ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Opgenra 3.3 mg powders for suspension for implantation
2.
One vial contains 1g powder with 3.3 mg of eptotermin alfa*.
After reconstitution, Opgenra contains 1 mg/ml eptotermin alfa.
*Eptotermin alfa is human recombinant Osteogenic protein 1 (OP-1) produced in Chinese hamster
ovary (CHO) cell line.
For a full list of excipients, see section 6.1.
3.
Powders for suspension for implantation.
The powder containing the active substance is granular and white to off-white.
The powder containing the excipient carmellose (carboxymethylcellulose) is yellowish white.
4.
Opgenra is indicated for posterolateral lumbar spinal fusion in adult patients with spondylolisthesis
where autograft has failed or is contra-indicated.
This medicinal product should be used by an appropriately qualified surgeon.
Opgenra is intended only for single use in each patient. Treatment requires a single surgery. To fuse a
single level of the lumbar region of the spine, one unit of medicinal product is used on each side of the
spine. The maximum human dose should not exceed 2 units since efficacy and safety for spinal fusion
requiring higher doses has not been established.
Method of administration:
The reconstituted product is administered by direct surgical placement into the lumber region of the
spine following surgical preparation of the site. The surrounding soft tissues are then closed around
the implanted material.
For detailed recommendations on the reconstitution and administration of the medicinal product see
section 6.6.
Special populations
Paediatric population:
Opgenra is contraindicated in children, adolescents and the skeletally immature
(see section 4.3).
Renal/hepatic impairment:
Care should be used when Opgenra is used in patients with renal or hepatic
impairment (see section 4.4).
2
Opgenra must not be used in patients who:
•
have a hypersensitivity to the active substance or to any of the excipients;
•
have an autoimmune disease, including Crohn’s disease, rheumatoid arthritis, systemic lupus
erythematosus, scleroderma, Sjögren’s syndrome and dermatomyositis/polymyositis;
•
have an active infection at the site of spinal fusion or history of recurring infections;
•
have inadequate skin coverage and vascularity at the site of spinal fusion;
•
have prior history of exposure to any bone morphogenetic protein (BMP) product;
•
have an active malignancy or are undergoing treatment for a malignancy.
Opgenra is contraindicated in children, adolescents and the skeletally immature.
Use of Opgenra does not guarantee fusion; additional surgeries may be required.
Any material dislodged from the fusion site can cause ectopic ossification in the surrounding tissues
with potential complications. Therefore, Opgenra may only be administered to the fusion site under
adequate vision and with utmost care. Special care must be taken to prevent any leakage of Opgenra
due to irrigation, defective closure of surrounding tissue or inadequate haemostasis. CT examination
has suggested that significant medial displacement of Opgenra can occur post-operatively and this can
result in bone forming medially. This should be considered in follow-up of patients with CT or X-ray.
In a clinical study of the medicinal product, antibodies to the protein eptotermin alfa were detected in
194 out of 207 (94%) patients treated with it and 18 out of 86 (21%) treated with autograft bone
(control group). Within the test group, 26% of patients produced antibodies with neutralizing capacity
versus 1% in the control group. The peak antibody response was seen 3 months following treatment.
There were no patients with neutralizing antibodies 2 years following treatment.
The clinical
significance of these antibodies is not known. The clinical study results suggest that there does not
appear to be any association between neutralizing antibodies and the development of adverse events
related to the immune system. However, an immune response to eptotermin alfa should be considered
and appropriate validated tests for the presence of antibodies in serum should be performed in cases
where an immune-mediated undesirable effect is suspected, including cases where the medicinal
product is ineffective.
Opgenra is intended only for single use in each patient. Repeated use of the medicinal product cannot
be recommended. Studies with anti-OP-1 antibodies demonstrated some cross-reactivity with closely
related bone morphogenetic proteins BMP-5 and BMP-6. Anti-OP-1 antibodies have the ability to
neutralise the
in vitro
biological activity of at least BMP-6. Therefore, upon re-administration of
Opgenra, a risk of developing autoimmunity towards the endogenous BMP proteins may exist.
There is limited experience on the use of the medicinal product in patients with renal or hepatic
impairment therefore caution with its use in such patients is advised.
Clinical studies to investigate the efficacy and safety of this medicinal product in cervical spine
surgery have not been performed; consequently its use outside the region of the lumbar spine cannot
be recommended.
The concomitant use of Opgenra with a synthetic bone void filler is not recommended (see
section 4.5).
3
Post- marketing surveillance data includes reports that the use of the medicinal product in combination
with a synthetic bone void filler, may lead to an increase in local inflammation, infection and
occasionally migration of the implanted materials (see section 4.4).
Animal studies that have been conducted cannot rule out possible effects of anti-OP-1 antibodies on
embryofoetal development (see section 5.3). Due to the unknown risks to the foetus associated with
the potential development of neutralizing antibodies to OP-1 protein, the medicinal product should not
be used during pregnancy unless the potential benefit justifies the potential risks to the foetus (see
sections 4.4 and 5.3).
Women of childbearing potential should be advised to use effective contraception for a period of at
least 2 years after treatment. Women of child-bearing potential should inform their surgeon of the
possibility of pregnancy prior to treatment with Opgenra.
In animal studies, excretion of IgG class anti-OP-1 antibodies into milk was shown. As human IgG is
secreted into human milk, and the potential for harm to the infant is unknown, women should not
breast-feed during Opgenra therapy (see section 5.3). The medicinal product should be used in
breast-feeding women only when the attending physician decides that the benefits outweigh the risks.
It is recommended that breast-feeding be discontinued following treatment.
No studies on the effects on the ability to drive and use machines have been performed. Opgenra has
no known pharmacological effect on neuro-motor co-ordination or performance consequently it is
unlikely to alter any pre-existing skills used for driving vehicles or operating machines.
Opgenra is implanted during an invasive surgical procedure performed under general anaesthesia.
Adverse events recorded during the clinical studies following such surgery and not specifically
causally related to the implanted materials included superficial wound infection, wound dehiscence,
osteomyelitis, complications of mechanical support, haematoma formation, nausea, vomiting, fever
and pain. The frequency and severity of post-operative adverse events was similar in both test and
control groups. The pattern of unrelated post-operative adverse events varied with the extent of
surgical trauma, procedural complications and the pre-operative health of the patient.
The following undesirable effects were reported as possibly causally related to Opgenra. The
frequency of undesirable effects listed in the table below is based on the following convention:
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 the available data).
Infections and
infestations
Common: post-operative infection
General disorders and
administration site
conditions
Uncommon: localised swelling, seroma, product migration when mixed with
synthetic bone void filler
Surgical and medical
procedures
Common: wound dehiscence, secretion, erythema; heterotopic bone formation,
pseudarthrosis.
In the study populations, some patients with common pre-existing co-morbidities (e.g. cardiovascular,
respiratory, genitourinary disorders, neoplasms) experienced exacerbations of their prior disease
4
during the long term (three year) follow up period. Patients with a known history of heart disease or
frequent infections should be identified and observed more closely following surgery.
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Bone morphogenetic proteins, ATC code: M05BC02
Opgenra is an osteoinductive and osteoconductive medicinal product.
Eptotermin alfa, the active substance, initiates bone formation through the induction of cellular
differentiation in mesenchymal cells, which are recruited to the implant site from bone marrow,
periosteum and muscle. Once bound at the cell surface, the active substance induces a cascade of
cellular events leading to the formation of chondroblasts and osteoblasts, which play a key role in the
bone formation process. The collagen matrix is insoluble and consists of particles with a size range of
75-425µm. This provides an appropriate bioresorbable scaffold for the anchorage dependent cell
proliferation and differentiation processes induced by the active substance. The carmellose imparts a
putty-like consistency to the medicinal product for ease of molding and placement on each side of the
spine. The cellular events induced by the active substance take place within the product matrix. The
matrix is also osteoconductive and it allows bone in-growth into the defect area from the adjacent
healthy bone.
The pivotal study with 295 patients involved un-instrumented postero-lateral lumbar spine fusion in
208 patients treated with Opgenra.
5.2 Pharmacokinetic properties
There are no data on the pharmacokinetics of the active substance in man. However, results from
implantation studies in animals demonstrate that the active substance eptotermin alfa is released from
the implant site over several weeks and never reaches a level higher than 3% of the total amount
implanted in the peripheral blood.
5.3 Preclinical safety data
Single dose and repeat dose studies in a range of animal models (rats and primates) were performed.
The results of these showed no unanticipated or systemic effects of toxicity during the observation
period and after administration.
In a 2 year subcutaneous implantation study in rats, heterotopic bone formation was observed, as
expected. Sarcoma was associated with the long-term presence of the heterotopic bone. This effect,
termed solid state carcinogenicity, has been frequently observed in rats in which solid materials
(plastics or metals) were implanted subcutaneously.
Heterotopic ossification commonly occurs in humans following accidental or surgical trauma to the
skeleton. It has been observed following use (see section 4.8). However, there is no evidence to
suggest that heterotopic ossification is linked to sarcoma development in humans.
The effect of anti-OP-1 antibodies on the bone healing process was studied in dogs with two long bone
defects treated with repeat implantations. The results of radiological and histological examinations in
this study showed bone healing following the initial and repeat exposure in the same animal.
Antibodies to OP-1 and bovine bone collagen type 1 were found after both exposures. Not
5
surprisingly, the antibody peak concentration was higher after the second exposure. The antibody
levels declined towards baseline during the follow-up period.
Controlled studies of the effects of exposure to eptotermin alfa on pre and postnatal development were
performed in rabbit models. Eptotermin alfa in Freund’s adjuvant was first administered
subcutaneously with booster doses given after 14 and 28 days. Blood and milk samples were collected
at regular intervals and analysed using a solid phase enzyme-linked immunoassay (ELISA) test.
Detectable levels of IgG and IgM antibodies to eptotermin alfa had developed and were found in the
serum of all exposed adult animals. Antibodies to eptotermin alfa were also found in sera from pooled
foetal and umbilical cord blood, at levels that correlated to that of the maternal blood. Antibodies were
detectable in adults and offspring during the gestation and lactation periods. Significantly high titers of
IgG class anti-OP-1 antibodies were detected in milk throughout the whole post-natal phase study until
the lactation day 28 (see section 4.6).
A statistically significant increase in foetal malformations (misaligned sternabrae) was seen in litters
of the OP-1 immunized group. However the rate of malformations was similar to those from historical
controls. In another study a difference in body weight gain was seen in the immunized adult females
between lactation days 14 to 21 when compared to the control animals. The weight of the offspring in
the treated group was noted to be less than that of the control group during the observation period. The
clinical implications of these observations for human use of the finished medicinal product remain
uncertain (see section 4.6).
6.
6.1 List of excipients
Bovine collagen
Carmellose
6.2 Incompatibilities
Potential interaction with Calstrux, a bone void filler has been reported (see section 4.5).
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
2 years.
The reconstituted product should be used immediately.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
Keep the blisters in the outer carton.
6.5
Nature and contents of container
One unit of Opgenra is supplied in two Type I glass vials, sealed with a butyl rubber stopper and
aluminium crimp cap.
The vials are maintained sterile within individual blisters and packaged together in an outer tray and
box.
One vial containing 1g of powder (3.3 mg eptotermin alfa);
One vial containing 230 mg carmellose powder.
6
Pack sizes:
-a single unit pack with 1 vial containing 1g of powder (3.3 mg eptotermin alfa) and 1 vial containing
230 mg carmellose powder
-a pack of two units with 2 x 1 vial containing 1g of powder (3.3 mg eptotermin alfa) and 2 x 1vial
containing 230 mg carmellose powder.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Each unit of Opgenra consists of two vials of powder, which are first combined and then reconstituted
with 2.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection prior to use. Once Opgenra is
prepared it should be used immediately.
1.
Using sterile technique, remove the vials from the packaging.
2.
Lift the plastic flip-tops and remove the crimp caps from the vials.
Handle the crimp caps with care. The edges of the crimp caps are sharp and may cut or damage
gloves.
3.
Aligning a thumb with the internal gaps of the stoppers, pry up the edges of the stoppers. Once
the vacuums are broken, remove the vial stoppers while holding the vials upright to prevent loss of
contents.
Do not insert a needle through the stoppers. Puncture of the stoppers with a needle may result in
particles of stopper material contaminating the medicinal product.
4.
Place the contents of the eptotermin alfa vial and carmellose vial in a sterile bowl.
5.
Using a sterile syringe, add 2.5 ml of sterile 9 mg/ml sodium chloride solution for injection
(0.9% w/v) to the sterile bowl slowly and carefully.
6.
Gently stir the contents of the bowl with a sterile spatula to aid mixing.
7.
The same procedure should be used to prepare the medicinal product for the contralateral side of
the spine. Use the product promptly following reconstitution.
8.
Debride and decorticate bone so that the reconstituted medicinal product will directly contact
viable tissue.
9.
Provide adequate haemostasis to ensure that the material stays at the surgical site. Irrigate the
surgical site as necessary prior to the implantation of the medicinal product. Where practical,
surgical manipulations to the site should be completed prior to product implantation.
10.
Remove the reconstituted product from the sterile bowl with a sterile instrument such as a spatula
or curette. The product should have a malleable, coherent putty-like consistency
11.
Carefully apply the product to the prepared site on each side of the spine, bridging the dorsal
surfaces of the adjacent transverse processes.
12.
Close soft tissues around the site containing the product using suture material of choice. Closure is
critical for containment and maintenance of the product in the area of intended fusion.
13.
Do not place a drain directly in the implant or fusion site. Place it subcutaneously if possible.
7
14.
After closure of the soft tissues around the implant, irrigate the field if necessary to remove any
stray particles of the medicinal product which may have been dislodged during soft tissue closure.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Howmedica International S. de R. L.
Raheen Business Park
Limerick,
Ireland
Tel +353 61 498200
Fax +353 61 498247
8.
EU/1/08/489/001
EU/1/08/489/002
9.
19 February 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/.
8
ANNEX II
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
9
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Stryker Biotech
9 Technology Drive
West Lebanon NH 03784
USA
Name and address of the manufacturer responsible for batch release
Howmedica International S. de R. L.
Raheen Industrial Estate
Raheen, Limerick
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The MAH shall agree the details of an education programme for surgeons with the National
Competent Authorities and must implement such programme nationally to ensure that:
Prior to use of the product, surgeons should be provided with educational material containing:
-
a copy of the SPC
-
a detailed description of:
•
the recommended methods for reconstitution of the product prior to implantation
•
the preparation of the selected paraspinal site where the intended implantation will occur
•
the recommended manner of placement of the material together with some comments on the
importance of local haemostasis
•
the methods for soft tissue closure around the implant. These descriptive texts are included in
the product information.
-
Information about:
Hypersensitivity and antibody formation
Embryo-foetotoxicity and the need for women with childbearing potential to use effective
contraception for 2 years following implant
•
the risks of ectopic bone formation
interaction with bone void fillers
that the product should only be used once
-
details of the post marketing surveillance studies including information on how to enroll patients
10
In addition, prior to use, surgeons intending to use Opgenra should receive a Training DVD containing
animated images of an operation on a patient
and including the
following information:
-
Product description
-
Placement in sterile field
-
Wound opening (soft and hard tissues)
-
Reconstitution of product
-
Implant field preparation (haemostasis)
-
Administration (implantation)
-
Containment of implanted materials (soft tissues)
-
Instrumentation
-
Wound closure (drainage)
-
Follow-up measures
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 1.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.1 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
Protocols for a study or studies to investigate the long term safety and efficacy of patients treated with
Opgenra and also actual drug utilisation in real life will be submitted by the MAH and agreed with the
CHMP before product launch and before the study is started.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
11
ANNEX III
LABELLING AND PACKAGE LEAFLET
12
A. LABELLING
13
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Opgenra 3.3 mg powders for suspension for implantation
eptotermin alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial containing 3.3 mg of eptotermin alfa.
After reconstitution, Opgenra contains 1 mg/ml eptotermin alfa.
3.
LIST OF EXCIPIENTS
Excipients : Bovine collagen, carmellose.
4.
Powders for suspension for implantation.
1 vial containing 1 g of powder (3.3 mg eptotermin alfa).
1 vial containing 230 mg carmellose.
4 vials:
2 x 1 vial containing 1 g of powder (3.3 mg eptotermin alfa).
2 x 1 vial containing 230 mg carmellose.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intraosseous use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2 C – 8 C).
The reconstituted product should be used immediately.
Keep the blisters in the outer carton.
14
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements
11.
Howmedica International S. de R. L.
Raheen Business Park
Limerick
Ireland
Tel +353 61 498200
Fax +353 61 498247
12.
EU/1/08/489/001
EU/1/08/489/002
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted”
15
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
BLISTER FOIL ACTIVE SUBSTANCE POWDER VIAL
1.
Opgenra
3.3 mg powders for suspension for implantation
epotermin alfa
Intraosseous use
2.
METHOD OF ADMINISTRATION
One vial containing 3.3 mg of eptotermin alfa
3.
LIST OF EXCIPIENTS
Excipients : Bovine collagen
4.
Powders for suspension for implantation.
1 vial containing 1 g of powder (3.3 mg eptotermin alfa).
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intraosseous use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED
OUT OF THE REACH AND SIGHT OF CHILDREN
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2 C – 8 C).
The reconstituted product should be used immediately.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements
16
11.
Howmedica International S. de R. L.
Raheen Business Park
Limerick
Ireland
Tel +353 61 498200
Fax +353 61 498247
12.
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted”
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL OF ACTIVE SUBSTANCE POWDER
1.
Opgenra 3.3 mg
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 g (3.3 mg eptotermin alfa)
6.
OTHER
18
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
BLISTER FOR THE CARMELLOSE POWDER VIAL
1.
Carmellose powder for suspension for implantation for Opgenra
Intraosseous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
230 mg
6.
OTHER
Do not open before use
The reconstituted product should be used immediately
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
CARMELLOSE VIAL
1.
Carmellose (Opgenra)
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
230 mg
6.
OTHER
20
MEDICAL OR HEALTHCARE PROFESSIONAL EDUCATIONAL STICKER
To be attached to the patients medical record.
“{
Patient Name} was implanted with a medicinal product containing eptotermin alfa on
{dd/mm/yyy}. Repeat use of this bone morphogenetic protein (BMP) is not recommended.”
21
B. PACKAGE LEAFLET
22
PACKAGE LEAFLET: INFORMATION FOR THE USER
Opgenra 3.3 mg powders for suspension for implantation
eptotermin alfa
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor.
-
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Opgenra is and what it is used for.
2.
Before you use Opgenra.
4.
Possible side effects.
5
How to store Opgenra.
6.
Further information.
1.
WHAT OPGENRA IS AND WHAT IT IS USED FOR
Opgenra is a type of medicine known as a bone morphogentic protein (BMP). This group of
medicines cause new bone to grow at the location where the surgeon has placed (implanted) it.
Opgenra is implanted in adult patients with slippage of the spine (spondylolisthesis) in cases where
treatment with autograft (transplanted bone from your hip) has failed or should not be used.
2.
BEFORE YOU USE OPGENRA
Opgenra must not be used
-
if you are allergic (hypersensitive) to eptotermin alfa or to any of the ingredients of Opgenra
(see section 6).
-
if you have an autoimmune disease (disease arising from or directed against your own tissues),
including Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus, scleroderma,
Sjögren’s syndrome and dermatomyositis/ polymyositis.
-
if you have an active infection in your spine or have been told that you have an active internal
(systemic) infection.
-
if you have inadequate skin coverage and inadequate blood supply at the site of surgery (your
doctor should have told you if this is the case).
-
if you require a spinal fusion because of a metabolic bone disease or tumours
-
if you are receiving chemotherapy, radiation treatment or immunosuppression
.
-
have had Opgenra, eptotermin alfa
or any similar medicine before.
-
if you are a child.
-
if you are an adolescent and your skeleton is not yet be fully formed (you are still growing).
Take special care with Opgenra:
The following are precautions for use of Opgenra to be discussed with your doctor.
•
There is a possibility that new antibodies can form in your body when Opgenra is used. Your
doctors will monitor you if they suspect this is the case.
23
3.
How to use Opgenra.
-
have any tumours in the area intended for surgery.
•
Inform your doctor or surgeon if you have a history of heart problems or are prone to frequent
infections so that they can closely monitor you.
•
Repeated use of Opgenra cannot be recommended. Laboratory studies have demonstrated that
there is a theoretical risk of developing autoimmunity towards the natural (endogenous) BMP
proteins in your body following repeat exposure to this medicine.
Use of Opgenra does not guarantee fusion; additional surgeries may be required.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
Opgenra should not be used during pregnancy unless the benefits to the mother outweigh the risks to
the unborn child. Women of child-bearing potential should inform their surgeon of the possibility of
pregnancy before undergoing treatment with Opgenra. Women of childbearing potential are advised to
use effective contraception for a period of 2 years after their treatment.
Do not breast-feed your baby during Opgenra therapy. As the potential for harm to the breast fed
infant is unknown, women should not breast-feed during the period immediately following treatment
with Opgenra. If you are nursing, you should receive Opgenra only if your treating physician or
surgeon considers the benefits to you outweigh the risks to your child.
Driving and using machines
Studies on the effects on the ability to drive and use machines have not been performed with Opgenra.
3.
HOW TO USE OPGENRA
Opgenra is only used by an appropriately qualified surgeon during the course of spinal fusion surgery.
This is normally done under a full general anasethetic so you will not be awake during the surgery.
A small quantity (one unit) of Opgenra is placed directly on each side of the spine at the site requiring
fusion. The surrounding muscle tissue is then closed around the implanted medicine as is the skin on
top of the muscle. This specialised medicine is used instead of autograft bone (some of a patients own
bone taken from the hip) to fuse the spine.
The maximum dose of this medicine should not exceed 2 units (6.6 mg eptotermin alfa) since its
effectiveness and safety in higher doses has not been studied.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Opgenra can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, which are defined as follows:
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
In clinical studies, the following side effects were reported:
Common reported side effects included:
•
erythema (redness of the skin),
•
tenderness and swelling over the implant site,
•
heterotopic ossification (bone formation outside of the fusion area),
•
pseudarthrosis (failure of the spine to fuse),
•
wound infections.
Uncommon reported side effects included:
•
localised swelling
24
•
seroma (a collection of fluid in the tissues)
•
product migration (this has been observed when the product was mixed with a synthetic
product used to fill the bone void)
Some common undesirable side effects can follow spine surgery itself and these include:
•
wound infection,
•
osteomyelitis (infection of the bone),
•
complications of mechanical support (such as instruments used for stabilisation),
•
bleeding at the wound site,
•
failure of the wound to heal,
•
nausea,
•
fever and
•
pain.
If the side effects gets serious or you notice any side effects not listed in this leaflet, please tell your
doctor.
5.
HOW TO STORE OPGENRA
Keep out of the reach and sight of children.
Do not use Opgenra after the expiry date which is stated on the carton and blisters. The expiry date
refers to the last day of the month. Opgenra should be used immediately after reconstitution.
Store in a refrigerator (2°C - 8˚C).
Keep the blisters in the outer carton.
The hospital pharmacist or surgeon is responsible for the correct storage of the product both before
and during its use, as well as for the correct disposal.
6.
FURTHER INFORMATION
What Opgenra contains
The active substance is eptotermin alfa (a recombinant human Osteogenic protein 1 produced in a
recombinant Chinese hamster ovary (CHO) cell line). One vial of Opgenra contains 1 g of powder
including 3,3 mg of eptotermin alfa and the excipient bovine collagen. The other vial contains the
excipient carmellose.
What Opgenra looks like and contents of the pack
One unit of Opgenra powders for suspension for implantation comes as two separate powders. The
powder containing the active substance and the excipient bovine collagen has the appearance of a
white to off-white granular powder; the carmellose powder is a yellowish white powder.
The powders come in glass vials. Each vial is secured in a sterile blister. Each outer carton contains
one 3.3 mg eptotermin alfa vial containing 1 g of powder and one carmellose powder vial containing
230 mg powder.
Pack sizes:
-a single unit pack with 1 vial containing 1g of powder (3.3 mg eptotermin alfa) and 1 vial containing
230 mg carmellose powder
25
-a pack of two units with 2 x 1 vial containing 1g of powder (3.3 mg eptotermin alfa) and 2 x 1vial
containing 230 mg carmellose powder.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Howmedica International S. de R. L.
Raheen Business Park
Limerick
Ireland
Tel +353-61-498200
Fax +353-61-498247
This leaflet was last approved in
.
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/
26
Source: European Medicines Agency
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