1 deficiency
Accessed 28/01/20
Links available in External Resources

MHRA information on Increlex

New medicines and vaccines that are under additional monitoring have an inverted black triangle symbol (▼) displayed in their package leaflet and summary of product characteristics, together with a short sentence explaining what the triangle means – it does not mean the medicine is unsafe. You should report all suspected adverse drug reactions (ADRs) for these products. ADRs can be reported by your doctor, pharmacist or online via the Yellow Card system.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions (side effects) after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals or patients are asked to report any suspected adverse reactions via the Yellow Card Scheme at yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.


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