OSIGRAFT Powder for suspension for implantation Ref.[9362] Active ingredients: Eptotermin alfa

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 of 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 for 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 void 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).

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 void filler may lead to an increase in local inflammation, infection and occasional migration of the implanted materials and it is therefore not recommended.

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.

Not relevant.

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).

Musculoskeletal and connective tissue disorders: Bone formation increased (Heterotopic ossification/Myositis ossificans)

Investigations: Antibody test positive (Antibody formation)

Injury, poisoning and procedural complications: Postoperative wound site erythema (Erythema), Post procedural tenderness (Tenderness), Post procedural swelling (Swelling)

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