GLYBERA Solution for injection Ref.[27946] Active ingredients: Alipogene tiparvovec

This medicinal product contains genetically-modified organisms. Local biosafety guidelines applicable for such products should be followed (see section 6.6).

Glybera should only be administered to patients with an LPL protein mass of at least 5% of normal. LPL protein mass should be determined by ELISA or equivalent methods. LPL protein mass should be measured in a blood sample from the patient against a control sample from healthy volunteers.

Diet

Treatment with Glybera does not eliminate attacks of acute pancreatitis. Patients are advised to continue to follow a low-fat diet and refrain from alcohol consumption.

Diabetic patients

Limited data are available in diabetic patients. Diabetes mellitus is common in patients who have the most severe symptoms of LPLD. The opportunity to treat diabetic patients suffering from LPLD should be carefully considered by the physician.

Immunosuppressants (see section 5.2)

Immediately prior to initiation of the immunosuppressant regimen and prior to Glybera injection the patient must be checked for symptoms of active infectious disease of any nature, and in case of such infection the start of treatment must be postponed until after the patient has recovered.

Thromboembolic events

LPLD involves a state of hyperviscosity/hypercoagulability. Spinal anaesthesia and multiple intramuscular injections may further increase the risk of (thrombo) embolic events at and shortly after administration of Glybera. Assessment of each individual subject’s risk profile prior to Glybera administration is advised. Follow applicable local or international guidelines for prophylaxis (See also section 4.5).

Cell and tissue donation

Treated patients should not donate blood, organs, tissues and cells for transplantation. This information is also provided in the Glybera Patient’s Alert Card.

Serum creatine kinase

Recipients of Glybera may display a rise in serum creatine kinase activity that becomes evident about 2 weeks after administration, peaks at around 8 weeks and then returns to baseline by week 26. One patient developed myoglobinuria in association with raised serum creatine kinase activity.

Muscle biopsies obtained up to 52 weeks after administration of Glybera show an infiltrate of lymphocytes and macrophages. The long term consequences of this cellular infiltration are not known.

Sodium content and potassium content

This medicinal product contains 47.5 mg sodium per administration at 27 injection sites to 105.6 mg sodium per administration at 60 injection sites. To be taken into consideration by patients on a controlled sodium diet.

The product contains less than 1 mmol (39 mg) potassium per administration of 27-60 injection sites; i.e. essentially potassium-free.

No interaction studies other than preclinical and clinical studies with mycophenolate mofetil and ciclosporin have been performed.

Anti-platelet or other anti-coagulant medicinal products must not be used concomitantly with Glybera at the time of injection. Correction of bleeding parameters should be instituted prior to Glybera administration. Anti-platelet or other anti-coagulant medicinal products must not be taken for at least one week before the leg injections or one day after the injection (see section 4.3).

Oral contraceptive use is contraindicated in LPLD patients (see section 4.3) as this may exacerbate the underlying disease.

Contraception in males and females

Women of childbearing potential must be advised to use reliable barrier contraception methods in accordance with the guidelines for immunosuppressants for a minimum of 12 months from the start of therapy (9 months following cessation of immunosuppressants). Therefore, use of barrier contraception methods for at least 12 months following Glybera administration is recommended.

Oral contraceptive use is contraindicated in LPLD patients (see section 4.3) as this may exacerbate the underlying disease.

Male patients, including vasectomised males, are advised to practise barrier contraception methods for at least 12 months following Glybera administration.

Pregnancy

Very limited data on pregnancies exposed to Glybera is available. Animal studies do not indicate any harmful effects on pregnancy or embryonal/foetal development from Glybera (see section 5.3). Glybera should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus.

Breast-feeding

It is not known whether Glybera is excreted in human milk. Glybera should not be administered to women who are breast-feeding as long as breastfeeding is ongoing.

Fertility

No clinical data on the effect of Glybera on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.

Glybera has minor influence on the ability to drive and use machines¸ dizziness was commonly observed after Glybera administration (see section 4.8). Patients experiencing dizziness are advised to not drive or use machines.

Summary of the safety profile

The most commonly reported adverse reaction is pain in extremity occurring in approximately one third of patients. One patient was diagnosed with pulmonary embolism 7 weeks after therapy. Given the small patient population and size of the cohorts, captured adverse reactions and serious adverse reactions do not provide a complete perspective on the nature and frequency of these events.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA body system organ class and by frequency. Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Immunogenicity

An immune response was seen despite the use of immunosuppressants. In clinical trials with Glybera, antibodies against the adeno-associated virus (AAV) protein shell were present prior to treatment, in 18 out of 27 subjects; anti-AAV antibodies appeared or increased after Glybera administration, in all of the subjects. The clinical relevance of the antibody response is unknown (see section 4.2 on re-administration). No neutralising assay was used.

T-cell responses against AAV were detected in approximately half of the subjects post therapy only. No T-cell response to LPL was detected in any subject.

With the exception of a case of fever (39.9°C) in study CT-AMT-011-01 which reversed within a day, no Glybera or immunosuppression related serious adverse events occurred.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.