Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: uniQure biopharma B.V., Meibergdreef 61, 1105 BA Amsterdam, The Netherlands
Glybera is indicated for adult patients diagnosed with familial lipoprotein lipase deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The diagnosis of LPLD has to be confirmed by genetic testing. The indication is restricted to patients with detectable levels of LPL protein (see section 4.4).
Glybera should only be used when the diagnosis of LPLD has been confirmed by an adequate genetic test (see section 5.1).
Glybera therapy must be prescribed by and administered under the supervision of a physician with expertise in treating LPLD patients and in gene therapy administration, in full consultation with the patient. During administration of Glybera appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration.
The maximum total dose of Glybera for administration is 1 × 1012 gc/kg body weight.
Glybera is authorised for single treatment only. No data on re-administration of Glybera are available, therefore Glybera should not be re-administered.
Glybera is administered as a one-time series of intramuscular injections in the legs. The dose per injection site is 1.5 × 1012 gc, or 0.5 ml of solution for injection. For each injection site, one syringe of 1 ml with clear volume marks of 0.5 ml must be used. Volumes per injection site must not exceed 0.5 ml. Syringes must not be used more than once.
The treatment should be monitored by measuring neutralising antibodies and T-Cell response against AAV1 and LPLS447X and T-Cell response at baseline as well as 6 and 12 months after treatment.
To calculate the number of vials, the patient’s weight is determined to the nearest whole kg. The patient’s weight should be divided by 3, and rounded up to the next higher whole number. This is the number of vials that must be dispensed.
To calculate the number of injection sites and the number of syringes, the patient’s weight is determined to the nearest whole kg. The patient’s weight should be divided by 3, then without rounding up this number multiplied by 2 and rounded up to the next higher whole number. This is the number of injection sites and the total number of syringes (each filled with 0.5ml) required for the patient’s treatment.
Examples of typical dose schedules based on the body weight of patients are shown in the table below:
| Body weight (kg) | Number of vials (1 mL) | Number of 1 ml syringes (each filled) with 0.5 ml) | Number of injection sites |
|---|---|---|---|
| 40 | 14 | 27 | 27 |
| 50 | 17 | 34 | 34 |
| 60 | 20 | 40 | 40 |
| 65 | 22 | 44 | 44 |
| 70 | 24 | 47 | 47 |
| 75 | 25 | 50 | 50 |
| 80 | 27 | 54 | 54 |
| 90 | 30 | 60 | 60 |
From three days prior to and for 12 weeks following Glybera administration an immunosuppressive regimen should be administered: ciclosporin (3 mg/kg/day) and mycophenolate mofetil (2 × 1 g/day) is recommended.
In addition, half an hour prior to Glybera injection an intravenous bolus of 1mg/kg of methylprednisolone should be administered (see section 4.4).
The safety and efficacy of Glybera in children and adolescents below 18 years has not been established. No data are available.
There is limited experience in the use of Glybera in elderly subjects. No dose adjustment of Glybera is necessary in the elderly population. Dose of immunosuppressant may need to be adjusted.
There is limited experience in the use of Glybera in patients with renal or hepatic impairment. No dose adjustment of Glybera is required.
Upon intramuscular injection, the patient will receive multiple injections of 0.5 ml (one injection per syringe), distributed over the muscles of both upper and lower legs, under aseptic conditions such as iodine.
Spinal or regional anaesthesia is advised prior to intramuscular administration, due to the number of injections required. In case of contraindication for such procedure deep sedation is advised instead.
Glybera should under no circumstances be administered intravascularly (see section 4.4).
To ensure intramuscular injection, ultrasound or electrophysiological guidance of injections is advised.
The instructions for use, handling and disposal are given in section 6.6.
Pre-clinical studies with doses ten times the recommended dose (1 × 1013 gc/kg) did not lead to any general systemic untoward signs or symptoms. Symptomatic and supportive treatment, as deemed necessary by the treating physician, is advised in case of overdose.
In the event two doses are administered by mistake to the identical injection site this might lead to more local reaction such as bruising or sensitivity.
Local pain or sensitivity may be managed by symptomatic treatment such as administration of local or systemic pain relievers.
18 months for frozen vials.
Once thawed the medicinal product must be used immediately; if not used immediately, the vials should be stored in a refrigerator at 2°C to 8°C, and protected from light for a maximum of 8 hours. Once thawed, the medicinal product should not be re-frozen.
If not stored in a refrigerator the medicinal product can be stored in syringes at not more than 25°C, and protected from light for a maximum of 8 hours.
Store and transport vial frozen -25°C to -15°C.
Keep the vial in the outer carton in order to protect from light.
1 ml solution in a 2 ml vial (glass) with siliconised chlorobutyl, injection stopper and flip-off seal.
Each preformed transparent sealed plastic casing contains either 2 or 3 individual vials with a liquid absorbing sheet. The final outer carton contains a variable number of casings according to the patient specific dose required.
Refer to local biosafety guidelines applicable for handling and disposal of medicinal products containing genetically-modified organisms.
Work surfaces and material which have potentially been in contact with Glybera must be decontaminated with appropriate virucidal disinfectants with activity for non-enveloped viruses (such as hypochlorite and chlorine releasers) for at least 10 minutes.
After the amount of Glybera to be administered has been calculated (see section 4.2) remove the correct number of single use vials from the freezer to thaw at room temperature (15°C to 25°C), approximately 30-45 minutes in advance of syringe filling.
After thawing, each vial should be gently inverted twice to ensure even mixing. Vials should be visually inspected for particulate matter and colour. The clear to slightly opalescent and colourless solution must be free of visible particles. Only clear and colourless solutions without visible particles should be used. If a vial is showing damage, syringes for the injection should not be prepared and the injection procedure should be postponed and rescheduled. The Marketing Authorisation Holder should be informed immediately.
Glybera is delivered in a patient-specific pack and will therefore contain the precise amount of vials per patient, calculated according to the patient’s weight.
The calculated amount of syringes should be filled from the thawed vials, and they should be labelled and placed in a container protected from light suitable for transportation to the room where the patient will undergo the intramuscular injections.
To avoid any injection of particles from the stopper due to two withdrawals, one needle for the withdrawal from the vial (to be left inside the stopper) and a separate needle for each syringe must be used.
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