TruScient

TruScient is indicated for single-level lumbar interbody spine fusion as a substitute for autogenous bone graft in adults with degenerative disc disease who have had at least 6 months of non-operative treatment for this condition.

TruScient is indicated for the treatment of acute tibia fractures in adults, as an adjunct to standard care using open fracture reduction and intramedullary unreamed nail fixation.

TruScient should be used by an appropriately qualified surgeon.

Posology

TruScient must be prepared exactly in accordance with the directions for preparation.

The appropriate dose is determined by the volume of wetted matrix required for the intended indication.

If the surgical setting requires that only a portion of the product is needed, the wetted matrix should be cut to the desired size, and the unused portion must be discarded.

Dosing table for TruScient 4 mg pack

Dosing table for TruScient 12 mg pack

Lumbar interbody fusion surgery

The required volume of TruScient is determined by the intervertebral disc space and the size, shape, and internal volume of the lumbar interbody fusion device(s) being used. Care must be taken not to compress the product or overfill the volume intended for new bone formation.

Typically, 4 mg (2.7 cm³ of wetted matrix) of TruScient is used in the intervertebral disc space. The maximum dosage is limited to 8 mg (5.3 cm³ of wetted matrix) of TruScient in the intervertebral disc space. TruScient must be placed within the lumbar interbody fusion device(s) or in the anterior portion of the intervertebral disc space.

Acute tibia fracture surgery

The volume of TruScient to be implanted is determined by the fracture anatomy and the ability to close the wound without overly packing or compressing the product. Generally, each fracture site is treated with the contents of one 12 mg pack. The maximum dosage is limited to 24 mg (2 entire 12 mg pack matrices).

Paediatric population

The safety and efficacy of TruScient in children below 18 years of age have not been established.

No data are available.

Method of administration

The medicinal product is administered by implantation.

Failure to follow the method of administration of TruScient may compromise its safety and efficacy.

Forceps should be used to handle TruScient. During handling and implantation, minimize fluid loss from the matrix. Do not squeeze.

Lumbar interbody fusion surgery

TruScient must not be used alone for this indication, but should be used with an approved (CE-marked) lumbar interbody fusion device(s). Compatibility has been demonstrated with titanium, polyetheretherketone (PEEK), and allograft bone.

Care and caution must be used to prevent overfilling the lumbar interbody fusion device and/or the anterior portion of the intervertebral disc space.

Pre-Implantation

4 mg pack:

The matrix is pre-cut in 2 pieces each of 2.5 x 5 cm.

12 mg pack:

The matrix is in 1 piece of 7.5 cm x 10 cm. The wetted matrix should be cut into 6 equal pieces (approximately 2.5 x 5 cm) as an aid for dose selection. The selected pieces can be further cut as required.

The hollow geometry of the lumbar interbody fusion device must be carefully and loosely filled with the volume of TruScient corresponding to the internal volume of the device.

Implantation

As per standard practice, disc material and the cartilaginous portions of the vertebral endplates should be removed, preserving the cortical portions of the endplates, and haemostasis should be achieved.

For instructions to implant the lumbar interbody fusion device, please refer to the manufacturer's instructions for use.

TruScient must not be implanted posterior to the lumbar interbody fusion device where direct access to the spinal canal and/or nerve root(s) is possible. If leakage into the spinal canal and the nerve root is possible, a physical barrier between the matrix and any neurological tissue must be re-created by using, for example, local bone or allograft.

Post-Implantation

Once TruScient and the lumbar interbody fusion device(s) are implanted, the inside of the intervertebral disc space must not be irrigated. Outside the intervertebral disc space, the surgical field should be irrigated as needed, and any fluid loss from the wetted matrix should be washed away.

If a surgical drain is required, the drain should be placed remotely from the implantation site or, preferably, one layer superficial to the implantation site.

Acute tibia fracture surgery

Pre-Implantation

Definitive fracture reduction, fixation, and haemostasis should be achieved prior to TruScient implantation.

TruScient should be folded or cut as needed prior to implantation.

Implantation

TruScient is implanted after the completion of standard fracture and wound management (i.e. at the time of soft-tissue closure).

To the extent possible, the accessible surface area of the fracture (fracture lines and defects) should be covered with TruScient. TruScient should be placed bridging the fracture region and making good contact with the major proximal and distal fragments.

TruScient may be placed into a void (loosely packed), folded, rolled or wrapped, as the geometry of the fracture requires. TruScient does not provide mechanical stability and should not be used to fill a void in the presence of compressive forces.

Post-Implantation

Once TruScient is implanted, do not irrigate the wound.

If a surgical drain is required, the drain should be placed remotely from the implantation site or, preferably, one layer superficially to the implantation site.

To achieve maximum potential efficacy, it is important to attain complete soft-tissue coverage of TruScient following its implantation.

TruScient is contraindicated for patients with:

-

- Skeletal immaturity

- Any active malignancy or patient undergoing treatment for a malignancy

- An active infection at the operative site

- Persistent compartment syndrome or neurovascular residua of compartment syndrome

- Pathological fractures such as those observed in (but not limited to) Paget's disease or in metastatic bone

2 may compromise the safety and efficacy of TruScient.

Cervical spine surgery

The safety and efficacy of TruScient in cervical spine surgery have not been established, and TruScient should not be used in this condition. Localised oedema associated with the use of TruScient has been reported in patients undergoing cervical spine surgery. The oedema was delayed in onset and usually occurred in the first week post-operation. In some cases, the oedema was severe enough to result in airway compromise.

Malignancy

TruScient should not be used in patients with history or clinical suspicion of malignancy at the site of application.

Heterotopic ossification

Use of TruScient may cause heterotopic ossification at the site of implantation and/or the surrounding tissues, which may result in complications.

Bone resorption increased

TruScient can cause initial resorption of surrounding trabecular bone as evidenced by radiolucency. Therefore, in the absence of clinical data, the product should not be used for direct applications to trabecular bone where transient bone resorption may create a risk of bone fragility.

Fluid collections

Formation of a fluid collection (pseudocyst, localised oedema, implant site effusion), sometimes encapsulated and in some cases resulting in nerve compression and pain, has been reported associated with the use of TruScient. Clinical intervention (aspiration and/or surgical removal) may be required if symptoms persist.

Immune response

Both dibotermin alfa and bovine Type I collagen have been found to elicit immune responses in patients.

Anti-dibotermin alfa antibodies: In spine fusion studies, 1.3% of patients receiving TruScient developed antibodies to dibotermin alfa versus 0.8% of patients receiving autogenous bone graft. In long-bone fracture studies, 6.3% of patients receiving dibotermin alfa with bovine Type I collagen matrix developed antibodies to dibotermin alfa versus 1.3% in the control group. All patients who were tested for neutralizing antibodies to bone morphogenetic protein-2 were negative.

Anti-bovine Type I collagen antibodies: In spine fusion studies, 13.5% of patients receiving TruScient developed antibodies to bovine Type I collagen versus 14.3% of patients receiving autogenous bone graft. In long-bone fracture studies, 13.0% of patients receiving dibotermin alfa with bovine Type I collagen matrix developed antibodies to bovine Type I collagen versus 5.3% of control patients. None of the patients with positive titers to bovine Type I collagen had cross-reacting antibodies to human type I collagen.

Although no association with clinical outcome or undesirable effects could be observed in clinical studies, the possibility of developing neutralising antibodies or hypersensitivity-type reactions cannot be excluded. The possibility of an immune response to the product should be considered in cases where an undesirable effect with immunological background is suspected. Special consideration of risks and benefits should be given for patients who have previously received injectable collagen. In the absence of any experience, the repeat use of TruScient is not recommended.

Special populations

The safety and efficacy of the use of TruScient in patients with known autoimmune disease have not been established. These autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögren's syndrome and dermatomyositis/polymyositis.

The safety and efficacy of TruScient have not been demonstrated in patients with metabolic bone diseases.

No studies have been performed in patients with hepatic, renal or cardiac impairment.

For these special populations, the physician is advised to give a careful consideration to the benefits and risks for the specific patient before using TruScient. A close monitoring of the patient for any adverse reactions and the success of the treatment is recommended.

Excipients

This medicinal product contains less than 1 mmol (23 mg) sodium per maximum dose (two 12 mg packs), i.e. it is essentially 'sodium-free'.

Special warnings and precautions for use specific to lumbar interbody fusion

The safety and efficacy of TruScient have not been established in the following conditions:

- used with interbody fusion devices made from material other than titanium, PEEK or bone

- implanted at locations other than lumbar spine

- used in surgical techniques other than lumbar interbody fusion

To avoid exaggerated pharmacological effects of TruScient, care and caution should be used to prevent overfilling the lumbar interbody fusion device and/or the anterior portion of the intervertebral disc space.

Heterotopic ossification

Bone formation outside the intervertebral disc space is not desirable as it may have a deleterious impact on local neurovascular structures.

In clinical trials when degenerative disc disease was treated by a posterior lumbar interbody fusion procedure with dibotermin alfa, posterior bone formation was observed in CT scans. In some cases it may lead to nerve compression potentially requiring surgical intervention. As a precaution, a physical barrier between the matrix and any neurological tissue must be re-created.

Device dislocation

Device dislocation can occur after the use of TruScient in spinal fusion surgery that may necessitate surgical revision.

Special warnings and precautions for use specific to acute tibia fractures

TruScient is intended for use in patients with the following:

- adequate fracture reduction and stabilization to ensure mechanical stability

- adequate neurovascular status (e.g. absence of compartment syndrome, low risk of amputation)

- adequate haemostasis (i.e., providing a relatively dry implantation site)

- absence of large segmental defect repair of long bones, in which significant soft tissue compression can occur

The implant may only be administered to the fracture site under adequate vision and with utmost care.

Efficacy information in tibia fracture is available only from controlled clinical trials in which open tibial fractures were treated using intramedullary nail fixation. In a clinical study in which the intramedullary canal was reamed to cortical chatter, an increased rate of infection was observed in the TruScient-treated group versus the standard of care control group. The use of TruScient with reamed nails in open tibial fracture repair is not recommended.

TruScient does not provide mechanical stability and should not be used to fill a void in the presence of compressive forces. Long-bone fracture and soft-tissue management procedures should be based on standard practice, including control of infection.

TruScient has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions for TruScient in lumbar interbody fusion surgery were radiculopathic events, and in acute tibia fracture surgery it was localised infection. The most severe adverse reaction is localised oedema in cervical spine surgery. The incidence of adverse reactions with TruScient was not affected by gender, age or race.

Tabulated list of adverse reactions

Over 1700 patients have received TruScient in clinical studies. In the long-bone fracture studies, over 500 patients received TruScient. In lumbar interbody fusion studies, over 600 patients received TruScient. The remaining patients participated in studies using TruScient for indications not currently approved in the EU. These data are supplemented with information from use of TruScient in the general population.

The frequency of adverse reactions in patients exposed to treatment with TruScient is presented in the table below. Frequencies are defined as very common (>1/10) or common (>1/100 to <1/10). No reactions are observed with the frequency uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000) or very rare (<1/10,000).

The frequencies of adverse reactions identified during post-marketing use of TruScient are not known as these reactions were reported from a population of uncertain size.

¹ Observed during use in lumbar interbody fusion

² Fluid collection includes localised oedema, pseudocyst and implant site effusion.

³ Heterotopic ossification includes exostosis, extraskeletal ossification, postoperative heterotopic calcification, bone formation increased and implant site calcification.

⁴ Radiculopathic events includes radiculitis, lumbar radiculopathy, radicular pain, radiculitis lumbosacral, radiculopathy and sciatica.

⁵ Observed during use in acute tibia fractures

* Additional information provided below

Description of selected adverse reactions

New bone formation and bone remodelling

As part of the pharmacological mechanism of action of dibotermin alfa, bone remodelling occurs. In this process, both bone resorption and formation occur. In some circumstances an exaggeration of these processes can lead to complications such as nerve compression (due to heterotopic ossification) or device dislocation (associated with bone resorption or osteolysis).

During two years follow-up in clinical trials for lumbar interbody fusion using a posterior approach, heterotopic ossification seen on radiographs occurred more often in patients treated with TruScient compared with autograft. This radiographic finding may be asymptomatic or symptomatic.

Fluid collection

Due to the angiogenic activity of TruScient, fluid collection (pseudocyst, localised oedema, implant site effusion) can occur, sometimes encapsulated, sometimes resulting in nerve compression and/or pain.

Localised oedema was common when TruScient was used for cervical spine fusion. The oedema was delayed in onset and, in some cases, severe enough to result in airway compromise.

Localised infection

Localised infection specific to the fractured limb was very common (>1/10) in patients in a clinical study in which the intramedullary canal was reamed to cortical chatter.). For use with unreamed nails, estimated rates of infection were similar between treatment and control groups in a study (21% versus 23%, respectively).

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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

In case of overdose (i.e. a patient receives a concentration or amount of dibotermin alfa greater than recommended), treatment should be supportive.

Use of TruScient in patients undergoing cervical spine surgery in amounts lower than or similar to those for lumbar interbody fusion has been associated with reports of localised oedema severe enough to result in airway compromise.

Pharmacotherapeutic group: Drugs for treatment of bone diseases, Bone Morphogenetic Proteins, ATC code: M05BC01

Dibotermin alfa is an osteoinductive protein that results in the induction of new bone tissue at the site of implantation. Dibotermin alfa binds to receptors on the surface of mesenchymal cells and causes cells to differentiate into cartilage- and bone-forming cells. The differentiated cells form trabecular bone as the matrix is degraded, with vascular invasion evident at the same time. The bone formation process develops from the outside of the implant towards the centre, until the entire TruScient implant is replaced by trabecular bone.

Placement of TruScient into trabecular bone resulted in transient resorption of the bone surrounding the implant, followed by replacement with new, more dense bone. Remodeling of the surrounding bone occurs in a manner that is consistent with the biomechanical forces placed on it. The ability of TruScient to support bone remodeling may be responsible for the biological and biomechanical integration of the new bone induced by TruScient with that of the surrounding bone. Radiographic, biomechanical and histologic evaluation of the induced bone indicates that it functions biologically and biomechanically as native bone. Furthermore, non-clinical studies have indicated that the bone induced by TruScient, if fractured, can repair itself in a manner indistinguishable from native bone.

Non-clinical studies have suggested that bone formation initiated by TruScient is a self-limiting process, forming a well-defined volume of bone. This self-limitation is likely due to the loss of dibotermin alfa from the implant site, as well as the presence of BMP inhibitors in the surrounding tissues. In addition, several non-clinical studies indicate that there is a negative feedback mechanism at the molecular level that limits bone induction by BMPs.

Histological evidence from animal studies of lumbar interbody fusion using anterior or posterior surgical approaches showed dibotermin alfa administered with titanium, PEEK or allograft interbody devices was biocompatible and produced consistently high rates of fusion independent of surgical approach or device material with less fibrous tissue evident compared with autograft.

Clinical pharmacology studies demonstrate that the matrix alone is not osteoinductive and is no longer present in biopsies taken as early as 16 weeks post-implantation.

Pharmacodynamic information specific to lumbar interbody fusion studies

The efficacy and safety of TruScient were demonstrated in a randomised, controlled, multicenter, non-inferiority study of 279 patients aged 19-78 years undergoing an open anterior lumbar interbody fusion procedure. Patients had received at least six months of non-operative treatment prior to treatment with TruScient for anterior lumbar spine fusion. Patients were randomised to receive a titanium interbody fusion device filled with either TruScient or autogenous bone graft taken from the iliac crest.

At 24 months post-operation, TruScient was demonstrated to be statistically non-inferior to autogenous bone graft with a success rate for radiologically determined fusion of 94.4% for TruScient versus 88.9% for autogenous bone graft (95% two-sided CI of the difference: -1.53, 12.46). For pain and disability (Oswestry score), the success rate was 72.9% in the group using TruScient versus 72.5% in the group using autogenous bone graft (95% two-sided CI of the difference: -11.2, 12.0).

A post-hoc meta-analysis of 6 controlled clinical trials with data from patients treated with TruScient or autogenous bone graft administered using CE-marked interbody fusion devices or allograft bone spacers and various surgical approaches showed that, at 24 months post-surgery, TruScient was associated with a higher fusion success rate (95%, 241 out of 255 patients) compared with autogenous bone graft (85 %, 177 out of 209 patients), with an odds ratio of 3.26 (95% CI: 1.172, 9.075; P = 0.024). The estimated absolute difference in fusion success rate between TruScient and autogenous bone graft was 11.7% (95% CI: 0.8%, 22.5%; P = 0.035).

In a pooled safety data analysis of 8 clinical trials at 24 months post-surgery, the frequency of patients with pseudarthrosis was approximately 2-fold lower following treatment with TruScient (4.8%, 22 out of 456 patients) compared with autogenous bone graft (12.7%, 31 out of 244 patients).

Pharmacodynamic information specific to acute tibia fracture studies

The efficacy of TruScient was demonstrated in a multinational, randomized, controlled, single-blind study of 450 patients (age range 18 to 87 years; 81% male) with open tibial shaft fractures requiring surgical management. Patients received (in a 1:1:1 ratio) standard care (control group) consisting of intramedullary (IM) nail fixation and routine soft-tissue management, standard care plus TruScient 0.75 mg/ml, or standard care plus TruScient 1.5 mg/ml. Patients were followed for 12 months after soft-tissue closure.

In the acute tibia fracture pivotal trial, TruScient increased the probability of fracture healing; patients treated with TruScient 1.5 mg/ml had a 44% reduced risk for treatment failure (secondary intervention to promote fracture healing) compared with patients in the standard-care group (RR = 0.56; 95% CI = 0.40 to 0.78). These results were independently corroborated by a radiology panel blinded to treatment. The number of secondary and subsequent interventions was significantly reduced for the TruScient patients, particularly with regard to more invasive interventions, such as bone graft and exchange nailing (P = 0.0326).

The proportion of patients healed after treatment with TruScient 1.5 mg/ml was significantly higher at all visits from 10 weeks to 12 months post-operative, suggesting accelerated fracture healing.

TruScient 1.5 mg/ml was significantly effective (compared to standard care) in patients both with or without a history of smoking.

Severity of fractures: Treatment with TruScient 1.5 mg/ml was significantly effective in all fracture classes, including severe Gustilo IIIB fractures (52% reduced risk of secondary interventions as compared to standard-care patients).

The proportion of patients with healed soft-tissue wounds was significantly higher at the 6-week post-treatment visit in the TruScient 1.5 mg/ml group compared with the standard-care group (83% versus 65%; P= 0.0010). The proportion of patients with hardware failure (locking screws bent or broken) was significantly lower in the TruScient 1.5 mg/ml group as compared to standard-care group (11% versus 22%; P= 0.0174).

TruScient is active at the site of implantation. In two exploratory studies, pre- and post-surgery serum samples were collected from a few long-bone fracture patients. Dibotermin alfa was not detectable in serum.

In animal studies (rats) using TruScient containing radiolabelled dibotermin alfa, the mean residence time at the site of implantation was 4-8 days. Peak levels of circulating dibotermin alfa (0.1% of the implanted dose) were observed within 6 hours following implantation. When injected intravenously, the terminal half-life of dibotermin alfa was 16 minutes in rats and 6.7 minutes in cynomolgus monkeys. It is concluded, therefore, that at the site of implantation, dibotermin alfa is slowly released from the matrix and rapidly cleared when taken up into the systemic circulation.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated exposure toxicity and genotoxicity.

In reproductive toxicity studies in rats, where dibotermin alfa was administered intravenously to maximize systemic exposure, increased foetal weight and increased foetal ossification was observed and a treatment-related effect could not be ruled out.).

TruScient has been studied in a canine spinal implantation model. TruScient was implanted directly onto the exposed dura following a laminectomy. Although narrowing of the neuroforamen and stenosis was observed, no mineralization of the dura, no spinal cord stenosis, and no neurological deficits subsequent to the application of TruScient were observed.

TruScient is prepared immediately prior to use. Dibotermin alfa must only be used following reconstitution with the solvent and matrix provided in the TruScient pack.

Once prepared, TruScient contains dibotermin alfa at a concentration of 1.5 mg/ml.

TruScient must not be used in concentrations higher than 1.5 mg/ml.

Product preparation

To prevent overloading the matrix, it is important to reconstitute the dibotermin alfa and to wet the entire matrix as described below.

4 mg pack:

In the non-sterile field

1. Using sterile technique, place one syringe, one needle and the matrix inner package in the sterile field.

2. Disinfect the stoppers of the dibotermin alfa and solvent vials.

3. Using the remaining syringe and needle from the pack, reconstitute the dibotermin alfa vial with 3.2 ml of solvent. Slowly inject the solvent into the vial containing the lyophilised dibotermin alfa. Swirl the vial gently to aid reconstitution. Do not shake. Discard syringe and needle after use.

4. Disinfect the stopper of the reconstituted dibotermin alfa vial.

5. Peel open the interior package of the matrices and leave the matrices in their trays.

6. Using aseptic transfer technique and the syringe and needle from step 1, withdraw 2.8 ml of the reconstituted dibotermin alfa solution from the vial in the non-sterile field, holding up the inverted vial to facilitate withdrawal.

7. Leaving the matrix in its tray, UNIFORMLY distribute 1.4 ml of dibotermin alfa solution on each of the two 2.5 x 5 cm matrices, following the pattern in the figure below.

9. Wait a MINIMUM of 15 minutes before using the prepared TruScient product. The product must be used within 2 hours after preparation.

12 mg pack:

In the non-sterile field

1. Using sterile technique, place one syringe, one needle and the matrix inner package in the sterile field.

2. Disinfect the stoppers of the dibotermin alfa and solvent vials.

3. Using the remaining syringe and needle from the pack, reconstitute the dibotermin alfa vial with 8.4 ml of solvent. Slowly inject the solvent into the vial containing the lyophilised dibotermin alfa. Swirl the vial gently to aid reconstitution. Do not shake. Discard syringe and needle after use.

4. Disinfect the stopper of the reconstituted dibotermin alfa vial.

In the sterile field

5. Peel open the interior package of the matrix and leave the matrix in its tray.

6. Using aseptic transfer technique and the syringe and needle from step 1, withdraw 8.0 ml of the reconstituted dibotermin alfa solution from the vial in the non-sterile field, holding up the inverted vial to facilitate withdrawal.

7. Leaving the matrix in its tray, UNIFORMLY distribute the dibotermin alfa solution on the matrix, following the pattern in the figure below.

8. Wait a MINIMUM of 15 minutes before using the prepared TruScient product. The product must be used within 2 hours after preparation.

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