- nonacog gamma
POM: Prescription only medicine
This information is intended for use by health professionals
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
RIXUBIS 250 IU powder and solvent for solution for injectionOne vial contains nominally 250 IU nonacog gamma, recombinant human coagulation factor IX (rDNA), corresponding to a concentration of 50 IU/ml after reconstitution with 5 ml solvent.
RIXUBIS 500 IU powder and solvent for solution for injectionOne vial contains nominally 500 IU nonacog gamma, recombinant human coagulation factor IX (rDNA), corresponding to a concentration of 100 IU/ml after reconstitution with 5 ml solvent.
RIXUBIS 1000 IU powder and solvent for solution for injectionOne vial contains nominally 1000 IU nonacog gamma, recombinant human coagulation factor IX (rDNA), corresponding to a concentration of 200 IU/ml after reconstitution with 5 ml solvent.
RIXUBIS 2000 IU powder and solvent for solution for injectionOne vial contains nominally 2000 IU nonacog gamma, recombinant human coagulation factor IX (rDNA), corresponding to a concentration of 400 IU/ml after reconstitution with 5 ml solvent.
RIXUBIS 3000 IU powder and solvent for solution for injectionOne vial contains nominally 3000 IU nonacog gamma, recombinant human coagulation factor IX (rDNA), corresponding to a concentration of 600 IU/ml after reconstitution with 5 ml solvent.The potency (IU) is determined using the European Pharmacopoeia one stage clotting assay. The specific activity of RIXUBIS is approximately 200-390 IU/mg protein.Nonacog gamma (recombinant coagulation factor IX) is a single-chain purified glycoprotein that has 415 amino acids. It is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) cell line.Excipient(s) with known effect:One vial contains 19 mg sodium.For the full list of excipients, see section 6.1.
Treatment monitoringDuring the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor IX, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.To ensure that the desired factor IX activity plasma level has been attained, careful monitoring using an appropriate factor IX activity assay is advised and, if necessary, appropriate adjustments to the dose and the frequency of repeated infusions should be performed. When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining factor IX activity in patients' blood samples, plasma factor IX activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. This is of importance particularly when changing the laboratory and/or reagents used in the assay.
PosologyDose and duration of the substitution therapy depends on the severity of the factor IX deficiency, on the location and extent of the bleeding, and on the patient's clinical condition, age and pharmacokinetic parameters of factor IX, such as incremental recovery and half-life.The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor IX in plasma).One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.
On demand treatmentThe calculation of the required dose of factor IX is based on the empirical finding that 1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 0.9 IU/dL (range from 0.5 to 1.4 IU/dL) or 0.9% of normal activity in patients 12 years and older (further information see section 5.2).The required dose is determined using the following formula:Patients 12 years and older For an incremental recovery of 0.9 IU/dL per IU/kg, the dose is calculated as follows: The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or IU/dL) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:
|Degree of haemorrhage/Type of surgical procedure||Factor IX level required (%) or (IU/dL)||Frequency of doses (hours)/Duration of therapy (days)|
|Haemorrhage Early haemarthrosis, muscle bleeding or oral bleeding More extensive haemarthrosis, muscle bleeding or haematoma Life-threatening haemorrhages.||20 40 30 60 60 100||Repeat every 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved. Repeat infusion every 24 hours for 3 4 days or more until pain and acute disability are resolved. Repeat infusion every 8 to 24 hours until threat is resolved.|
|Surgery Minor surgery including tooth extraction||30 60||Every 24 hours, at least 1 day, until healing is achieved.|
|Major surgery||80 100 (pre- and postoperative)||Repeat infusion every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor IX activity of 30% to 60% (IU/dl).|
ProphylaxisFor long-term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 40 to 60 IU of factor IX per kilogram of body weight at intervals of 3 to 4 days for patients 12 years and older. In some cases, depending upon the individual patient´s pharmacokinetics, age, bleeding phenotype and physical activity, shorter dosage intervals or higher doses may be necessary.
Continuous infusionDo not administer RIXUBIS by continuous infusion.
Paediatric populationOn demand treatment:The calculation of the required dose of factor IX is based on the empirical finding that 1 International Unit (IU) factor IX per kg body weight raises the plasma factor IX activity by 0.7 IU/dL (range from 0.31 to 1.0 IU/dL) or 0.7% of normal activity in patients less than 12 years of age (further information see section 5.2).The required dosage is determined using the following formula:Patients less than 12 years: For an incremental recovery of 0.7 IU/dL per IU/kg, the dose is calculated as follows: The same table as for adults can be used to guide dosing in bleeding episodes and surgery (see above).Prophylaxis:The recommended dose range for paediatric patients less than 12 years is 40 to 80 IU/kg at intervals of 3 to 4 days. In some cases, depending upon the individual patient´s pharmacokinetics, age, bleeding phenotype and physical activity, shorter dosage intervals or higher doses may be necessary.
Method of administrationIntravenous use.In case of self-administration or administration by a caregiver appropriate training is needed.RIXUBIS should be administered using a rate that ensures the comfort of the patient, up to a maximum of 10 ml/min.After reconstitution, the solution is clear, colourless, free from foreign particles and has a pH of 6.8 to 7.2. The osmolality is greater than 240 m osmol/kg.For instructions on reconstitution of the medicinal product before administration, see section 6.6.Only plastic luer-lock syringes should be used with this product.
Cardiovascular eventsIn patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.
Catheter-related complicationsIf a central venous access device (CAVD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
Excipient related considerationsAfter reconstitution this medicinal product contains 0.83 mmol (19 mg) sodium per vial. To be taken into consideration by patients on a controlled sodium diet.It is strongly recommended that every time that RIXUBIS is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product.
Paediatric populationThe listed warnings and precautions apply both to adults and children.
ElderlyClinical studies of RIXUBIS did not include subjects aged 65 and over. It is not known whether they respond differently from younger subjects. As for all patients, dose selection for an elderly patient should be individualised.
Summary of the safety profileHypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also 4.4).Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reactions.Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with such adverse reactions.
Tabulated list of adverse reactionsClinical studies with RIXUBIS included 99 subjects with at least one exposure to RIXUBIS reporting in total 5 adverse reactions. The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).Frequencies have been evaluated according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
|Adverse Drug Reactions, from clinical trials and spontaneous reports|
|MedDRA Standard System Organ Class||Adverse reactions||Frequency per Patient|
|Immune system disorders||Hypersensitivity a)||Not known|
|Nervous system disorders||Dysgeusia||Common|
|Musculoskeletal and connective tissue disorders||Pain in extremity||Common|
Description of selected adverse reactions
HypersensitivityAllergic type reactions have been manifested by dyspnea, pruritus, generalised urticaria and rash.
Paediatric populationFrequency, type and severity of adverse reactions in children are expected to be the same as in adults. However, no data are available on previously untreated patients as only previously treated patients have been enrolled in the clinical studies; no immunogenicity investigation on inhibitor development was therefore made in this at risk population.
Reporting of suspected adverse reactionsReporting 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with RIXUBIS in previously untreated patients in the treatment and prophylaxis of bleeding in haemophilia B (see section 4.2 for information on paediatric use).
|Parameter||RIXUBIS Initial cross-over study (N=25)||RIXUBIS Repeat Evaluation (N=23)|
|AUC0-72h (IU.hr/dL)a Mean±SD Median (range)||1067.81±238.42 1108.35 (696.07-1571.16)||1156.15±259.44 1170.26 (753.85-1626.81)|
|Incremental recovery at Cmax (IU/dL:IU/kg)b Mean ±SD Median (range)||0.87±0.22 0.88 (0.53-1.35)||0.95±0.25 0.93 (0.52-1.38)|
|Half-life (hr) Mean±SD Median (range)||26.70±9.55 24.58 (15.83-52.34)||25.36±6.86 24.59 (16.24-42.20)|
|Cmax (IU/dL) Mean±SD Median (range)||66.22±15.80 68.10 (41.70-100.30)||72.75±19.73 72.40 (38.50-106.30)|
|Mean residence time (hr) Mean±SD Median (range)||30.82±7.26 28.93 (22.25-47.78)||29.88±4.16 29.04 (21.32-37.52)|
|Vss c (dL/kg) Mean±SD Median (range)||2.02±0.77 1.72 (1.10-3.94)||1.79±0.45 1.74 (1.12-2.72)|
|Clearance (dL/(kg.hr)) Mean±SD Median (range)||0.0644±0.0133 0.0622 (0.0426-0.0912)||0.0602±0.0146 0.0576 (0.0413-0.0945)|
|Exposure Day 1 (N=73)||Week 5 (N=71)||Week 13 (N=68)||Week 26 (N=55)||At study completion/ terminationb (N=23)|
|Incremental recovery 30 min after infusion (IU/dL: IU/kg)a Mean±SD Median (range)||0.79±0.20 0.78 (0.26-1.35)||0.83±0.21 0.79 (0.46-1.48)||0.85±0.25 0.83 (0.14-1.47)||0.89±0.12 0.88 (0.52-1.29)||0.87±0.20 0.89 (0.52-1.32)|
Paediatric population (previously treated patients younger than 12 years)All 23 male subjects underwent an initial pharmacokinetic evaluation of RIXUBIS in a non-bleeding state as part of the combined phase 2/3 paediatric study. Subjects were randomised to one of two blood sampling sequences to reduce the burden of frequent blood draws on the individual subjects. The mean (± SD) and median dose of RIXUBIS in the full analysis set (n=23) was 75.50 ± 3.016 and 75.25 IU/kg, respectively, with a range of 70.0 to 83.6 IU/kg. The pharmacokinetic parameters were calculated from factor IX activity measurements in blood samples obtained up to 72 hours following the infusion.Pharmacokinetic parameters for all subjects (full analysis set) are presented in the table below.
|Parameter||< 6years (N=11)||6 - < 12 years (N=12)||All (N=23)|
|AUCinf (IU.hr/dL)a Mean±SD Median (range)||723.7 ± 119.00 717.2 (488-947)||886.0 ± 133.66 863.7 (730-1138)||808.4 ± 149.14 802.9 (488-1138)|
|Half-life (hr) Mean±SD Median (range)||27.67 ± 2.66 27.28 (24.0-32.2)||23.15 ± 1.58 22.65 (21.8-27.4)||25.31 ± 3.13 24.48 (21.8-32.2)|
|Mean residence time (hr) Mean±SD Median (range)||30.62 ±3.27 30.08 (26.2-36.2)||25.31 ± 1.83 24.74 (23.7-30.3)||27.85 ± 3.73 26.77 (23.7-36.2)|
|Vss b (dL/kg) Mean±SD Median (range)||3.22 ± 0.52 3.16 (2.65-4.42)||2.21 ± 0.32 2.185 (1.70-2.70)||2.7 ± 0.67 2.69 (1.70-4.42)|
|Clearance (dL/(kg.hr)) Mean±SD Median (range)||0.1058 ± 0.01650 0.1050 (0.081-0.144)||0.0874 ± 0.01213 0.0863 (0.069-0.108)||0.0962 ± 0.01689 0.0935 (0.069-0.144)|
|Incremental recovery 30 min after infusion||PK (ED 1) All (N=22)||Week 5 All (N=23)||Week 13 All (N=21)||Week 26 All (N=21)|
|(IU/dL: IU/kg)a Mean±SD Median (range)||0.67 ±0.16 0.69 (0.31 1.00)||0.68 ± 0.12 0.66 (0.48 0.92)||0.71 ± 0.13 0.66 (0.51-1.00)||0.72 ± 0.15 0.734 (0.51-1.01)|
|Incremental recovery 30 min after infusion||PK (ED 1) All (N=10)||Week 5 All (N=11)||Week 13 All (N=10)||Week 26 All (N=10)|
|(IU/dL: IU/kg)a Mean±SD Median (range)||0.59 ± 0.13 0.59 (0.31-0.75)||0.63 ± 0.10 0.6 (0.49-0.80)||0.68 ± 0.12 0.66 (0.51-0.84)||0.65 ± 0.13 0.61 (0.51-0.84)|
|Incremental recovery 30 min after infusion||PK (ED 1) All (N=12)||Week 5 All (N=12)||Week 13 All (N=11)||Week 26 All (N=11)|
|(IU/dL: IU/kg)a Mean±SD Median (range)||0.73 ± 0.16 0.71 (0.51-1.00)||0.73 ± 0.13 0.70 (0.48-0.92)||0.73 ± 0.14 0.70 (0.54 1.00)||0.8 ± 0.14 0.78 (0.56-1.01)|
PowderSucroseMannitolSodium chlorideCalcium chlorideL-HistidinePolysorbate 80
SolventSterilised water for injections
ReconstitutionUse Aseptic Technique1. If the product is stored in a refrigerator, take both the RIXUBIS powder and solvent vials from the refrigerator and let them reach room temperature (between 15°C and 30°C).2. Wash your hands thoroughly using soap and warm water.3. Remove caps from powder and solvent vials.4. Cleanse stoppers with alcohol swabs. Place the vials on a flat clean surface.5. Open the package of BAXJECT II device by peeling away the paper lid without touching the inside (Fig. a). Do not remove the device from the package.6. Turn the package over and insert the clear plastic spike through the solvent stopper. Grip the package at its edge and pull the package off BAXJECT II (Fig. b). Do not remove the blue cap from the BAXJECT II device.7. With BAXJECT II attached to the solvent vial, invert the system so that the solvent vial is on top of the device. Insert the white plastic spike through the RIXUBIS stopper. The vacuum will draw the solvent into the RIXUBIS vial (Fig. c).8. Swirl gently until all material is dissolved. The product dissolves rapidly (within 2 minutes). Be sure that RIXUBIS is completely dissolved, otherwise not all reconstituted solution will pass through the device filter. Reconstituted medicinal products should be inspected visually for particulate matter and discoloration prior to administration. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Do not refrigerate the preparation after reconstitution.Use immediately. Administration Use Aseptic Technique1. Remove the blue cap from BAXJECT II. Do not draw air into the syringe. Connect the syringe to BAXJECT II (Fig. d).2. Invert the system (the vial with the reconstituted solution has to be on top). Draw the reconstituted solution into the syringe by pulling the plunger back slowly (Fig. e).3. Disconnect the syringe.4. Attach a butterfly needle to the syringe. Inject intravenously. The solution should be administered slowly, at a rate as determined by the patient's comfort level, not to exceed 10 ml per minute. Whenever possible, please record the name of the product and the batch number every time you use RIXUBIS (e.g. in your diary) to keep track of the products and product batches you have used.Any unused medicinal product or waste material should be disposed of in accordance with local requirements.