When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Approval of 2 Type II variations
EMEA/H/C/408/II/41 - Update SPC (4.4 & 4.8) and PIL to include warning about device migration (approved 26th March 2010)
4.1 Therapeutic indications
The following text has been added:
...
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.
4.4 Special warnings and precautions for use
Failure to follow the product preparation instructions for InductOsrhBMP-2/ACS 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 InductOsrhBMP-2/ACS. Many of these reports have occurred when InductOsrhBMP-2/ACS 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.
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-CAGE 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 (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.
4.8 Undesirable effects
Over 1490 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-marketing 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 (see section 4.4).
There have been post-marketing 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 (see section 4.4).
Nerve compression associated with ectopic bone formation has been reported in patients undergoing spine surgery with InductOs (see section 4.4).
Placement of InductOs can cause initial resorption of trabecular bone (see section 4.4 and section 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 (≥1/10) undesirable effects: accidental injury, neuralgia, back pain and bone disorder, were similar in both control and InductOs treatment groups.
Nerve compression associated with ectopic bone formation has been reported in patients undergoing spine
surgery with InductOs (see section 4.4).
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-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 groups in a study (21% versus 23% respectively).
Very common (≥1/10) undesirable effects were similar in both control and InductOs treatment groups, with the following two exceptions which were observed more frequently in the control group than in the InductOs treatment group:
• localised infection,
• and pain in extremity (both specific to the fractured limb).
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,
5.1 Pharmacodynamic properties
The following section has changed:
Pharmacodynamic information specific to acute tibia fracture studies
The efficacy of InductOs 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 InductOs 0.75 mg/ml, or standard care plus InductOs 1.5 mg/ml. Patients were followed for 12 months after soft-tissue closure.
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-care group (RR = 0.56; 95% CI =
0.40 to 0.78). These results were independentlycorroborated by a radiology panel blinded to treatment. The number of secondary and subsequent interventions was significantly reduced for the InductOs patients, particularly with regard to more invasive interventions such as bone graft and exchange nailing (P=0.0326).
In the subgroup of patients who received reamed IM nail fixation, InductOs was not observed to reduce the rate of secondary intervention. However, statistically significant differences in favour of InductOs were observed for some of the secondary efficacy variables (i.e. acceleration of the rate of fracture and soft tissue healing, and reduction of the rate of hardware failure).
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-operative, suggesting accelerated fracture healing.
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-care patients). Moreover, patients with Gustilo III fractures treated with InductOs 1.5 mg/ml had significantly less infections of the limb studied.
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 9 September 2002
Date of latest renewal: 9 September 2007
Section 4.2 Posology and method of administration - inserted 'Follow exactly the directions for preparation for each kit and use the appropriate amount of rhBMP-2/ACS for the intended indication' and 'Failure to follow the product preparation instructions for rhBMP-2/ACS may compromise its safety and effectivness. Care and caution should be used to prevent overfilling of the construct and/or intervertebral space (see section 4.4)'.
Section 4.4 Special warnings and precautions for use - inserted most of the paragraphs and deleted 4 paragraphs.
Section 4.8 Undesirable effects - inserted 'There have been post-marketing 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 rhBMP-2/ACS (see section 4.4).'
Section 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION - Inserted 'Date of first athorisation'.
Section 10 DATE OF REVISION OF THE TEXT - Inserted '29th March 2007'.