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Drug Details

InductOs 12mg

• Presentation
  Kit for implant. The kit consists of a white powder for solution, a clear colourless solvent and a white matrix.
• Description
  One vial contains 12 mg dibotermin alfa*. After reconstitution, InductOs contains 1.5 mg/ml dibotermin alfa. *dibotermin alfa (recombinant human Bone Morphogenetic Protein2; rhBMP2) is a human protein derived from a recombinant Chinese Hamster Ovary (CHO) cell line.
• Indications
  

  InductOs is indicated for singlelevel (L4– S1) anterior lumbar spine fusion as a substitute for autogenous bone graft in adults with degenerative disc disease who have had at least 6 months of nonoperative treatment for this condition.

  InductOs 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.

• Adult Dosage
  

  InductOs should be used by an appropriately qualified surgeon.

  The directions for preparation for each kit should be followed exactly, using the appropriate amount of InductOs for the intended indication.

  InductOs is prepared immediately prior to use from a kit containing all necessary components. Once prepared, InductOs contains dibotermin alfa at a concentration of 1.5 mg/ml (12 mg per vial ).

  InductOs should not be used in concentrations higher than 1.5 mg/ml.

  There is very limited experience of the efficacy and safety of the medicinal product in the elderly (>65 years of age).

  Paediatric use is not recommended until further data become available.

  Product preparation

  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 kit, 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 ml of the reconstituted dibotermin alfa solution from the vial in the nonsterile 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 InductOs product. The product must be used within 2 hours after preparation.

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

  9. Follow instructions relevant to the planned surgery – anterior lumbar spine fusion or acute tibia fracture repair.

  Instructions for use in anterior lumbar spine fusion surgery

  InductOs should not be used alone for this indication, but must be used with the LTCAGE Lumbar Tapered Fusion Device.

  Failure to follow the product preparation instructions for InductOs may compromise its safety and effectiveness. Care and caution should be used to prevent overfilling of the construct and/or intervertebral space.

  Pre-Implantation

  Cut the wetted matrix of InductOs into 6 equal (approximately 2.5 x 5 cm) pieces. During cutting and handling, avoid excessive fluid loss from InductOs. Do not squeeze.

  The number of pieces of InductOs required is determined by the size of the LTCAGE Lumbar Tapered Fusion Device being used. Using the table below, identify the number of 2.5 x 5 cm pieces of InductOs required for the size of LTCAGE Lumbar Tapered Fusion Device.

  LT-CAGE Lumbar Tapered Fusion Device Size (lead diameter x length)	Number of 2.5 x 5 cm pieces of InductOs per LTCAGE Lumbar Tapered Fusion Device
  14 mm x 20 mm	1
  14 mm x 23 mm	1
  16 mm x 20 mm	1
  16 mm x 23 mm	2
  16 mm x 26 mm	2
  18 mm x 23 mm	2
  18 mm x 26 mm	2

  Implantation

  Using forceps to avoid excessive squeezing, carefully roll the required number of InductOs pieces for each LTCAGE device and insert each roll into the matching LTCAGE Lumbar Tapered Fusion Device, as shown in the figure below.

  For instructions of implantation of the LTCAGE Lumbar Tapered Fusion Device, please refer to the package leaflet for the LTCAGE device.

   

   

  Post-Implantation

  Once InductOs and the LTCAGE device are implanted, do not irrigate the wound region.

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

  Instructions for use in acute tibia fractures

  Pre-Implantation

  • Achieve definitive fracture reduction, fixation, and hemostasis prior to InductOs implantation.

  • InductOs does not provide mechanical stability and should not be used to fill spaces in the presence of compressive forces.

  • Fold or cut InductOs as needed prior to implantation. During handling, avoid excessive fluid loss from InductOs. Do not squeeze. If the surgical setting requires that only a portion of the product is needed, first prepare the entire InductOs product (following steps 18 above), cut the product to the desired size and discard the unused portion.

  Implantation

  InductOs is implanted after the completion of standard fracture and wound management, i.e., at the time of softtissue closure. The number of InductOs kits to use and the volume of InductOs to be implanted are 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 kit. The maximum dosage of InductOs is limited to 2 kits. To the extent possible, the accessible surface area of the fracture (fracture lines and defects) should be covered with InductOs. Place InductOs so that it bridges the fracture region and makes good contact with the major proximal and distal fragments. It is not necessary to overlay the contents of multiple kits to achieve the desired effect.

  During implantation, use forceps to handle InductOs to avoid excessive loss of fluid.

  InductOs may be placed into a void (loosely packed), folded, rolled, or wrapped, as the geometry of the fracture requires. Do not squeeze.

  Post-Implantation

  Once InductOs is implanted, do not irrigate the wound.

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

  In order to achieve maximum potential efficacy, it is important to achieve complete softtissue coverage of InductOs following its implantation.

• Contra Indications
  

  InductOs is contraindicated for patients with:

  • Hypersensitivity to the active substance or to any of the excipients

  • 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

• Special Precautions
  

  Failure to follow the product preparation instructions for InductOs may compromise its safety and effectiveness. Care and caution should be used to prevent overfilling of the construct and/or intervertebral space.

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

  Formation of fluid collections (pseudocysts, localised oedema, implant site effusion), sometimes encapsulated, in some cases resulting in nerve compression and pain has been reported in patients undergoing spine surgery associated with the use of InductOs. Many of these reports have occurred when InductOs was used in unapproved approaches/devices or in a manner inconsistent with the instructions for use. Clinical intervention (aspiration and/or surgical removal) may be required if symptoms persist.

  There are no data on the efficacy and safety of the product in concomitant use with bone graft.

  In the absence of any experience, the repeated use of the medicinal product is not recommended.

  Nerve compression associated with ectopic bone formation and InductOs use has been reported. Additional surgical intervention may be required.

  InductOs can cause initial resorption of surrounding trabecular bone. Therefore, in the absence of clinical data, the product should not be used for direct applications to trabecular bone when transient bone resorption may create a risk of bone fragility. When InductOs was used with the LTCAGE device in clinical trials for anterior lumbar spine fusion, the frequency and severity of resorption of bone as evidenced by radiolucencies and/or device migration was similar to that observed for patients treated with autogenous bone graft.

  Device migration can occur after the use of InductOs in spinal fusion surgery, which may necessitate surgical revision.

  Use of InductOs may cause heterotopic ossification in the surrounding tissues, which can result in complications. Exuberant bone formation at the site of implantation and ectopic bone formation have been observed.

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

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

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

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

  Anti-dibotermin alfa antibodies: In anterior lumbar spine fusion studies, 0.7% of patients receiving InductOs developed antibodies versus 0.8% of patients receiving autogenous bone graft. In acute tibia fracture studies, 4.4% of patients receiving InductOs developed antibodies versus 0.6% in the control group.

  Anti-bovine Type I collagen antibodies: In anterior lumbar spine fusion studies, 19% of patients receiving InductOs developed antibodies to bovine Type I collagen versus 13% of patients receiving autogenous bone graft. In acute tibia fracture studies,15.7% of patients receiving InductOs developed antibodies to bovine Type I collagen versus 11.8% of control patients. In either of the two indications, no patients who tested positive for antibovine Type I collagen antibodies developed antibodies to human Type I collagen.

  Although no clear association with clinical outcome or undesirable effects could be observed in clinical studies, the possibility of developing neutralising antibodies or hypersensitivitytype reactions cannot be excluded. Special consideration of risks and benefits should be given for patients who have previously received injectable collagen. The possibility of an immune response to the product should be evaluated in cases where an undesirable effect with immunological background is suspected.

   

  Special warnings and precautions for use specific to anterior lumbar spine fusion

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

  • used with spinal implants other than the LTCAGE device

  • implanted at locations other than L4 – S1 in the lower lumbar spine

  • used in surgical techniques other than anterior open or anterior laparoscopic approaches

  When degenerative disc disease was treated by a posterior lumbar interbody fusion procedure with cylindrical threaded cages and dibotermin alfa, posterior bone formation was observed in some instances.

   

  Special warnings and precautions for use specific to acute tibia fractures

  InductOs 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 hemostasis (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 InductOstreated group versus the standard of care control group. The use of InductOs with reamed nails in open tibial fracture repair is not recommended.

  InductOs does not provide mechanical stability and should not be used to fill space in the presence of compressive forces. Longbone fracture and softtissue management procedures should be based on standard practice, including control of infection.

• Interactions
  

  No interaction studies have been performed. As dibotermin alfa is a protein and has not been identified in the general circulation, it is an unlikely candidate for pharmacokinetic drugdrug interactions.

  Information from clinical studies in acute tibia fractures indicated that the use of InductOs in patients receiving glucocorticoids was not associated with any apparent adverse effect. In preclinical studies, concurrent administration of glucocorticoids depressed bone repair (measured as a % change from control), but the effects of InductOs were not altered.

  In acute tibia fracture clinical trials, more InductOs patients receiving concomitant NSAIDs for 14 consecutive days experienced mild or moderate adverse events related to wound healing (e.g., wound drainage) than InductOs patients not taking NSAIDs. Although patient outcome was not affected, an interaction between NSAIDs and InductOs cannot be excluded.

• Adverse Drug Reactions
  

  Over 1,490 patients have been evaluated in clinical studies, of which more than 955 received InductOs treatment. In the long-bone fracture studies, over 418 patients received InductOs. In the anterior lumber spine fusion studies, over 288 patients received InductOs.

  There have been postmarketing reports of localised oedema in patients undergoing cervical spine surgery associated with the use of InductOs. The oedema was delayed in onset and, in some cases, severe enough to result in airway compromise.

  There have been postmarketing reports of formation of fluid collections (pseudocysts, localised oedema, implant site effusion), sometimes encapsulated, in some cases resulting in nerve compression and pain in patients undergoing spine surgery with InductOs.

  Nerve compression associated with ectopic bone formation has been reported in patients undergoing spine surgery with InductOs.

  Radiculitis after spinal fusion surgery can occur in patients who have received InductOs.

  Device migration can occur after the use of InductOs in spinal fusion surgery, which may necessitate surgical revision. In some cases device migration has been reported in association with bone resorption and formation of fluid collections (pseudocysts, localised oedema, implant site effusion).

  Placement of InductOs can cause initial resorption of trabecular bone.

  Undesirable effects specific to use in anterior lumbar spine fusion

  The undesirable effects observed in anterior lumbar spine fusion patients were generally representative of the morbidity associated with spine fusion using autogenous bone graft taken from the iliac crest.

  Very common (1/10) undesirable effects: accidental injury, neuralgia, back pain and bone disorder, were similar in both control and InductOs treatment groups.

  Undesirable effects specific to use in acute tibia fractures

  The undesirable effects observed in long-bone fracture patients were generally representative of the morbidity associated with either orthopaedic trauma or the surgical procedure.

  Localised infection specific to the fractured limb occurred in >1/10 patients in a clinical study in which the intramedullary canal was reamed to cortical chatter. An increased rate of infection was observed in the InductOstreated group versus the standard of care control group (19% versus 9%, respectively. For use with unreamed nails, estimated rates of infection were similar between treatment groups in a study (21% versus 23%, respectively).

  Common (1/100 to <1/10 ) undesirable effects were observed with equal incidence in control and InductOs treatment groups, with the following four exceptions, which were observed significantly more frequently in the InductOs treatment group than in the control group:

  • blood amylase increased (without overt signs of pancreatitis in InductOs-treated patients)

  • tachycardia

  • hypomagnesemia

  • headache