InductOs 1.5 mg/ml powder, solvent and matrix – patient leaflet, side effects, dosage

1. What InductOs is and what it is used for

InductOs contains the active substance, dibotermin alfa. It is a copy of a protein called bone morphogenetic protein 2 (BMP‑2), which is produced naturally by the body and helps with the formation of new bone tissue.

InductOs may be used either in lower back spine fusion surgery or to repair fractures of the shin bone.

Lower back spine fusion surgery

If you have a lot of pain from a damaged disc in your lower back, and other treatments have not proven effective, you may be considered for lower back spine fusion surgery. InductOs is used instead of taking a bone graft from your hip; this avoids the problems and pain that can be caused by an operation to collect the bone graft.

When used in lower back fusion surgery, InductOs is used in combination with a medical device, which corrects the position of your spine. If you have any question about the medical device, please ask your doctor.

Fractures of the shin bone

If you have broken your shin bone, InductOs is used, to help your fracture heal and to reduce the need for additional surgeries. It is used in addition to standard treatment and care of shin bone fractures.

2. What you need to know before you receive InductOs

You should not receive InductOs

• if you are allergic to dibotermin alfa or bovine collagen or any of the other ingredients of this medicine (listed in section 6).
• if you are still growing (skeletally immature).
• if you have an active infection at the surgery site.
• if the doctor treating you decides that you have inadequate blood supply at the fracture site.
• for treating a fracture that is disease‑related (e.g., fractures due to Paget’s disease or cancer).
• if you have been diagnosed with or are being treated for cancer.

Warnings and precautions to be discussed with your doctor

• You should inform your doctor if you have an autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögren’s syndrome or dermatomyositis/polymyositis.
• You should inform your doctor if you have any bone disease.

• You should inform your doctor of any history of cancer.

  • The product should not be placed in direct contact with certain types of bones. Your surgeon will know which bones to avoid.
  • Use of InductOs may cause bone formation (heterotopic ossification) in the surrounding tissues, which can result in complications.
  • Some patients may develop nerve pain due to localised fluid collection, which would require drainage or a surgical procedure to remove the fluid.
  • Some patients may develop antibodies (made by your body to fight a foreign protein) to InductOs. While no harmful effects have been noted, the long‑term effects are unknown.
  • You should inform your doctor if you have kidney or liver disease.
  • Localised swelling, in some cases resulting in breathing difficulty, has been reported in patients when InductOs has been used in surgery of the upper (neck) region of the spine. The safety and effectiveness of InductOs in spine surgery in the neck have not been established, and InductOs should not be used in this situation.

Other medicines and InductOs

Tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

The effects of InductOs on pregnancy are not known. The use of the product in pregnant women is not advised.

It is not known if InductOs passes into breast milk.

If you are pregnant or breast‑feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before receiving this medicine.

Driving and using machines

InductOs will not affect your ability to drive or operate machines.

InductOs contains bovine collagen, a protein obtained from cattle

Some patients may develop antibodies (made by your body to fight a foreign protein) against the collagen in the medicine. In clinical studies, the presence of antibodies to collagen was not associated with side effects, such as allergies, nor was it shown to decrease the effectiveness of InductOs. If you think you have an allergic reaction to collagen, contact your doctor.

InductOs contains sodium

This medicine contains less than 1 mmol (23 mg) sodium per maximum dose (two 12 mg packs), i.e. it is essentially ‘sodium‑free’.

3. How InductOs is given

The doctor treating you will implant InductOs during surgery. The medical staff will prepare InductOs in the operating room. The powder is dissolved in the sterile water to form a solution that is used to soak the sponge. The soaked sponge is then implanted where bone growth is needed. Over time, the sponge will gradually disappear as new bone is formed.

If you are receiving InductOs for lower back spine fusion, your surgeon will remove the damaged disc that is causing the pain and replace it with a medical device filled with InductOs. The medical device corrects the position of your spine, and InductOs encourages bone to grow between the two vertebrae to fix them permanently in the correct position.

If you are receiving InductOs for a broken shin bone, your doctor will place InductOs around your broken bone when your fracture is treated. The doctor will determine how much InductOs you will receive, depending on the size and number of fractures. Generally, one 12 mg pack is used; however, a maximum of two 12 mg packs may be used.

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4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Serious side effects

Tell your doctor immediately, or go immediately to the emergency department of your nearest hospital if you have localised swelling, which may result in breathing difficulties, after InductOs has been used in surgery of the upper (neck) region of your spine. The frequency of this side effect is unknown and cannot be estimated from the available data.

Other side effects

Lower back spine fusion surgery

Talk to your doctor if you have any of the following:

• Common (may affect up to 1 in 10 people): Additional bone growth, movement of the implanted medical device, localised fluid build‑up and pain radiating from your back to your leg (sciatica)
• Unknown (cannot be estimated from available data): Increased breakdown of the bone

Fractures of the shin bone

Talk to your doctor if you have any of the following:

• Very common (may affect more than 1 in 10 people): Localised infection
• Common (may affect up to 1 in 10 people): Localised fluid build‑up
• Unknown (cannot be estimated from available data): Increased breakdown of the bone

Reporting of side effects

If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store InductOs

You will not be required to store this product.

6. Contents of the pack and other information

What InductOs contains

• The active substance in InductOs is dibotermin alfa (also called recombinant human Bone Morphogenetic Protein‑2), 4 mg (4 mg pack) or 12 mg (12 mg pack).
• The other ingredients are sucrose, glycine, glutamic acid, sodium chloride, sodium hydroxide and polysorbate 80, water for injections, and bovine Type I collagen.

What InductOs looks like and contents of the pack

InductOs is supplied to your doctor as a kit for implanting during surgery.

• Dibotermin alfa is a white powder presented in a glass vial.
• Water for injections is a clear colourless liquid presented in a glass vial.

• The sponge is white and it is presented in a plastic blister.

  Marketing Authorisation Holder and Manufacturer

  Medtronic BioPharma B.V.

  Earl Bakkenstraat 10

  6422 PJ Heerlen

  The Netherlands

  This leaflet was last revised in 10/2021

  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.

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

Description of selected adverse reactions

New bone formation and bone remodelling

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. Fluid collection

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

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 of suspected adverse reactions

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

United Kingdom (Northern Ireland)

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

In case of overdose (i.e. a patient receives a concentration or amount of dibotermin alfa greater than recommended), treatment should be supportive. Use of InductOs in patients undergoing cervical spine surgery in amounts lower than or similar to those for lumbar interbody fusion has been associated with reports of localised oedema severe enough to result in airway compromise (see section 4.4).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs for treatment of bone diseases, 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‑ and bone‑forming cells. The differentiated cells form trabecular bone as the matrix is degraded, with vascular invasion evident at the same time. The bone formation process develops from the outside of the implant towards the centre, until the entire InductOs implant is replaced by trabecular bone.

Placement of InductOs into trabecular bone resulted in transient resorption of the bone surrounding the implant, followed by replacement with new, more dense bone. Remodeling of the surrounding bone occurs in a manner that is consistent with the biomechanical forces placed on it. 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, non‑clinical studies have indicated that the bone induced by InductOs, if fractured, can repair itself in a manner indistinguishable from native bone.

Non‑clinical studies have suggested that bone formation initiated by InductOs is a self‑limiting process, forming a well‑defined volume of bone. This self‑limitation is likely due to the loss of dibotermin alfa from the implant site, as well as the presence of BMP inhibitors in the surrounding tissues. In addition, several non‑clinical studies indicate that there is a negative feedback mechanism at the molecular level that limits bone induction by BMPs.

Histological evidence from animal studies of lumbar interbody fusion using anterior or posterior surgical approaches showed dibotermin alfa administered with titanium, PEEK or allograft interbody devices was biocompatible and produced consistently high rates of fusion independent of surgical approach or device material with less fibrous tissue evident compared with autograft. 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‑implantation.

Pharmacodynamic information specific to lumbar interbody fusion studies The efficacy and safety of InductOs were demonstrated in a randomised, controlled, multicenter, non‑inferiority study of 279 patients aged 19–78 years undergoing an open anterior lumbar interbody fusion procedure. Patients had received at least six months of non‑operative treatment prior to treatment with InductOs for anterior lumbar spine fusion. Patients were randomised to receive a titanium interbody fusion device filled with either InductOs or autogenous bone graft taken from the iliac crest. At 24 months post‑operation, InductOs was demonstrated to be statistically non‑inferior to autogenous bone graft with a success rate for radiologically determined fusion of 94.4% for InductOs versus 88.9% for autogenous bone graft (95% two‑sided CI of the difference: ‑1.53, 12.46). For pain and disability (Oswestry score), the success rate was 72.9% in the group using InductOs versus 72.5% in the group using autogenous bone graft (95% two‑sided CI of the difference: ‑11.2, 12.0). A post‑hoc meta‑analysis of 6 controlled clinical trials with data from patients treated with InductOs or autogenous bone graft administered using CE‑marked interbody fusion devices or allograft bone spacers and various surgical approaches showed that, at 24 months post‑surgery, InductOs was associated with a higher fusion success rate (95%, 241 out of 255 patients) compared with autogenous bone graft (85%, 177 out of 209 patients), with an odds ratio of 3.26 (95% CI: 1.172, 9.075; P = 0.024). The estimated absolute difference in fusion success rate between InductOs and autogenous bone graft was 11.7% (95% CI: 0.8%, 22.5%; P = 0.035).

In a pooled safety data analysis of 8 clinical trials at 24 months post‑surgery, the frequency of patients with pseudarthrosis was approximately 2‑fold lower following treatment with InductOs (4.8%, 22 out of 456 patients) compared with autogenous bone graft (12.7%, 31 out of 244 patients).

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 independently corroborated 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). 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). The proportion of patients with healed soft‑tissue wounds was significantly higher at the 6‑week post‑treatment visit in the InductOs 1.5 mg/ml group compared with the standard‑care group (83% versus 65%; P=0.0010). The proportion of patients with hardware failure (locking screws bent or broken) was significantly lower in the InductOs 1.5 mg/ml group as compared to standard‑care group (11% versus 22%; P=0.0174).

5.2 Pharmacokinetic properties

InductOs is active at the site of implantation. In two exploratory studies, pre‑ and post‑surgery serum samples were collected from a few long‑bone fracture patients. Dibotermin alfa was not detectable in serum.

In animal studies (rats) using InductOs containing radiolabelled dibotermin alfa, the mean residence time at the site of implantation was 4‑8 days. Peak levels of circulating dibotermin alfa (0.1% of the implanted dose) were observed within 6 hours following implantation. When injected intravenously, the terminal half‑life of dibotermin alfa was 16 minutes in rats and 6.7 minutes in cynomolgus monkeys. It is concluded, therefore, that at the site of implantation, dibotermin alfa is slowly released from the matrix and rapidly cleared when taken up into the systemic circulation.

5.3 Preclinical safety data

Non‑clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, acute and repeated exposure toxicity and genotoxicity.

In reproductive toxicity studies in rats, where dibotermin alfa was administered intravenously to maximize systemic exposure, increased foetal weight and increased foetal ossification was observed and a treatment‑related effect could not be ruled out. The clinical relevance of these effects is unknown. Anti‑dibotermin antibodies have been investigated in pregnant rabbits following hyper‑immunisation with dibotermin alfa to experimentally induce anti‑dibotermin alfa antibodies. In some foetuses with decreased body weights, there were decreases in ossification of frontal and parietal bones (4 out of 151 foetuses), which is generally considered to be reversible, and antibody related effects could not be ruled out. There were no other alterations in foetal external, visceral, or skeletal morphology.

Dibotermin alfa has demonstrated variable effects on human tumour cell lines in vitro. The available in vivo data on human tumour cell lines do not suggest a potential for promotion of tumour growth or metastasis. As a single use product, InductOs has not been tested for in vivo carcinogenicity (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.

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 in order to protect from light.

6.5 Nature and contents of container

InductOs 4 mg pack contains:

• Powder in a vial (10 ml; Type I glass) with a stopper (bromobutyl rubber).
• Solvent in a vial (10 ml; Type I glass) with a stopper (bromobutyl rubber).
• Two matrices (2.5 cm x 5 cm) in a blister package (polyvinyl chloride ‑ PVC).
• Two syringes (5 ml; polypropylene).
• Two needles (stainless steel).

6.6 Special precautions for disposal and other handling

InductOs is prepared immediately prior to use. Dibotermin alfa must only be used following reconstitution with the solvent and matrix provided in the InductOs pack. Once prepared, InductOs contains dibotermin alfa at a concentration of 1.5 mg/ml. InductOs must not be used in concentrations higher than 1.5 mg/ml (see section 4.9). Product preparation

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

4 mg pack:

In the non-sterile field

1. 1. Using sterile technique, place one syringe, one needle and the matrix inner package in the sterile field.
2. 2. Disinfect the stoppers of the dibotermin alfa and solvent vials.
3. 3. Using the remaining syringe and needle from the pack, reconstitute the dibotermin alfa vial with 3.2 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. 4. Disinfect the stopper of the reconstituted dibotermin alfa vial. In the sterile field
5. 5. Peel open the interior package of the matrices and leave the matrices in their trays.
6. 6. Using aseptic transfer technique and the syringe and needle from step 1, withdraw 2.8 ml of the reconstituted dibotermin alfa solution from the vial in the non‑sterile field, holding up the inverted vial to facilitate withdrawal.
7. 7. Leaving the matrix in its tray, UNIFORMLY distribute 1.4 ml of dibotermin alfa solution on each of the two 2.5 x 5 cm matrices, following the pattern in the figure below.
8. 8. Wait a MINIMUM of 15 minutes before using the prepared InductOs product. The product must be used within 2 hours after preparation. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Medtronic BioPharma B.V. Earl Bakkenstraat 10 6422 PJ Heerlen The Netherlands tel +31 (0) 45 566 8000 fax +31 (0) 45 566 8012

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 43872/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 01/01/2021

10 DATE OF REVISION OF THE TEXT 01/01/2021

Additional educational materials for healthcare professionals are available on the following URL: www.inductoseducationalmaterials.eu.

solvent 3.2 ml

1.4 ml 1.4 ml