1. Name Of The Medicinal Product
InductOs 12 mg kit for implant
2. Qualitative And Quantitative Composition
One vial contains 12 mg dibotermin alfa*. After reconstitution, InductOs contains 1.5 mg/ml dibotermin alfa.
*dibotermin alfa (recombinant human Bone Morphogenetic Protein
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Kit for implant.
The kit consists of a white powder for solution, a clear colourless solvent and a white matrix.
4. Clinical Particulars
4.1 Therapeutic Indications
InductOs is indicated for single
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.
See section 5.1.
4.2 Posology And Method Of Administration
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 (see section 4.9).
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 non
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 LT
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 (see section 4.4).
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 LT
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Implantation
Using forceps to avoid excessive squeezing, carefully roll the required number of InductOs pieces for each LT
For instructions of implantation of the LT
Post-Implantation
Once InductOs and the LT
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 1
Implantation
InductOs is implanted after the completion of standard fracture and wound management, i.e., at the time of soft
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 soft
4.3 Contraindications
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
4.4 Special Warnings And Precautions For Use
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 (see section 4.8).
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 LT
Device migration can occur after the use of InductOs in spinal fusion surgery, which may necessitate surgical revision (see section 4.8).
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 (see section 4.3).
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 anti
Although no clear association with clinical outcome or undesirable effects could be observed in clinical studies, the possibility of developing neutralising antibodies or hypersensitivity
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 LT
• 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 (see section 4.2).
Efficacy information in tibia fracture is available only from controlled clinical trials in which open tibial fractures were treated using intramedullary nail fixation (see section 5.1). In a clinical study in which the intramedullary canal was reamed to cortical chatter, an increased rate of infection was observed in the InductOs
InductOs does not provide mechanical stability and should not be used to fill space in the presence of compressive forces. Long
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 drug
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.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of dibotermin alfa in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Animal studies have been conducted that cannot rule out effects of anti
Lactation
It is unknown whether dibotermin alfa is excreted in human breast milk. The excretion of dibotermin alfa has not been studied in animals. Lactation is not recommended during treatment with InductOs.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed, but since InductOs has no systemic effect, it is not likely to interfere with the ability to drive or use machinery.
4.8 Undesirable Effects
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 post
There have been post
Nerve compression associated with ectopic bone formation has been reported in patients undergoing spine surgery with InductOs (see section 4.4).
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 (see section 4.4). 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 (see sections 4.4 and 5.1).
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 (
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 InductOs
Common (
• blood amylase increased (without overt signs of pancreatitis in InductOs-treated patients)
• tachycardia
• hypomagnesemia
• headache
4.9 Overdose
Use of InductOs in patients undergoing cervical spine surgery in concentrations or amounts greater than those recommended in section 4.2 for the approved indications has been associated with reports of localised oedema (see section 4.4).
In the case of patients receiving concentrations or amounts greater than those recommended, treatment should be supportive.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: 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
Remodeling of the surrounding trabecular bone occurs in a manner that is consistent with the biomechanical forces placed on it. Placement of InductOs into trabecular bone resulted in transient resorption of the bone surrounding the implant, followed by replacement with new, more dense bone. The ability of InductOs to support bone remodeling may be responsible for the biological and biomechanical integration of the new bone induced by InductOs 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, preclinical studies have indicated that the bone induced by InductOs, if fractured, can repair itself in a manner indistinguishable from native bone.
Preclinical studies have suggested that bone formation initiated by InductOs is a self
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
Pharmacodynamic information specific to anterior lumbar spine fusion studies
The efficacy and safety of InductOs were demonstrated in a randomised, controlled, multicenter, non
At 24 months post
1. Radiographically demonstrated fusion
2. Oswestry pain/disability improvement
3. Maintenance or improvement in neurological status
4. No Grade 3 or 4 adverse event classified as implant
5. No additional surgical procedure performed that was classified as a “failure”
At 24 months post
An additional, non
Pharmacodynamic information specific to acute tibia fracture studies
The efficacy of InductOs was demonstrated in a multinational, randomized, controlled, single
In the acute tibia fracture pivotal trial, InductOs increased the probability of fracture healing; patients treated with InductOs 1.5 mg/ml had a 44% reduced risk for treatment failure (secondary intervention to promote fracture healing) compared with patients in the standard
The proportion of patients healed after treatment with InductOs 1.5 mg/ml was significantly higher at all visits from 10 weeks to 12 months post
InductOs 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 InductOs 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
The proportion of patients with healed soft
5.2 Pharmacokinetic Properties
InductOs is active at the site of implantation. In two exploratory studies, pre- and post
In animal studies (rats) using InductOs containing radiolabelled dibotermin alfa, the mean residence time at the site of implantation was 4
5.3 Preclinical Safety Data
Non
In reproductive toxicity studies in rats, where dibotermin alfa was administered intravenously to maximize systemic exposure, increased fetal weight and increased fetal ossification was observed and a treatment-related effect could not be ruled out. The clinical relevance of these effects is unknown.
Anti-immunisation with dibotermin alfa to experimentally induce anti-BMP
InductOs has not been tested for in vivo carcinogenicity. Dibotermin alfa has demonstrated variable effects on human tumour cell lines in vitro. Although the available in vitro data suggest a low potential for promotion of tumour growth, the use of InductOs is contraindicated in patients with an active malignancy or in patients undergoing treatment for a malignancy (see also section 4.3).
InductOs has been studied in a canine spinal implantation model. InductOs 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 InductOs were observed. The significance of these data for humans is not known.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Powder:
Sucrose
Glycine
Glutamic acid
Sodium chloride
Polysorbate 80
Sodium hydroxide
Solvent:
Water for injections
Matrix:
Bovine Type I collagen
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
6.3 Shelf Life
3 years
6.4 Special Precautions For Storage
Do not store above 30 ° C. Do not freeze.
Store in the original package.
6.5 Nature And Contents Of Container
Each kit of InductOs is provided with:
• 12 mg of sterile dibotermin alfa powder in a 20 ml vial (Type I glass) stoppered with a bromobutyl rubber closure sealed with an aluminum flip
• Solvent for reconstitution in a 10 ml vial (Type I glass) stoppered with a bromobutyl rubber closure sealed with an aluminum flip
• One sterile matrix in a polyvinyl chloride (PVC) blister package sealed with a Tyvek lid.
• Two sterile 10 ml disposable polypropylene syringes.
• Two sterile needles (stainless steel).
6.6 Special Precautions For Disposal And Other Handling
Any unused product or waste material should be disposed of in accordance with local requirements.
Dibotermin alfa must be used only with the accompanying solvent and matrix provided in the InductOs kit. See section 4.2.
7. Marketing Authorisation Holder
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
8. Marketing Authorisation Number(S)
EU/1/02/226/001
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 9 September 2002
Date of latest renewal: 9 September 2007
10. Date Of Revision Of The Text
31/08/2010
Detailed information on this product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu
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