RIXUBIS - Recombinant Coagulation Factor IX (rFIX)
Contents
1. 56 3 7 2 Median range 54 0 50 83 The prophylactic regimen consisted of 40 to 60 IU kg RIXUBIS twice weekly The individual dose could be increased up to 75 IU kg twice weekly On Demand Treatment RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 22 of 30 An additional 14 PTPs from an on demand cohort received RIXUBIS for treatment of bleeding episodes only Subjects in this cohort had to have at least 12 documented bleeding episodes requiring treatment within 12 months prior to enrollment The mean treatment duration was 3 5 1 00 months median 3 4 ranging from 1 2 to 5 1 months and the mean total annualized bleeding rate ABR was 33 9 17 37 with a median of 27 0 ranging from 12 9 to 73 1 Treatment of Bleeding Episodes in PTPs gt 12 Years of Age A total of 249 bleeding episodes were treated with RIXUBIS of which 115 were recorded for subjects who had breakthrough bleeding episodes while on prophylaxis and 134 bleeds were recorded for those who received on demand treatment only There were 197 were joint bleeds and 52 non joint bleeds soft tissue muscle body cavity intracranial and other Of the total of 249 bleeding episodes 163 were moderate 71 were minor and 15 were major Treatment was individualized based on the severity cause and site of bleed Of the total of 249 bleeding episodes the majority 211 84 7 were treated with 1 2 infusions Hemostatic efficacy at resolutio2. Structural BAX 326 AA position formula 1 145 181 415 4618 GLA EGF1 EGF2 Serine Protease v o i L vv a y Carboxyglutamate partial O Glu7 Glu8 Glu15 Glu17 Glu20 Glu21 gt Glu26 Glu27 Glu30 Glu33 Glu36 Glu40 ca A O glycosylation 2 Ser53 Ser61 9 O glycosylation partial Thr159 Thr169 Thr172 Thr179 N glycosylation a Asn157 Asn167 ro a A mature FIX 56 kDa Sulfation partial FIX light chain 19 kDa Tyr155 FIX heavy chain 28 kDa Hydroxylation partial activation peptide 11 kDa Asp64 Physicochemical RIXUBIS is synthesized in the production CHO cells as a single chain properties polypeptide and secreted in its mature 415 amino acid form into the fermentation medium The molecule consists of several discrete functional domains including a Gla domain two epidermal growth factor EGF domains an activation peptide and the catalytic domain As in other vitamin K dependent proteins RIXUBIS undergoes a number of post translational maturation events prior to secretion cleavage of pre pro leader sequence glycosylation gamma carboxylation and partial sulfation and hydroxylation RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 19 of 30 Product Characteristics RIXUBIS Recombinant Coagulation Factor IX rFIX is a purified protein produced by recombinant DNA technology It has a primary amino acid sequence that is identical to the Ala 148 allelic form o
3. factor X containing product and were not associated with adverse events DETAILED PHARMACOLOGY See ACTION AND CLINICAL PHARMACOLOGY MICROBIOLOGY Not applicable RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 24 of 30 TOXICOLOGY Carcinogenesis Mutagenesis Impairment of Fertility Nonclinical studies evaluating the carcinogenic and mutagenic potential of RIXUBIS have not been conducted No adverse effects on reproductive organs were observed by macroscopic and microscopic pathological investigations in repeated dose toxicity studies No investigations on impairment of fertility have been conducted REFERENCES 1 Roberts HR Eberst ME Current management of hemophilia B Hematol Oncol Clin North Am 1993 7 6 1269 1280 2 Ware JE Jr Kosinski M Bjorner JB Turner Bowker DM Gandek B Maruish ME User s Manual for the SF 36v2 Health Survey 2nd ed Lincoln RI QualityMetric Incorporated 2007 3 Wasley LC Rehemtulla A Bristol JA Kaufman RJ PACE furin can process thevitamin K dependent pro factor IX precursor within the secretory pathway J Biol Chem 1993 268 8458 8465 2 RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 25 of 30 PART Ill CONSUMER INFORMATION RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma This leaflet is part III of a three part Product Monograph published when RIXUBIS was approved for sale in Canada and is designed specifica
4. for effective hemostasis The activated partial thromboplastin time aPTT is prolonged in people with hemophilia B Treatment with factor IX concentrate may normalize the aPTT by temporarily replacing the factor IX Pharmacodynamics The administration of RIXUBIS increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients by decreasing aPTT Pharmacokinetics PTPs gt 12 Years of Age A randomized blinded controlled crossover pharmacokinetic study of RIXUBIS and another commercial recombinant factor IX product was conducted in non bleeding subjects 15 years of age The subjects received either of the products as an IV infusion The dose range of RIXUBIS and another recombinant factor IX product ranged from 71 27 to 79 38 IU kg and 70 12 to 80 RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 15 of 30 IU kg respectively The pharmacokinetic parameters were calculated from factor IX activity measurements in blood samples obtained up to 72 hours following each infusion The pharmacokinetics evaluation was repeated for RIXUBIS in an open label uncontrolled study with RIXUBIS in subjects who participated in the initial study and had received RIXUBIS for 26 1 mean SD weeks for prophylaxis and accumulated at least 30 exposure days to RIXUBIS The RIXUBIS dose range in the repeat pharmacokinetic study was 64 48 to 79 18 IU kg Pharmacokinetic parameters for evaluab
5. part bleach and 9 parts water soap and water or any household disinfecting solution 13 Dispose of the used vials and BAXJECT II system in your hard walled Sharps container without taking them apart Do not dispose of these supplies in ordinary household trash You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways Report online at www healthcanada gc ca medeffect Call toll free at 1 866 234 2345 Complete a Canada Vigilance Reporting Form and Fax toll free to 1 866 678 6789 or Mail to Canada Vigilance Program Health Canada Postal Locator 0701D Ottawa Ontario K1A 0K9 Postage paid labels Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect Canada Web site at www healthcanada gc ca medeffect NOTE Should you require information related to the management of side effects contact your health professional The Canada Vigilance Program does not provide medical advice RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 29 of 30 MORE INFORMATION Th This document plus the full product monograph prepared for health professionals can be found by contacting the sponsor Baxalta Canada Corporation at 1 800 387 8399 This leaflet was prepared by Baxalta Canada Corporation Last revised June 05 2015 RIXUBIS Recombinant Coagulation Fa
6. pooled normal human plasma The specific activity of RIXUBIS is greater than or equal to 200 IU per milligram of protein RIXUBIS is formulated as a sterile nonpyrogenic lyophilized powder preparation RIXUBIS is intended for intravenous IV infusion It is available in single use vials containing the labeled amount of factor IX activity expressed in IU Factor IX preactivation the percent of FIXa FIX as measured by activity assays is lt 0 10 Each vial contains nominally 250 500 1000 2000 or 3000 IU of Coagulation Factor IX Recombinant After reconstitution of the lyophilized drug product the concentrations of excipients are 20 mM L histidine 60 mM sodium chloride 4 mM calcium chloride 110 mM mannitol 35 mM sucrose 0 005 polysorbate 80 All dosage strengths yield a clear colorless solution upon reconstitution Viral Inactivation RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 20 of 30 Three barriers have been introduced to the manufacture of rFIX to prevent viruses from entering the final product 1 testing for adventitious viruses performed on the cell culture bulk harvest 2 the Solvent Detergent S D treatment step used in the rFIX BDS purification process and 3 a 15 nm nanofiltration step S D treatment and nanofiltration are dedicated effective virus inactivation removal steps and have been introduced to provide an additional safety margin for the final product Complete inactivation to bel
7. 50 days received at least 1 infusion of RIXUBIS for either on demand treatment of bleeding episodes in the perioperative management of major and minor surgical dental or other invasive procedures for routine prophylaxis or for the evaluation of the pharmacokinetics of RIXUBIS Six subjects 6 6 were lt 6 years of age 10 11 0 were 6 to lt 12 years of age 3 3 3 were adolescents 12 to lt 16 years of age and 72 79 1 were adults 16 years of age and older Ninety one treated subjects received a total of 7 353 infusions with a median of 85 infusions of RIXUBIS range 3 to 212 infusions and for a median of 83 exposure days range 83 to 209 days A total of 161 adverse events were reported in 48 52 7 of the 91 subjects Adverse reactions that occurred in gt 1 of subjects are shown in Table 1 Table 1 Summary of Adverse Reactions Number of Percent Number Subjects per System Organ Class SOC Events Ea N 91 Infusion n N 7353 Nervous System Disorders Dysgeusia 2 1 1 1 0 03 Musculoskeletal and Pain in extremity 1 1 1 1 0 01 Comnective Tissue Disorders Investigations Furin antibody test positive 1 1 1 1 0 01 See Immunogenicity RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 7 of 30 Immunogenicity All 91 subjects were monitored for inhibitory and binding antibodies to factor IX and binding antibodies to CHO protein and furin at the followi
8. CT II device Figure E Do not inject air 2 Turn the system upside down factor concentrate vial now on top Draw the factor concentrate into the syringe by pulling the plunger back slowly Figure E 3 Disconnect the syringe attach a suitable needle and inject intravenously as instructed under Administration by Bolus Infusion If a patient is to receive more than one vial of RIXUBIS the contents of multiple vials may be drawn into the same syringe 4 Maximum infusion rate of 10 mL min Figure A RIXUBIS is a white or almost white lyophilized powder which is supplied in single dose vials 250 IU 500 IU 1000 IU 2000 IU or 3000 IU Reconstitution using BAXJECT II Vial Si Volume of Diluent to Approximate Nominal TERIER be Added to Vial Available Volume Concentration per mL 50 U ml RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 14 of 30 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL 5 mL OVERDOSAGE No symptoms of overdose have been reported As with other products of the same class overdose may increase the risk for thrombotic and thromboembolic events e g DIC pulmonary embolism venous thrombosis and arterial thrombosis For management of a suspected drug overdose contact your regional Poison Control Centre ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action RIXUBIS temporarily replaces the missing clotting factor IX that is needed
9. ICAL TRIALS alas 21 DETAILED PHARMACOLOGY oiei r i a a a ii ds 24 MICROBIOLOG Y ta AAA A ai 24 TOXICOLOG Yo At ts 23 RERERENCE SR eee eee ee eee Cpr aer er aeee 25 PART TI CONSUMER INFORMA TION coccisiiciinnicaai aia ci 26 RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 2 of 30 RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma PART I HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form Clinically Relevant Nonmedicinal Administration Strength Ingredients For a complete listing see Dosage Forms Composition and Packaging section Intravenous Injection Lyophilized Powder for Intravenous injection 250 500 1000 2000 3000 International Units IU per vial reconstituted with 5 mL of water for injection DESCRIPTION RIXUBIS Recombinant Coagulation Factor IX rFIX is a glycoprotein consisting of 415 amino acids RIXUBIS is synthesized by a genetically engineered Chinese hamster ovary CHO cell line No exogenous materials of human or animal origin are employed in the manufacture purification or formulation of the final product The growth medium is chemically defined and the downstream process does not use monoclonal antibodies for the purification of RIXUBIS The production process also includes two independent viral removal inactivation steps solvent detergent treatment and nanofiltration Biological potency is determined by a one stage cl
10. Method for Calculating Initial Estimated Dose A guide for calculating the dose for treatment of bleeding episodes is provided in Table 2 RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 9 of 30 Table 2 Method for Calculating Initial Estimated Dose Number of factor Desired factor Reciprocal IX International Body Weight of Observed IX increase Units required kg x or IU dL x recovery IU IU kg per IU dL The calculation of the required dose of RIXUBIS is based on the empirical finding that one international unit of RIXUBIS per kg body weight is expected to increase the circulating level of factor IX by 0 9 IU dL of plasma 0 9 of normal range from 0 5 to 1 4 IU dL in patients 12 years and older Incremental Recovery in Previously Treated Patients PTPs For an incremental recovery of 0 9 IU dL of plasma 0 9 of normal the dose is calculated as follows Table 3 Calculating Incremental Dose Adjustment Number of factor IX Desired factor International Units Body Weight required kg x IX increase a 1 1 dL kg IU or IU dL It is recommended to base the calculation of the required dose on the patient s individual incremental recovery using serial factor IX activity assays due to the wide range of inter individual differences in incremental recovery Titrate the dose based on the patient s clinical response and individual pharmacokinetics in
11. PRODUCT MONOGRAPH RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Lyophilized Powder 250 500 1000 2000 and 3000 International Units 1U per vial Coagulant Manufactured by Imported and Distributed by Date of Revision Baxalta U S Inc ON Canada eee June 04 2015 Westlake Village CA 23 Mississauga Koa 91362 Mississauga ON Canada L5N 0C2 USA Submission Control No 183079 Date of Approval Jun 05 2015 RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page l of 30 Table of Contents PART I HEALTH PROFESSIONAL INFORMATION ooncncocconnonnonnonnoaconoonosnncnocnncanonnosncnnosos 3 SUMMARY PRODUCT INFORMATION 0 csssescosctevsosnsossvesnsotesvesessesessbesnednecessesseans 3 DESCRIPTION vai dd aeons ear AN 3 INDICATIONS AND CLINICAL USE siii diia dadas dada 3 CONTRAINDICATION Saori di 4 WARNINGS AND PRECAUTIONS csosniteiiai alii ias edades 4 ADVERSE REACIIONS diia to RR A measaatees 6 DRUG INTERACTIONS osito A io dea 9 DOSAGE AND ADMINISTRATION disciccctsssadasercuentsuavatessrbendten e a oa 9 OVERDOSAGE onde oia bas flia IESO 15 ACTION AND CLINICAL PHARMACOLOGY encosicocioonicnsncisncocnnicnninonion aos ccoccnscads ins 15 STORAGE AND STABILIFY caria iena ia 17 SPECIAL HANDLING INSTRUCTIONS tai idas 17 DOSAGE FORMS COMPOSITION AND PACKAGING onccciccncccononononanonaninnananananinnass 18 PART II SCIENTIFIC INFORMATION societaria 19 PHARMACEUTICAL INFORMATIONS ioio aa era a A sien 19 CEIN
12. a B were excluded from participation The majority of subjects 88 had arthropathy at screening and target joints 66 Routine Prophylaxis Fifty nine 59 PTPs received RIXUBIS for prophylaxis Fifty six 56 of these PTPs who received the product for a minimum of 3 months were included in the efficacy evaluation for RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 21 of 30 prophylaxis see Table 8 The prophylactic regimen consisted of 40 to 60 international units kg of RIXUBIS twice weekly The mean total annualized bleeding rate ABR was 4 3 for all bleeds 1 7 for spontaneous bleeds and 2 9 for joint bleeds Table 8 The median total ABR was 2 0 with a range of 0 to 23 4 Table8 Efficacy of Prophylaxis with RIXUBIS in 56 PTPs with gt 3 months of exposure to RIXUBIS 12 years of age Treatment duration months Mean SD 6 0 0 65 Median range 6 0 5 4 9 1 Number of infusions per week Mean SD 1 8 0 11 Median range 1 8 1 5 1 9 Dose per infusion 1U kg Mean SD 49 4 4 92 Median range 50 5 40 0 62 8 Total annualized bleeding rate ABR Mean SD 4 3 5 80 Median range 2 0 0 0 23 4 ABR for joint bleeds Mean SD 2 9 4 25 Median range 0 0 0 0 21 5 ABR for spontaneous bleeds Mean SD 1 7 3 26 Median range 0 0 0 0 15 6 Subjects with zero bleeding episodes n 42 9 24 Subjects Number of Exposure Days Mean SD
13. ackage at its edge and pull the package off the device Figure C Do not remove the blue cap from the BAXJECT II device Do not touch the exposed white plastic spike 8 Turn the system over so that the diluent vial is on top Quickly insert the white plastic spike fully into the RIXUBIS vial stopper by pushing straight down Figure D The vacuum will draw the diluent into the RIXUBIS vial 9 Swirl gently until RIXUBIS is completely dissolved Do not refrigerate after reconstitution Use within 3 hours of reconstitution For intravenous use after reconstitution only e The safety and efficacy of RIXUBIS administration by continuous infusion has not been established Do not administer RIXUBIS by continuous infusion see Warnings and Precautions e Initiate treatment under the supervision of a physician experienced in the treatment of hemophilia see Warnings and Precautions e Inspect parenteral drug products for particulate matter and discoloration prior to administration whenever solution and container permit The solution should be clear and colorless in appearance If not do not use the solution and notify Baxter e Administer RIXUBIS at room temperature within 3 hours of reconstitution Discard any unused product e Only use a plastic syringe with this product RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 13 of 30 1 Remove the blue cap from the BAXJECT II device Connect the syringe to the BAXJE
14. and the results of the assessment of the hemostatic response at various points in time Table9 Efficacy of RIXUBIS for Surgical Procedures in PTPs Assessment of Response Procedure category of subjects At kime ol dra P Intra operative removal or on At Time of post operative Discharge day 3 Removal of intramedullary nail Excellent Good Excellent Major n 1 Joint Replacement Major n 5 Excellent Good 3 Excellent 3 Excellent 2 Good 2 Open synovectomy Major n 1 Excellent Excellent Excellent Excision neurofibroma Major n 1 Excellent Excellent Excellent Hernioplastic Major n 2 Excellent Excellent Good 1 Excellent 1 Tooth extraction Major n 1 Excellent Excellent Excellent Tooth extraction Minor n 2 Excellent Excellent Excellent Intra articular injection Minor n 1 Excellent Not applicable Excellent Where no drain was employed response was assessed on postoperative day 3 Thrombogenicity In all studies subjects were monitored for the presence of thrombosis see Warnings and Precautions There was no clinical evidence of thrombotic complications in any of the subjects Out of range values for thrombogenicity markers Thrombin antithrombin III TAT Prothrombin fragment 1 2 and D dimer determined during the pharmacokinetic portion of the combined study did not reveal any pattern indicative of clinically relevant thrombogenicity with either RIXUBIS or a comparitor
15. aryngeal 50 100 12 24 and healing begins about 7 retroperitoneal CNS 10 days Adapted from Roberts and Eberst Table 5 Dosing for Perioperative Management Type of Surgery Circulating Dosing Interval Duration of Therapy Factor IX Level hours days Required or IU dL Minor 30 60 24 Treat for at least 1 day until eg tooth extraction healing begins Major 80 100 8 24 Treat for 7 10 days until eg intracranial bleeding stops and healing intraabdominal begins intrathoracic joint replacement RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 11 of 30 Careful monitoring of replacement therapy is especially important in cases of major surgery or life threatening hemorrhages Routine Prophylaxis RIXUBIS can be administered for routine prophylaxis against bleeding in patients with severe and moderately severe hemophilia B The recommended dose for previously treated patients PTPs 40 to 60 IU kg twice weekly for patients more than 12 years of age Titration of dose may be necessary depending upon the individual patient s pharmacokinetics age bleeding pattern and physical activity Instructions for Use Administer RIXUBIS by intravenous IV infusion after reconstitution Perform reconstitution product administration and handling of the administration set and needles with caution Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses inclu
16. assay eg the one stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained when clinically indicated see Dosage and Administration If necessary appropriate adjustments to the dose and the frequency of repeated infusions should be performed Monitor for the development of inhibitors if expected factor IX activity plasma levels are not attained or if bleeding is not controlled with the recommended dose of RIXUBIS Assays used to determine factor IX inhibitors if present should be titred in Bethesda units ADVERSE REACTIONS Adverse Drug Reaction Overview The most common adverse reactions observed in gt 1 of subjects of RIXUBIS clinical trials were a positive Furin antibody test dysgeusia and pain in extremity See Table for Summary of Adverse Reactions Clinical Trial Adverse Drug Reactions RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 6 of 30 Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug Adverse drug reaction information from clinical trials is useful for identifying drug related adverse events and for approximating rates During clinical development in a combined trial 91 unique previously treated patients PTPs exposed to a factor IX concentrate on gt 1
17. comes in five different dosage strengths 250 International Units IU 500 IU 1000 IU 2000 IU and 3000 IU The actual strength will be imprinted on the label and on the box The five different strengths are color coded as follows Tachi blie Dosage strength of approximately 250 International Units per vial Dosage strength of approximately 500 International Pink i Units per vial Dosage strength of approximately 1000 Green International Units per vial Dosage strength of approximately 2000 International Units per vial Dosage strength of approximately 3000 International Units per vial Silver Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider Always check the expiration date printed on the carton Do not use the product after the expiration date printed on the carton and the vial WARNINGS AND PRECAUTIONS BEFORE you use RIXUBIS talk to your doctor or pharmacist if you e have or have had any medical problems e take any medicines including prescription and non prescription medicines such as over the counter medicines supplements or herbal remedies e have any allergies including allergies to hamsters e are breastfeeding Itis not known if RIXUBIS passes into your milk and if it can harm your baby e are pregnant or planning to become pregnant It is not known if RIXUBIS may harm y
18. ctor IX rFIX Nonacog gamma Page 30 of 30
19. ding HIV AIDS and hepatitis Obtain immediate medical attention if injury occurs Place needles in a sharps container after single use Discard all equipment including any reconstituted RIXUBIS in an appropriate container Administration Preparation and Reconstitution The procedures below are provided as general guidelines for the preparation and reconstitution of RIXUBIS Always work on a clean surface and wash your hands before performing the following procedures 1 Use aseptic technique during reconstitution procedure 2 Allow the RIXUBIS vial dry factor concentrate and Sterile Water for Injection USP vial diluent to reach room temperature 3 Remove caps from the factor concentrate and diluent vials 4 Cleanse stoppers with germicidal solution and allow to dry prior to use Place the vials on a flat surface RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 12 of 30 5 Open the BAXJECT II device package by peeling away the lid without touching the inside Figure A Do not remove the device from the package Note that the BAXJECT II device is intended for use with a single vial of RIXUBIS and Sterile Water for Injection USP only therefore reconstituting and withdrawing a second vial into the syringe requires a second BAXJECT II device 6 Turn the package over Press straight down to fully insert the clear plastic spike through the diluent vial stopper Figure B 7 Grip the BAXJECT II p
20. experienced in the treatment of hemophilia The safety and efficacy of RIXUBIS administration by continuous infusion has not been established The dosage and duration of the replacement therapy depend on the severity of factor IX deficiency the location and extent of bleeding and the patients clinical condition age and pharmacokinetic parameters of factor IX such as incremental recovery and half life Monitor patients using an appropriate factor IX activity assay to ensure that the desired factor IX activity plasma has been attained If necessary adjust the dose and the frequency of repeated infusions as appropriate Careful monitoring of replacement therapy is especially important in cases of major surgery or life threatening hemorrhages Evaluate the patient for the development of factor IX inhibitors if the expected factor IX activity plasma levels are not attained or if bleeding is not controlled with an appropriate dose see Warnings and Precautions Each vial of RIXUBIS has the factor IX rFIX potency in international units stated on the vial Dosing of RIXUBIS may differ from that of plasma derived factor IX products see Clinical Pharmacology Subjects at the low end of the observed factor IX recovery may require dose adjustment of RIXUBIS FIX potency results can be affected by the type of aPTT reagent and reference standard used in the assay differences of up to 40 have been observed Recommended Dose and Dosage Adjustment
21. f plasma derived factor IX and has structural and functional characteristics similar to those of endogenous factor IX RIXUBIS is produced by a genetically engineered Chinese hamster ovary CHO cell line that is extensively characterized No human or animal proteins are added during any stage of manufacturing or formulation of RIXUBIS RIXUBIS is not derived from human blood or plasma products and its manufacture does not include animal or human components RIXUBIS contains no preservatives The CHO cell line secretes recombinant factor IX into a defined cell culture medium that does not contain any proteins derived from animal or human sources as well as hormones and the recombinant factor IX is purified by a chromatography purification process that does not require a monoclonal antibody step The process includes validated virus inactivation removal steps namely solvent detergent S D treatment and 15 nm nanofiltration The S D treatment has the ability to inactivate lipid enveloped viruses whereas the nanofiltration step has the ability to remove both lipid enveloped and non lipid enveloped viruses RIXUBIS is predominantly a single component by SDS polyacrylamide gel electrophoresis evaluation The potency in international units IU is determined using an in vitro one stage clotting assay against the World Health Organization WHO International Standard for Factor IX concentrate One IU is the amount of factor IX activity present in 1 mL of
22. gs were observed in any of these 15 subjects In a study of 500 normal volunteers using the same assay as in the clinical trial 7 had titers of 1 20 or 1 40 and 1 2 had higher titers ranging from 1 80 to 1 320 These antibodies are thought to be part of a natural immune system response To date these antibodies have not been associated with any clinical adverse findings The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay Additionally the observed incidence of antibody including neutralizing antibody positivity in an assay may be influenced by several factors including assay methodology sample handling timing of sample collection concomitant medications and underlying disease Post Market Adverse Drug Reactions Immune System Disorders Hypersensitivity including symptoms such as dyspnea pruritus Skin and Subcutaneous Tissue Disorders Urticaria rash The following class adverse reactions have been seen with another recombinant factor IX inadequate factor IX recovery inhibitor development anaphylaxis angioedema hypotension and thrombosis RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 8 of 30 DRUG INTERACTIONS Drug Drug Interactions No interactions of recombinant coagulation factor IX products with other medicinal products are known DOSAGE AND ADMINISTRATION General Treatment should be initiated under the supervision of a physician
23. le subjects per protocol analysis are presented in Table6 RIXUBIS was equivalent to another recombinant factor IX product based on AUC Table 6 Pharmacokinetic Parameters for RIXUBIS Following Single Repeat Dosing 212 years of age Parameter Initial cross over study Repeat Evaluation N 25 N 23 AUC gt o inr IU hrs dL Mean SD 1207 242 1305 300 Min Max 850 1710 838 1864 Incremental recovery at Cinax IU dL IU kg Mean SD 0 87 0 22 0 95 0 25 Min Max 0 53 1 35 0 52 1 38 Half life hrs Mean SD 26 7 9 6 25 4 6 9 Min Max 15 8 352 3 16 2 42 2 Cmax IU dL Mean SD 66 2 15 8 72 7 19 7 Min Max 41 7 100 3 38 5 106 3 Mean residence time hrs Mean SD 30 8 7 3 29 9 4 2 Min Max 22 3 47 8 21 3 37 5 Vos mL kg Mean SD 201 9 77 4 178 6 45 2 Min Max 110 0 394 0 112 0 272 0 Clearance mL kg hr Mean SD 6 4 1 3 6 0 1 5 Min Max 4 3 9 1 4 1 9 5 RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 16 of 30 Area under the plasma concentration time curve from time 0 to infinity hours post infusion P Calculated as Cmax baseline factor IX divided by the dose in IU kg where Cmax 18 the maximum post infusion factor IX measurement Volume of distribution at steady state Data from PTPs who underwent repeat in vivo recovery testing for up to 26 weeks demonstrated that the increme
24. lly for Consumers This leaflet is a summary and will not tell you everything about RIXUBIS Contact your doctor or pharmacist if you have any questions about the drug ABOUT THIS MEDICATION What the medication is used for RIXUBIS is a medicine used to replace clotting factor Factor IX that is missing in people with hemophilia B Hemophilia B is also called congenital factor IX deficiency or Christmas disease Hemophilia B is an inherited bleeding disorder that prevents blood from clotting normally e RIXUBIS is used to prevent and control bleeding in people with hemophilia B e Your healthcare provider may give you RIXUBIS when you have surgery e RIXUBIS can reduce the number of bleeding episodes when used regularly prophylaxis What it does RIXUBIS temporarily replaces the missing clotting factor IX that is needed for effective hemostasis When it should not be used You should not use RIXUBIS if you e are allergic to hamsters e are allergic to any ingredients in RIXUBIS Tell your healthcare provider if you are pregnant or breastfeeding because RIXUBIS may not be right for you What the medicinal ingredient is Recombinant Coagulation Factor IX rFIX Nonacog gamma What the important nonmedicinal ingredients are Calcium Chloride L Histidine Mannitol Sodium Chloride Sucrose For a full listing of nonmedicinal ingredients see Part 1 of the product monograph What dosage forms it comes in RIXUBIS
25. lthcare provider for information that is written for healthcare professionals Call your healthcare provider right away if bleeding is not controlled after using RIXUBIS Your healthcare provider will prescribe the dose that you should take Your healthcare provider may need to take blood tests from time to time Talk to your healthcare provider before traveling Plan to bring enough RIXUBIS for your treatment during this time Dispose of all materials including any leftover reconstituted RIXUBIS product in an appropriate container 1 Prepare a clean flat surface and gather all the materials you will need for the infusion Check the expiration date and let the vial with the RIXUBIS concentrate and the vial with the Sterile Water for Injection USP diluent warm up to room temperature Wash your hands and put on clean exam gloves If infusing yourself at home the use of gloves is optional 2 Remove caps from the RIXUBIS concentrate and diluent vials to expose the centers of the rubber stoppers RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 27 of 30 3 Disinfect the stoppers with an alcohol swab or other suitable solution suggested by your healthcare provider or hemophilia center by rubbing the stoppers firmly for several seconds and allow them to dry prior to use Place the vials on a flat surface 4 Open the BAXJECT II device package by peeling away the lid without touchi
26. n of a bleed was rated excellent full relief of pain and cessation of objective signs of bleeding after a single infusion no additional infusion is required for the control of bleeding or good definite pain relief and or improvement in signs of bleeding after a single infusion possibly requires more than one infusion for complete resolution in 96 of all treated bleeding episodes Perioperative Management Study The efficacy of RIXUBIS in perioperative management was evaluated in 14 surgeries performed in 14 previously treated patients PTPs between 19 and 54 years of age undergoing major or minor surgical see Table 5 for definition of major and minor dental or other surgical invasive procedures Eleven 11 procedures were considered major including 7 orthopedic surgeries and 1 dental surgery Three procedures including 2 dental extractions were considered minor Patients undergoing major surgeries had to perform a pharmacokinetics evaluation All patients were dosed based on their most recent individual incremental recovery The recommended initial loading dose of RIXUBIS was to ensure that during surgery factor IX activity levels of 80 100 for major surgeries and 30 60 for minor surgeries were maintained RIXUBIS was administered by bolus infusions Hemostasis was maintained throughout the study duration RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 23 of 30 Table 9 shows the types of surgical procedures
27. ng the inside of the package Do not remove the BAXJECT II device from the package 5 Turn the package with the BAXJECT II device upside down and place it over the top of the diluent vial Fully insert the clear plastic spike of the device into the center of the diluent vial s stopper by pushing straight down Grip the package at its edge and lift it off the device Be careful not to touch the white plastic spike Do not remove the blue cap from the BAXJECT II device The diluent vial now has the BAXJECT II device connected to it and is ready to be connected to the RIXUBIS vial 6 To connect the diluent vial to the RIXUBIS vial turn the diluent vial over and place it on top of the vial containing RIXUBIS concentrate Fully insert the white plastic spike into the RIXUBIS vial s stopper by pushing straight down Diluent will flow into the RIXUBIS vial This should be done right away to keep the liquid free of germs 7 Swirl the connected vials gently and continuously until the RIXUBIS is completely dissolved Do not shake The RIXUBIS solution should look clear and colorless If not do not use it and notify Baxalta immediately a bul d MW 8 Take off the blue cap from the BAXJECT II device and connect the syringe Be careful to not inject air RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 28 of 30 10 Turn over the connected vials so tha
28. ng time points at screening at 72 hours following the first infusion of RIXUBIS and the commercial recombinant factor IX product in the crossover portion of the pharmacokinetic study after 5 and 13 weeks following first exposure to RIXUBIS and thereafter every 3 months Antibodies against furin were tested by an in house enzyme linked immunosorbent assay ELISA A titer of 1 20 or 1 40 was considered to be indeterminate for the above validated assay as these titers were too low to be verified by the confirmatory assay No subjects developed neutralizing antibodies to factor IX Thirteen subjects 14 3 developed low titer non neutralizing antibodies against factor IX at one or more time points Two of these 13 subjects were found to have these antibodies at screening prior to receiving RIXUBIS No clinical adverse findings were observed in any of these 13 subjects Thirteen subjects 14 3 had signals for antibodies against furin indeterminate specificity Four of these 13 subjects expressed signals for antibodies at screening prior to RIXUBIS treatment An additional subject had an antibody signal after treatment with the comparator product and prior to RIXUBIS treatment Another additional subject had a positive titer of 1 80 that was not present when checked at a later time point and therefore considered transient A second subject had a positive antibody signal after the data cutoff date that was also transient No clinical adverse findin
29. ntal FIX recovery was consistent over time Incremental recovery 30 min after infusion was determined for all subjects in the combined study at exposure day 1 at their week 5 13 and 26 visits and at the time of study completion or termination if it did not coincide with the week 26 visit The data demonstrate that the incremental recovery is consistent over time Table 7 Table 7 Incremental Recovery for RIXUBIS 30 Minutes After Infusion 212 years of age Exposure Week 5 Week 13 Week 26 At study Day 1 completion termination N 73 N 71 N 68 N 55 N 23 Incremental recovery 30 min after infusion IU dL IU kg Mean SD 0 79 0 20 0 83 0 21 0 85 0 25 0 89 0 12 0 87 0 20 Median range 0 78 0 26 1 35 0 79 0 46 1 48 0 83 0 14 1 47 0 88 0 52 1 29 0 89 0 52 1 32 3 Calculated as C3omin baseline factor IX divided by the dose in IU kg where C3omin is the factor IX measurement 30 minutes after infusion gt Tf not coinciding with week 26 visit STORAGE AND STABILITY e Refrigerated temperature 2 to 8 C 35 to 46 F for up to 24 months Do not freeze SPECIAL HANDLING INSTRUCTIONS Inspect parenteral drug products for particulate matter and discoloration prior to administration Room temperature not to exceed 30 C 86 F for up to 12 months Do not use beyond the expiration date printed on the carton or vial Do not place back in the refrigerato
30. ontact their physician if such symptoms occur The risk is highest during the early phases of initial exposure to factor IX concentrates in previously untreated patients PUPs in particular in patients with high risk gene mutations Early signs of anaphylaxis or allergic reactions include angioedema chest tightness hypotension lethargy nausea vomiting paresthesia restlessness wheezing and dyspnea In some cases these reactions have progressed to severe anaphylaxis In the case of shock the current medical standards for treatment of shock should be observed In case of severe allergic reactions alternative hemostatic measures should be considered Discontinue administration and initiate appropriate treatment if allergic or anaphylactic type reactions occur There have been reports in the literature showing an association between the occurrence of a factor IX inhibitor and allergic reactions Therefore patients experiencing allergic reactions should be evaluated for the presence of an inhibitor RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 4 of 30 RIXUBIS contains trace amounts of hamster CHO proteins Patients treated with this product may develop hypersensitivity to these non human mammalian proteins Other factor IX products have had post marketing reports of thrombotic events in patients receiving continuous infusion through a central venous catheter including life threatening superior vena cava SVC
31. otting assay which employs a factor IX concentrate standard that is referenced to the World Health Organization WHO Internal Standard for factor IX concentrates INDICATIONS AND CLINICAL USE RIXUBIS is indicated in adult patients with hemophilia B congenital factor IX deficiency or Christmas disease for e Control of bleeding episodes RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 3 of 30 e Perioperative management e Routine prophylaxis to prevent or reduce the frequency of bleeding episodes Geriatrics gt 65 years of age Clinical studies of RIXUBIS did not include subjects aged 65 years 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 individualized Pediatrics lt 12 years of age Safety and efficacy of RIXUBIS in patients less than 12 years have not been established CONTRAINDICATIONS RIXUBIS contains trace amounts of Chinese Hamster ovary cell line CHO RIXUBIS is contraindicated in patients with known hypersensitivity to active substance to excipients or to hamster protein WARNINGS AND PRECAUTIONS General Anaphylaxis and other hypersensitivity reactions have been reported with factor X containing products Patients and or their caregivers should be informed of the early signs of hypersensitivity reactions They should be advised to discontinue use of the product immediately and c
32. our unborn baby e have been told that you have inhibitors to factor IX because RIXUBIS may not work for you INTERACTIONS WITH THIS MEDICATION Drugs that may interact with RIXUBIS include There are no known interactions of RIXUBIS with other medications PROPER USE OF THIS MEDICATION Usual dose e Your doctor will determine the dose of RIXUBIS you will RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 26 of 30 receive e The dose duration and frequency of infusions you receive will be influenced by the severity of your factor IX deficiency the location extent of bleeding and age Overdose No symptoms of overdose have been reported As with other products of the same class overdose may increase the risk for thrombotic and thromboembolic events e g DIC pulmonary embolism venous thrombosis and arterial thrombosis In case of drug overdose contact a health care practitioner hospital emergency department or regional Poison Control Centre immediately even if there are no symptoms Missed Dose If you miss a dose of this medicine check with your doctor as soon as possible for instructions HOW TO STORE IT e Store RIXUBIS at refrigerated temperature 2 to 8 C 35 to 46 F for up to 24 months or e Store at room temperature not to exceed 30 C 86 F for up to 12 months e Do not freeze e Do not use beyond the expiration date printed on the carton or vial e Do no
33. ow the limits of detection of the assay was observed during the S D treatment of three different enveloped model viruses i e X MuLV BVDV PRV The nanofiltration step for rFIX has also been demonstrated to effectively remove enveloped i e X MuLV and BVDV and non enveloped i e MMV and Reovirus 3 viruses from the product Altogether very high margins of safety with regards to adventitious viruses is demonstrated CLINICAL TRIALS Study demographics and trial design Prophylaxis and Control of Bleeding in PTPs gt 12 Years of Age The efficacy of RIXUBIS has been evaluated in one completed prospective open label uncontrolled multicenter combined study in which a total of 73 male PTPs between 12 and 65 years of age received RIXUBIS either for prophylaxis or on demand treatment In addition a prospective open label uncontrolled multicenter study where 14 PTPs underwent minor or major surgeries receiving RIXUBIS for perioperative management is ongoing PTPs were defined as subjects who were exposed to a factor IX containing products for gt 150 days All subjects had severe factor IX level lt 1 or moderately severe factor IX level lt 2 hemophilia B Subjects with a history of or a detectable FIX inhibitor 20 6 BU a history with severe allergic reactions following exposure to FIX evidence of a severe chronic liver disease INR gt 1 4 impaired renal function a CD4 count lt 200 cells mm or any hemostatic effect other than hemophili
34. particular incremental recovery and half life Examples assuming patient s baseline factor IX level is lt 1 of normal 1 A dose of 4550 IU RIXUBIS administered to a 70 kg patient should be expected to result in a peak post infusion factor IX increase of 4550 IU x 0 9 IU dL TU kg 70 kg 59 IU dL 59 of normal RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 10 of 30 2 A peak level of 70 is required in a 60 kg patient In this situation the appropriate dose would be 60 kg x 70 IU dL 0 9 IU dL 1U kg 4667 IU Treatment of Bleeding Episodes and Perioperative Management A guide for dosing in the treatment of bleeding episodes and perioperative management is provided in Table 4 and Table 5 respectively Ensure the factor IX activity level is achieved and maintained in the corresponding period Table 4 RIXUBIS Dosing for Control and Prevention of Bleeding Episodes Circulating Dosing Type of Bteeding Factor is level Interval Duration of Therapy Episodes Required hours or IU dL Manor Treat until bleeding stops Uncomplicated ka 20 30 12 24 and healing begins about 1 2 hemarthrosis superficial d i ays muscular or soft tissue Moderate Treat until bleeding stops Intramuscular or soft tissue 25 50 12 24 and with dissection mucous healing begins about 2 to 7 membranes or hematuria days Major Treat until bleeding stops Pharyngeal retroph
35. r once removed from refrigerated storage whenever solution and container permit The solution should be clear and colorless in appearance If not do not use the solution and notify Baxter immediately RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 17 of 30 RIXUBIS is to be reconstituted with the provided Sterile Water for Injection SWFI Administer RIXUBIS within 3 hours of reconstitution This product must not be mixed with other medicinal products DOSAGE FORMS COMPOSITION AND PACKAGING RIXUBIS is available single use vials which contain the following product strengths 250 IU 500 IU 1000 TU 2000 IU and 3000 TU Each kit also contains 5 mL of Sterile Water for Injection and BAXJECT II Transfer device Actual factor IX activity in international units is stated on the unit carton and vial label RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 18 of 30 PART Il SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Proper name Recombinant Coagulation Factor IX rFIX Nonacog gamma Chemical name Recombinant Coagulation Factor IX rFIX Nonacog gamma Molecular The molecular formula for the peptide backbone of FVIIa including the 12 formula and Gla residues and 11 disulfide bonds is C7053H3114N 5580665525 The theoretical molecular mass average molecular mass for the protein backbone of mature factor IX according to the above formula is 47 054 Da
36. syndrome in critically ill neonates Inhibitors Patients with hemophilia B may develop neutralizing antibodies inhibitors to factor IX Patients using RIXUBIS should be regularly evaluated for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests If expected plasma factor IX activity levels are not attained or if bleeding is not controlled with an expected dose an assay that measures factor IX inhibitor concentration should be performed If a patient develops an inhibitor it is recommended that a specialized hemophilia center be contacted In patients with high titer factor IX inhibitors RIXUBIS therapy may not be effective and other therapeutic options should be considered Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re exposed to factor IX Nephrotic Syndrome Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with factor IX inhibitors The safety and efficacy of using RIXUBIS for immune tolerance induction has not been established Thromboembolic Complications The use of factor IX products has been associated with the development of thromboembolic complications e g pulmonary embolism venous thrombosis arterial thrombosis cerebral artery thrombosis superior vena cava obstruction Factor IX containing products may be potentially hazardous in patients wi
37. t place back in the refrigerator once removed from refrigerated storage e Reconstituted product after mixing dry product with wet diluent must be used within 3 hours and cannot be stored or refrigerated Discard any RIXUBIS left in the vial at the end of your infusion INSTRUCTIONS FOR USE FOR RIXUBIS Recombinant Coagulation Factor IX rFIX For intravenous use only Do not attempt to do an infusion to yourself unless you have been taught how by your healthcare provider or hemophilia center See below for step by step instructions for reconstituting RIXUBIS at the end of this leaflet Always follow the specific instructions given by your healthcare provider The steps listed below are general guidelines for using RIXUBIS If you are unsure of the procedures please call your healthcare provider before using SIDE EFFECTS AND WHAT TO DO ABOUT THEM Allergic reactions may occur with RIXUBIS Call your doctor or get emergency treatment right away if you get a rash or hives itching tightness of the throat chest pain or tightness difficulty breathing light headedness dizziness nausea or fainting Some common side effects of RIXUBIS were stomach flu like symptoms such as nausea vomiting and stomach pain runny nose sore throat headache and diarrhea Tell your healthcare provider about any side effects that bother you or do not go away These are not all the side effects possible with RIXUBIS You can ask your hea
38. t the RIXUBIS vial is on top Draw the RIXUBIS solution into the syringe by pulling back the plunger slowly Disconnect the syringe from the vials Attach the infusion needle to the syringe using a winged butterfly infusion set if available Point the needle up and remove any air bubbles by gently tapping the syringe with your finger and slowly and carefully pushing air out of the syringe and needle If you are using more than one vial of RIXUBIS the contents of more than one vial may be drawn into the same syringe Make sure you mix each vial of RIXUBIS with the Sterile Water for Injection USP that is provided in the box Following Steps 1 9 You will need a separate BAXJECT II device to mix each additional vial of RIXUBIS Apply a tourniquet and get the infusion site ready by wiping the skin well with an alcohol swab or other suitable solution suggested by your healthcare provider or hemophilia center 11 Insert the needle into the vein and remove the tourniquet Slowly infuse the RIXUBIS Do not infuse any faster than 10 mL per minute 12 Take the needle out of the vein and use sterile gauze to put pressure on the infusion site for several minutes Do not recap the needle Place it with the used syringe in a hard walled Sharps container for proper disposal Remove the peel off label from the RIXUBIS vial and place it in your logbook Clean any spilled blood with a freshly prepared mixture of 1
39. th disseminated intravascular coagulation DIC and in patients with signs of fibrinolysis Clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing in particular when administering RIXUBIS to RIXUBIS Recombinant Coagulation Factor IX rFIX Nonacog gamma Page 5 of 30 patients with liver disease to patients peri and post operatively to new born infants or to patients at risk for thrombotic events or DIC In patients with DIC or those at risk for DIC or thromboembolic events the benefit of treatment with RIXUBIS should be weighed against the risk of these complications Special Populations Pregnancy Lactation and Fertility There are no data from the use of RIXUBIS in pregnant or lactating women Healthcare providers should balance the potential risks and only prescribe RIXUBIS if clearly needed There is no information on the effects of RIXUBIS on fertility Pediatrics There are insufficient data to recommend the use of RIXUBIS in children less than 12 years of age Geriatrics gt 65 years of age Clinical studies of RIXUBIS did not include subjects aged 65 years and over It is not known whether they respond differently from younger subjects Dose selection for an elderly patient should be individualized See Dosage and Administration Monitoring and Laboratory Tests Monitor factor IX activity levels by using an appropriate factor IX activity
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