Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Medtronic BioPharma B.V., Earl Bakkenstraat 10, 6422 PJ Heerlen, The Netherlands, tel +31 (0) 45 566 8000, fax +31 (0) 45 566 8012
InductOs is contraindicated for patients with:
Failure to follow the product preparation instructions in section 6.6 and the method of administration in section 4.2 may compromise the safety and efficacy of InductOs.
The safety and efficacy of InductOs in cervical spine surgery have not been established, and InductOs should not be used in this condition. Localised oedema associated with the use of InductOs 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.
InductOs should not be used in patients with history or clinical suspicion of malignancy at the site of application (see section 4.3).
Use of InductOs may cause heterotopic ossification at the site of implantation and/or the surrounding tissues, which may result in complications.
InductOs 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 (see section 4.8).
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 InductOs. Clinical intervention (aspiration and/or surgical removal) may be required if symptoms persist (see section 4.8).
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 InductOs 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 InductOs 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 (see section 4.3). In the absence of any experience, the repeat use of InductOs is not recommended.
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, 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 InductOs. A close monitoring of the patient for any adverse reactions and the success of the treatment is recommended.
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’.
The safety and efficacy of InductOs have not been established in the following conditions:
To avoid exaggerated pharmacological effects of InductOs, care and caution should be used to prevent overfilling the lumbar interbody fusion device and/or the anterior portion of the intervertebral disc space.
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 (see section 4.8). As a precaution, a physical barrier between the matrix and any neurological tissue must be re-created (see section 4.2).
Device dislocation can occur after the use of InductOs in spinal fusion surgery that may necessitate surgical revision (see section 4.8).
InductOs is intended for use in patients with the following:
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-treated group versus the standard of care control group (see section 4.8). 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 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.
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-drug interactions.
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.
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 reactions. In non-clinical studies, concurrent administration of glucocorticoids depressed bone repair (measured as a % change from control), but the effects of InductOs were not altered.
In an in vitro study, dibotermin alfa was shown to bind to fibrin-based haemostatic agents or sealants. The use of these products in close proximity to InductOs is not recommended as this may lead to bone formation at the site of implant of the fibrin-based haemostatic agent or sealant (see section 4.2).
There are no or limited amount of data from the use of dibotermin alfa in pregnant women.
Animal studies have shown reproductive toxicity (see section 5.3).
Due to the unknown risks to the foetus associated with the potential development of neutralising antibodies to dibotermin alfa, InductOs is not recommended during pregnancy and in women of childbearing potential not using contraception (see section 4.4).
There is no information on the excretion of dibotermin alfa/metabolites in human milk. Considering the type of product, systemic exposure of the suckling infant is not expected, however a risk to the newborn/infant cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to abstain from InductOs therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
No impact on fertility was detected in non-clinical studies. No clinical data are available; potential risk for human is unknown.
InductOs has no or negligible influence on the ability to drive and use machines.
The most common adverse reactions for InductOs 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 InductOs was not affected by gender, age or race.
Over 1700 patients have received InductOs in clinical studies. In the long-bone fracture studies, over 500 patients received InductOs. In lumbar interbody fusion studies, over 600 patients received InductOs. The remaining patients participated in studies using InductOs for indications not currently approved in the EU. These data are supplemented with information from use of InductOs in the general population.
The frequency of adverse reactions in patients exposed to treatment with InductOs 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 InductOs are not known as these reactions were reported from a population of uncertain size.
Common: Device dislocation1*, Fluid collection2*
Common: Heterotopic ossification1,3*
Unknown: Osteolysis*, Resorption bone increased*
Common: Radiculopathic events1,4
Very common: Localised infection5*
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
As part of the pharmacological mechanism of action of dibotermin alfa, bone remodelling occurs (see section 5.1). 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 InductOs compared with autograft (see section 4.4). This radiographic finding may be asymptomatic or symptomatic.
Due to the angiogenic activity of InductOs, 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 InductOs was used for cervical spine fusion. The oedema was delayed in onset and, in some cases, severe enough to result in airway compromise (see section 4.4).
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. An increased rate of infection was observed in the InductOs-treated group versus the standard of care control group (19% versus 9%, respectively; see section 4.4). For use with unreamed nails, estimated rates of infection were similar between treatment and control groups in a study (21% versus 23%, respectively).
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 listed in Appendix V.
This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
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