Dibotermin alfa interacts in the following cases:
In acute tibia fracture clinical trials, more dibotermin alfa patients receiving concomitant NSAIDs for 14 consecutive days experienced mild or moderate adverse events related to wound healing (e.g., wound drainage) than dibotermin alfa patients not taking NSAIDs. Although patient outcome was not affected, an interaction between NSAIDs and dibotermin alfa cannot be excluded.
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 dibotermin alfa is not recommended as this may lead to bone formation at the site of implant of the fibrin-based haemostatic agent or sealant.
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.
There are no or limited amount of data from the use of dibotermin alfa in pregnant women.
Animal studies have shown reproductive toxicity.
Due to the unknown risks to the foetus associated with the potential development of neutralising antibodies to dibotermin alfa, dibotermin alfa is not recommended during pregnancy and in women of childbearing potential not using contraception.
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 dibotermin alfa 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.
Dibotermin alfa has no or negligible influence on the ability to drive and use machines.
The most common adverse reactions for dibotermin alfa 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 dibotermin alfa was not affected by gender, age or race.
Over 1,700 patients have received dibotermin alfa in clinical studies. In the long-bone fracture studies, over 500 patients received dibotermin alfa. In lumbar interbody fusion studies, over 600 patients received dibotermin alfa. The remaining patients participated in studies using dibotermin alfa for indications not currently approved in the EU. These data are supplemented with information from use of dibotermin alfa in the general population.
The frequency of adverse reactions in patients exposed to treatment with dibotermin alfa is presented in the list 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 dibotermin alfa 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. 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 dibotermin alfa compared with autograft. This radiographic finding may be asymptomatic or symptomatic.
Due to the angiogenic activity of dibotermin alfa, 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 dibotermin alfa 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 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 dibotermin alfa-treated 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 and control groups in a study (21% versus 23%, respectively).
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