Opgenra - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Opgenra 3.3 mg powder for implantation suspension.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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 the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for implantation suspension.

The powder containing the active substance is granular and white to off-white.

The powder containing the excipient carmellose (carboxymethyl­cellulose) is yellowish white.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Opgenra is indicated for posterolateral lumbar spinal fusion in adult patients with spondylolisthesis where autograft has failed or is contra-indicated.

4.2 Posology and method of administration

This medicinal product should be used by an appropriately qualified surgeon.

Posology

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.

Paediatric population

Opgenra is contraindicated in children (<12 years old), adolescents (12–18 years old) 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).

Method of administration

For intraosseous use.

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 instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Opgenra must not be used in patients who:

• • have a hypersensitivity to the active substance or to any of the excipients listed in section 6.1;
• • have an autoimmune disease, including Crohn’s disease, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren’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;
• • require arthrodesis as a result of metabolic bone disease or tumour.

Opgenra is contraindicated in children aged 0 to 12 years old, adolescents aged 12 to 18 years and the skeletally immature.

4.4 Special warnings and precautions for use

Use of Opgenra does not guarantee fusion; additional surgeries may be required.

Containment

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.

Immune response

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.

Renal and hepatic impairment

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.

Use in cervical spine

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.

Use with bone void fillers

The concomitant use of Opgenra with a synthetic bone void filler is not recommended (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

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).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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.

Pregnancy

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 section 5.3).

Breast-feeding

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.

4.7 Effects on ability to drive and use machines

Opgenra has no known pharmacological effect on neuro-motor coordination or performance consequently it is unlikely to alter any pre-existing skills used for driving vehicles or operating machines.

4.8 Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

The following adverse reactions were reported with Opgenra. The frequency of adverse reactions 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 <1/10 0): rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Pre-existing co-morbidities

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 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.

Interaction with bone void fillers

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.

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

4.9 Overdose

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for the treatment of bone diseases, 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 75–425pm. 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 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. PHARMACEUTICAL PARTICULARS6.1 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

3 years.

The reconstituted medicinal 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.

For storage conditions after reconstitution, see section 6.3.

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.

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 × 1 vial containing 1g of powder (3.3 mg eptotermin alfa) and 2 × 1 vial 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. Using your thumb 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. To avoid breakage, do not tap the bottom of the vial when transferring contents.

• 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.

• 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.

7. MARKETING AUTHORISATION HOLDER

Olympus Biotech International Limited

Block 2, International Science Centre

National Technology Park

Castletroy

Limerick

Ireland

Tel +353 61 585100

Fax +353 61 585151

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/489/001

EU/1/08/489/002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 February 2009

Date of renewal: 19 February 2014