Dosing and Administration Guide

Transcription

1 Dosing and Administration Guide NULOJIX (belatacept) is available as 250 mg lyophilized powder for injection, for intravenous use. Indication r NULOJIX (in combination with basiliximab induction, mycophenolate mofetil [MMF], and corticosteroids) is indicated for prophylaxis of organ rejection in adults receiving a kidney transplant r Use NULOJIX only in patients who are Epstein-Barr virus (EBV) seropositive r Use of NULOJIX for prophylaxis of organ rejection in transplanted organs other than kidney has not been established Selected Important Safety Information r NULOJIX is associated with increased risk for post-transplant lymphoproliferative disorder (PTLD), predominantly in the central nervous system (CNS) NULOJIX is contraindicated in patients who are EBV seronegative or with unknown serostatus because the risk of PTLD is particularly increased in patients who are EBV seronegative NULOJIX is to be used only in patients who are EBV seropositive Patients should be monitored for new or worsening neurological, cognitive, or behavioral signs and symptoms Higher than recommended doses or more frequent dosing of NULOJIX and concomitant immunosuppressives is not recommended r Immunosuppression may result in increased susceptibility to infection and development of malignancies r NULOJIX should be prescribed only by physicians experienced in immunosuppressive therapy and management of kidney transplant patients r Use in liver transplant patients is not recommended due to an increased risk of graft loss and death

2 Introduction This booklet includes information and instructions on the following: r How NULOJIX (belatacept) is supplied r Information on the dosing of NULOJIX r The supplies required for preparation and administration r Step-by-step preparation and administration instructions including storage and compatibility information r Product support services r Important Safety Information How Supplied r Each single-use vial provides 250 mg of NULOJIX lyophilized powder for injection, for intravenous use r Full Prescribing Information, including Medication Guide, is enclosed in each package Package includes: mg vial 1 12-mL SILICONE-FREE disposable syringe Selected Important Safety Information Acute Rejection and Graft Loss with Corticosteroid Minimization r In NULOJIX postmarketing experience, corticosteroid minimization to 5 mg/day between Day 3 and Week 6 post-transplant was associated with an increased rate and grade of acute rejection, particularly Grade III These Grade III rejections occurred in patients with 4-6 human leukocyte antigen (HLA) mismatches Graft loss was a consequence of Grade III rejection in some patients r Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience Median (25th-75th percentile) corticosteroid doses were tapered to about 15 mg (10-20 mg)/day by the first 6 weeks and remained at about 10 mg (5-10 mg)/day for the first 6 months post-transplant 2

3 Step 1: Dosing r Administration of higher than recommended doses or more frequent dosing of NULOJIX is not recommended due to an increased risk of PTLD predominantly involving the CNS, progressive multifocal leukoencephalopathy (PML), and serious CNS infections r NULOJIX total infusion dose should be based on actual body weight at the time of transplantation Dose should not be modified during the course of therapy unless there is a change in body weight of >10% r NULOJIX is for intravenous infusion only r Patients do not require premedication prior to administration of NULOJIX r NULOJIX should be administered in combination with basiliximab induction, MMF, and corticosteroids Dosing Recommendations in Adult De Novo Kidney Transplant Recipients Dosing for Initial Phase Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1 dose) Dose 10 mg/kg End of Week 2 and Week 4 after transplantation End of Week 8 and Week 12 after transplantation Dosing for Maintenance Phase End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter 10 mg/kg 10 mg/kg Dose 5 mg/kg Calculate the dose: Weight (kg) x dose (5 or 10 mg/kg, see table above) = total dose (mg) NOTE: r The prescribed dose of NULOJIX must be evenly divisible by 12.5 mg in order for the dose to be prepared accurately using the reconstituted solution and the silicone-free disposable syringe provided. Evenly divisible increments are 0, 12.5, 25, 37.5, 50, 62.5, 75, 87.5, and 100 For example: r A patient weighs 64 kg. The dose is 10 mg per kg r Calculated dose: 64 kg x 10 mg per kg = 640 mg r The closest doses evenly divisible by 12.5 mg below and above 640 mg are mg and 650 mg r The nearest dose to 640 mg is mg r Therefore, the actual prescribed dose for the patient should be mg (continued) 3

4 Step 1: Dosing (continued) r Each single-use vial supplies 250 mg of NULOJIX (belatacept) lyophilized powder for intravenous infusion r To determine the number of vials that will be needed for a patient's dose, divide the total milligram dose by 250 Determine the number of vials needed per patient: Total dose (mg) 250 mg/vial = number of vials Note: Remember the dose is based on total milliliters (ml), not the number of vials. Please refer to the calculation on page 7. Overdosage r Single doses up to 20 mg/kg of NULOJIX have been administered to healthy subjects without apparent toxic effect r The administration of NULOJIX of higher cumulative dose and more frequent dosing than recommended in kidney transplant patients resulted in a higher frequency of CNS-related adverse reactions r In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted 4

5 Step 2: Supplies The following supplies should be available prior to preparation and administration: r NULOJIX vials Number based on calculated dose r Alcohol swabs r SILICONE-FREE * disposable syringe Supplied with drug r 18- to 21-gauge needle r Additional syringe and needle may be used (to withdraw excess fluid from infusion bag or bottle prior to addition of reconstituted NULOJIX solution) r Constitution fluid (diluent, 10.5 ml) Sterile water for injection (SWFI) or 0.9% sodium chloride (NS) or 5% dextrose in water (D5W) r Infusion bag or bottle (typically 100 ml) NS or D5W r Infusion set and STERILE, NON-PYROGENIC, LOW-PROTEIN BINDING FILTER (pore size, μm) Not supplied with drug * Note: If the NULOJIX powder is accidently reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. Total infusion volumes ranging from 50 ml to 250 ml may be used. 5

6 Step 3: Preparation r Caution: NULOJIX (belatacept) must be reconstituted/prepared using only the silicone-free disposable syringe provided with each vial Reconstitution r Fill silicone-free disposable syringe with 10.5 ml of constitution fluid SWFI, NS, or D5W r Remove the flip-top from the NULOJIX vial and wipe the top with an alcohol swab r Insert needle into the vial through the center of the rubber stopper r Direct the stream of diluent to the glass wall of the vial If the NULOJIX powder is accidentally reconstituted using a different syringe than the one provided, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. r Rotate vial and invert with gentle swirling motion (to minimize foam formation) until contents are completely dissolved. Avoid prolonged or vigorous agitation. Do not shake r The reconstituted solution contains a belatacept concentration of 25 mg/ml r The solution should be clear to slightly opalescent and colorless to pale yellow r For storage and disposal information, turn to page 9 Do not use if opaque particles, discoloration, or other foreign particles are present. If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Air-Tite at or 6

7 Dilution r Prior to intravenous infusion, the required volume of the reconstituted NULOJIX solution must be further diluted with a suitable infusion fluid to a final concentration in the infusion bag or bottle ranging from 2 mg/ml to 10 mg/ml r Select the appropriately sized infusion volume; typically 100 ml will be appropriate for most patients and doses, but total infusion volumes ranging from 50 ml to 250 ml may be used Infusion Bag or Bottle If NULOJIX was reconstituted with: SWFI NS D5W Dilute with: either NS or D5W r Withdraw a volume of infusion fluid that is equal to the volume of the reconstituted NULOJIX solution required to provide the prescribed dose Calculate the total volume of the reconstituted 25 mg/ml NULOJIX solution required to provide the total infusion dose Volume of 25 mg/ml NULOJIX solution (in ml) = Prescribed Dose (in mg) 25 mg/ml r The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately NS D5W r Using the same silicone-free disposable syringe used for reconstitution, withdraw the required amount of NULOJIX solution from the vial r Inject NULOJIX into the infusion bag or bottle r Gently rotate infusion bag or bottle to ensure mixing r Any unused solution remaining in the vials must be discarded 7

8 Step 4: Administration r Visually inspect the NULOJIX (belatacept) infusion bag or bottle for particulate matter and discoloration prior to administration Discard the infusion if any particulate matter or discoloration is observed. r NULOJIX is for intravenous infusion only r Must be administered with an infusion set and a STERILE, NON-PYROGENIC, LOW-PROTEIN BINDING FILTER (with a pore size of μm) r Administer the entire NULOJIX infusion over a period of 30 minutes r The NULOJIX infusion must be completed within 24 hours of reconstitution of the NULOJIX lyophilized powder If not used immediately, please see storage information on page 9 r NULOJIX should not be infused concomitantly in the same intravenous line with other agents. Infuse NULOJIX in a separate line. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of NULOJIX with other agents r Patients do not require premedication prior to administration of NULOJIX r Please provide the supplied Medication Guide to each patient prior to each infusion to help inform them of the risks and benefits of NULOJIX 8

9 Storage r Original packaging NULOJIX lyophilized powder is stored refrigerated at 2 C-8 C (36 F-46 F). Protect NULOJIX from light by storing in the original package until time of use r Infusion solution The reconstituted solution should be transferred from the vial to the infusion bag or bottle immediately. The NULOJIX infusion must be completed within 24 hours of reconstitution of the NULOJIX lyophilized powder If not used immediately, NULOJIX infusion solution may be stored under refrigeration conditions (2 C-8 C, 36 F-46 F) and protected from light for up to 24 hours (a maximum of 4 hours of the total 24 hours can be at room temperature [20 C-25 C, 68 F-77 F] and room light) r All of the supplies used in the preparation and administration of NULOJIX and any unused drug product solution should be properly disposed of in accordance with your institution s normal policies and procedures Compatibility NULOJIX should not be infused concomitantly in the same intravenous line with other agents. Infuse NULOJIX in a separate line from other concomitantly infused agents. r No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of NULOJIX with other agents Infusion Reactions r There have been no reports of anaphylaxis or drug hypersensitivity up to 3 years in Phase 3 clinical trials r Milder infusion-related reactions within 1 hour of infusion were reported in 5% of patients treated with the recommended dose of NULOJIX, similar to the placebo rate The most frequent reactions were hypotension and hypertension r A case of anaphylaxis was reported in the post-marketing experience (see section 6.2 Postmarking Experience of the Full Prescribing Information for additional information) 9

10 IMPORTANT SAFETY INFORMATION Post-Transplant Lymphoproliferative Disorder (PTLD) r NULOJIX (belatacept) patients are at increased risk for developing PTLD, predominantly involving the central nervous system (CNS) r Recipients without immunity to EBV (ie, seronegative) are at particularly increased risk; therefore, NULOJIX is contraindicated in transplant recipients who are EBV seronegative or with unknown serostatus r Monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms r As the total burden of immunosuppression is a risk factor for PTLD, higher than recommended doses or more frequent dosing of NULOJIX or concomitant immunosuppressive agents are not recommended r Other known risk factors for PTLD include cytomegalovirus (CMV) infection and T-cell depleting therapy CMV prophylaxis is recommended for at least 3 months after transplantation Use T-cell-depleting therapy to treat acute rejection cautiously r Patients who are EBV seropositive and CMV seronegative may be at increased risk of PTLD Since CMV seronegative patients are at increased risk for CMV disease (a known risk factor for PTLD), the clinical significance of CMV serology for PTLD remains to be determined; however, these findings should be considered when prescribing NULOJIX Management of Immunosuppression r Only physicians experienced in immunosuppressive therapy and management of kidney transplant patients should prescribe NULOJIX Patients should be managed in facilities with adequate laboratory and supportive medical resources The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient Progressive Multifocal Leukoencephalopathy (PML) r NULOJIX patients are at increased risk for PML, often a rapidly progressive and fatal opportunistic infection In clinical trials, two cases were reported in patients receiving NULOJIX at higher cumulative doses and more frequently than the recommended regimen, along with MMF and corticosteroids; one occurred in a kidney transplant recipient and one occurred in a liver transplant recipient r As PML has been associated with high levels of immunosuppression, higher than recommended doses or more frequent dosing of NULOJIX and concomitant immunosuppressive agents, including MMF, are not recommended r Monitor for new or worsening neurological, cognitive, or behavioral signs and symptoms PML is usually diagnosed by brain imaging, cerebrospinal fluid testing for JC viral DNA by polymerase chain reaction, and/or brain biopsy Consultation with a specialist should be considered If PML is diagnosed, consider reduction or withdrawal of immunosuppression, weighing risk to the graft (continued on next page) Please click for Full Prescribing Information, including Boxed WARNING. 10

11 IMPORTANT SAFETY INFORMATION (cont d) Other Malignancies and Serious Infections r Increased susceptibility to infection and possible development of malignancies may result from immunosuppression r Patients should avoid prolonged exposure to ultraviolet light and sunlight r Patients receiving immunosuppressants, including NULOJIX, are at increased risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections and tuberculosis. Some infections were fatal Polyoma virus-associated nephropathy can lead to deteriorating renal function and graft loss; consider reduction in immunosuppression, weighing risk to the graft Tuberculosis was more frequently observed in patients receiving NULOJIX. Evaluate for tuberculosis and initiate treatment for latent infection prior to NULOJIX use CMV and Pneumocystis jiroveci prophylaxis is recommended after transplantation Liver Transplant: use in liver transplant patients is not recommended due to increased risk of graft loss and death in a clinical trial with more frequent administration of NULOJIX than studied in kidney transplant, along with MMF and corticosteroids Acute Rejection and Graft Loss with Corticosteroid Minimization r In NULOJIX postmarketing experience, corticosteroid minimization to 5 mg/day between Day 3 and Week 6 posttransplant was associated with an increased rate and grade of acute rejection, particularly Grade III These Grade III rejections occurred in patients with 4-6 human leukocyte antigen (HLA) mismatches Graft loss was a consequence of Grade III rejection in some patients r Corticosteroid utilization should be consistent with the NULOJIX clinical trial experience Median (25th-75th percentile) corticosteroid doses were tapered to about 15 mg (10-20 mg)/day by the first 6 weeks and remained at about 10 mg (5-10 mg)/day for the first 6 months post-transplant Immunizations: avoid use of live vaccines during NULOJIX treatment Coadministration with Anti-Thymocyte Globulin: in de novo kidney transplant recipients, especially those with other predisposing risk factors for venous thrombosis of the renal allograft, coadministration (at the same or nearly the same time) with anti-thymocyte globulin may pose a risk for venous thrombosis of the renal allograft. If anti-thymocyte globulin (or any other cell-depleting induction treatment) and NULOJIX will be administered concomitantly, a 12-hour interval between the two administrations is suggested Pregnancy Category C: based on animal data, NULOJIX may cause fetal harm. NULOJIX should not be used in pregnancy unless potential benefit to the mother outweighs potential risk to the fetus. To monitor maternal-fetal outcomes of pregnant women who have received NULOJIX, or whose partners have received NULOJIX, healthcare providers are strongly encouraged to register pregnant patients in the National Transplant Pregnancy Registry (NTPR) by calling Nursing Mothers: discontinue NULOJIX or nursing, considering importance of NULOJIX to the mother Most Common Adverse Reactions ( 20%): anemia (45%), diarrhea (39%), urinary tract infection (37%), peripheral edema (34%), constipation (33%), hypertension (32%), pyrexia (28%), graft dysfunction (25%), cough (24%), nausea (24%), vomiting (22%), headache (21%), hypokalemia (21%), hyperkalemia (20%), and leukopenia (20%) Please click for Full Prescribing Information, including Boxed WARNING. 11

12 Product Support Services Manufacturer Quality-Control/Vial-Replacement Process r Vials of NULOJIX (belatacept) may be replaced by the manufacturer for product quality defects. Manufacturer-product quality defects may include, but are not limited to: Vial missing from manufacturer s packaging Empty vial Damaged vial (not due to shipping) r To report manufacturer quality issues, dial and hold the line for a live operator. You will be asked for a brief description of the issue, the lot and NDC numbers, and the number of vials. Replacement vials are usually shipped within 72 hours from the time of report. A separate prepaid label with a return address will be forwarded to you to send back the damaged vial(s) r For other issues, such as breakage due to shipping or product received outside of labeling requirements, please contact your specialty pharmacy, distributor, or wholesaler Syringe Ordering Process r If you would like a one-time free sample of eight (8) silicone-free disposable syringes (item #: AL10BMS-R2) or information on purchasing a box of 100 silicone-free disposable syringes (item #: AL10BMS-R2), please contact Air-Tite at: or 12

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14 NULOJIX is a registered trademark of Bristol-Myers Squibb Company. All other brands are the trademarks of their respective owners Bristol-Myers Squibb Company 721US /18