Osigraft - summary of medicine characteristics

Osigraft 3.3 mg powder for suspension for implantation

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 3.3 mg of eptotermin alfa

Produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for suspension for implantation.

White to off-white granular powder.

4.1 Therapeutic indications

Treatment of non-union of tibia of at least 9 month duration, se condary to trauma, in skeletally mature patients, in cases where previous treatment with autograft has failed or use of autograft is unfeasible.

4.2 Posology and method of administration

Posology

Osigraft should be used by an appropriately qualified surgeon.

The recommended dose is one singl e administration in adults. Depending on the size of the bone defect, more than one 1 g vial of Osigraft may be required. The recommended maximum dose should not exceed 2 vials since efficacy in the treatment on non-unions requiring higher doses has not been established.

Paediatric population

Osigraft is contraindicated in children and adolescents (less than 18 years old) and the skeletally immature (see section 4.3).

Method of administration :

Intraosseous use.

The r econstituted product is administered by direct surgical placement at the non-union site in contact with the prepared bone surface. The surrounding soft tissues are then closed around the implant.

Experience from controlled clinical trials is limited to stabilisation of the fracture by intramedullary nailing.

• 1. Using sterile technique, remove the vial from its packaging.

• 2. Lift the plastic flip-top and remove the crimp from the vial.

Handle the crimp with care. The edges of the crimp are sharp and may cut or damage gloves.

• 3. Using your thumb, pry up the edge of the stopper. Once the vacuum is broken, remove the vial stopper while holding the vial upright to prevent loss of powder.

Do not insert a needle through the stopper. Puncture of the stopper with a needle may result in particles of stopper material contaminating the powder.

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

• 5. Debride fibrous, necrotic or sclerotic tissue and appropriately decorticate bone fragments so that the reconstituted Osigraft is in direct contact with bleeding bone and viable osseous tissue.

• 6. Provide adequate haemostasis to ensure that the implanted material is not dislodged from the surgical site. Irrigate as necessary prior to the implantation of Osigraft. Where practical, surgical manipulations to the site should be completed prior to implantation of the product.

• 7. Apply the reconstituted product to the prepared osseous site using a sterile instrument such as a spatula or curette. The amount of Osigraft used should approximate the size of the bone defect.

• 8. Do not use suction or irrigation directly at the implant site as the particles of Osigraft may be removed. Remove excess fluid if necessary by suctioning adjacent to.lie implant site or carefully blotting the area with sterile sponge.

• 9. Close soft tissues around the defect containing the product using suture material of choice. Closure is critical for containment of the implant in the area of the bone defect.

• 10. After closure of the soft tissues around the bone defect, irrigate field if necessary to remove any of the product which may have become dislodged during soft tissue closure.

• 11. Do not place a drain directly in the implant site. If required, place it subcutaneously.

4.3 Contraindications

Osigraft must not be used in patients who:

• • have a known hypersensiti v ity to the active substance or to collagen;
• • have skeletal immaturity;
• • have know n autoimmune disease, including rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögren’s syndrome and dermatomyositis/po­lymyositis;
• • have active infection at the site of non-union or active systemic infection;
• • have inadequate skin coverage and vascularity of the non-union site;
• • have vertebral fractures;
• • have a non-union resulting from pathological fractures, metabolic bone disease or tumours;
• • have any tumour in the vicinity of the non-union site;
• • are receiving chemotherapy, radiation treatment or immunosuppression;

Osigraft is contraindicated in children and adolescents (less than 18 years old) and the skeletally

immature (see section 4.2).

Precaution for use

Osigraft does not provide any biomechanical strength and should be used with internal or external fixation where initial mechanical stabilisation is required. However, external fixation may not provide sufficient immobilisation. Motion in the non-union site may disrupt the fracture healing process. Experience from controlled clinical trials is limited to stabilisation of tibial non-union site using concomitant intramedullary nailing. Locking intramedullary rods were used in the majority of cases.

Use of Osigraft does not guarantee repair, additional surgery may be required.

Implanted material dislodged from the non-union site can cause ectopic ossification in the surrounding tissues with potential complications. Therefore, Osigraft may only be administered to the defect site under adequate vision and with utmost care. Special care must be taken to prevent any leakage oc^ Osigraft due to wound irrigation, defective closure of surrounding tissue or inadequate haemostasis.

Antibodies

Antibodies to OP-1 protein were detected in 66% of patients in the tibial non-union study following the administration of eptotermin alfa. Analysis of these antibodies showed that 9% had neutralizing capacity. No association with clinical outcome or adverse event could be observed in clinical studies. An immune response to Osigraft should be considered and appropriate tests fo r the presence of antibodies in serum should be performed in cases where an immune-mediated undesirable effect is suspected, including cases where the product is ineffective.

Repeat Use

Repeated use of the product cannot be recommended. Studies with anti-OP-1 antibodies demonstrated some cross-reactivity with closely related BMP 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 readministration of eptotermin alfa, a risk of developing autoimmunity towards the endogenous BMP proteins may exist.

Interaction with other medicine

The use of Osigraft with a synthetic bone v oid filler may lead to a risk of increase in local inflammation, infection and occasional migration of the implanted materials and is therefore not recommended (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

The pivotal clinical trial supporting the approval of Osigraft did not include the use of synthetic bone void fillers. Post market surveillance data has signalled that the use of the product in combination with a synthetic bone v oid filler may lead to an increase in local inflammation, infection and occasional migration of the implanted materials and it is therefore not recommended.

• 4.6 F ertility, pregnancy and lactation

Women of child-bearing potential

Women of child-bearing potential should inform their surgeon of the possibility of pregnancy prior to treatment with the medicine.

Contraception in males and females

Women of childbearing potential should be advised to use effective contraception up to at least 12 months after treatment.

Pregnancy

Animal studies were conducted that cannot rule out effects of anti-OP-1 antibodies on embryo-foetal 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, Osigraft should not be used during pregnancy unless the potential benefit justifies the potential risks to the foetus (see sections 4.4 and 5.3).

Breast-feeding

In animal studies, excretion of IgG class anti-OP-1 antibodies into milk has been shown. As human IgG is secreted into human milk, and the potential for harm to the infant is unknown, women should not breast-fed during Osigraft therapy (see section 5.3). Osigraft should be given to 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.

Fertility

There is no evidence to suggest that eptotermin alfa alters fertility.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

The following table of adverse reactions was compiled from those observed and recorded during clinical trials. A similar pattern of adverse reactions has been recorded from spontaneous reporting with an incidence significantly less than that seen in the clinical trials. Some patients treated with this product were also reported to have experienced various undesirable effects associated with recent orthopaedic surgery.

The following categories are used to rank the adverse reactions by frequency of occurrence: 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); and very rare (<1/10,000), not known (cannot be estimated from the available data).

No case of overdose has been reported.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases,ne morphogenetic proteins, ATC code: M05BC02

Osigraft is an osteoinductive and osteoconductive medicinal product.

Mechanism of action

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 75–425^m. This provides an appropriate bioresorbable scaffold for the anchorage dependent cell proliferation and differentiation processes induced by the active substance. The cellular events induced by the active substance take place within the collagen matrix. The matrix is also osteoconductive and it allows bone in-growth into the defect area from the surrounding healthy bone.

Pharmacodynamic effects

The new bone formed is mechanically and radiographically comparable to normal bone. The new bone remodels naturally, cortices are formed and marrow elements are generated. However, use of Osigraft does not guarantee repair; additional surgery may be required. ~

Clinical efficacy and safety

The Tibial Nonunion pivotal trial compared Osigraft with autograft, with a primary efficr cy endpoint at 9 months post-treatment. Clinical outcomes of pain and weight-bearing were comparable to the autograft (81% success in the Osigraft group, 77% success in the autograft group). T he radiographic healing results of the Osigraft treatment group were slightly inferior compared to the autograft control group (68% and 79% respectively).

5.2 Pharmacokinetic properties

There are no data on the pharmacokinetics of the active substance in man. However, results from Osigraft implantation studies in animals demonstrate that the active substance eptotermin alfa is largely unavailable systemically.

5.3 Preclinical safety data

Single dose and repeat dose studies in a range of animal models (rats, dogs 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 implant ation study in rats, heterotopic bone formation was observed, as expected. Sarcoma was associa'ed with the long-term presence of the heterotopic bone. This effect, termed solid state carcinogenicity, frequently has been observed in rats where solid materials (plastics or metals) were implanted subcutaneously.

Heterotopic ossification commonly occurs in humans following accidental or surgical trauma. Heterotopic ossification may also occur following use (see section 4.8). However, there is evidence to suggest that heterotopic ossification is not linked to sarcoma in humans.

The effec t of anti-OP-1 antibodies on the bone healing process was studied in dogs following two long bone defects treated with repeat implantations. The results of radiological and histological examinations in this non-clinical study showed bone healing with the initial and repeat exposure in the same animal. Antibodies to OP-1 and bovine bone collagen type 1 were found after both exposures; the antibody peak concentration was higher after the second implantation. 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 developed and were found in the serum of all exposed adult animals. Antibodies to eptotermin alfa were 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. 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 product remain uncertain (see section 4.6).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Bovine collagen (vacuum dried).

6.2 Incompatibilities

In the absence of comparability studies, this medicinal product must not be mi xed with other medicinal products.

6.3 Shelf life 3 years.

The reconstituted product should be used immediately.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

6.5 Nature and contents of container and special equipment for use, administration or implantation

Powder in a glass vial (Type 1, borosilicate) sealed with a stopper (butyl rubber) and a crimp cap (aluminium). X

The primary package is maintained sterile within a blister pack, comprised of two (inner and outer) plastic trays and lids.

Pack size oi 1 vial.

6.6 Special precautions for disposal and other handling

Reconstitution

Each vial of Osigraft is reconstituted with 2 to 3 ml of sterile 9 mg/ml sodium chloride solution (0.9% w/v) prior to use. Sterile sodium chloride solution for injection and contents of the Osigraft vial are transferred to a sterile bowl and mixed with a sterile spatula or curette. To avoid breakage, do not tap the bottom of the vial when transferring contents. After reconstitution, the single use suspension for implantation should be used immediately.

Administration

When reconstituted, Osigraft has the consistency of wet sand, which facilitates its implantation and placement at bone site defects.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Olympus Biotech International Limited

40 Upper Mount Street

Dublin 2

Ireland

Tel +353 87 9278653

8. MARKETING AUTHORISATION NUMBER(S)