Miscellaneous ePI Test
0.1.0 - CI Build
Miscellaneous ePI Test
0.1.0 - CI Build
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BeneFIX 250 IU powder and solvent for solution for injection
BeneFIX 500 IU powder and solvent for solution for injection
BeneFIX 1000 IU powder and solvent for solution for injection
BeneFIX 2000 IU powder and solvent for solution for injection
BeneFIX contains recombinant coagulation factor IX, (INN = nonacog alfa). Nonacog alfa is a purified protein that has 415 amino acids in a single chain. It has a primary amino acid sequence that is comparable to the Ala148 allelic form of plasma-derived factor IX, and some post-translational modifications of the recombinant molecule are different from those of the plasma-derived molecule. Recombinant coagulation factor IX is a glycoprotein that is secreted by genetically engineered mammalian cells derived from a Chinese hamster ovary (CHO) cell line.
BeneFIX 250 IU powder and solvent for solution for injection
Each vial contains nominally 250 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL of the solution contains approximately 50 IU nonacog alfa.
BeneFIX 500 IU powder and solvent for solution for injection
Each vial contains nominally 500 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL of the solution contains approximately 100 IU nonacog alfa.
BeneFIX 1000 IU powder and solvent for solution for injection
Each vial contains nominally 1000 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL of the solution contains approximately 200 IU nonacog alfa.
BeneFIX 2000 IU powder and solvent for solution for injection
Each vial contains nominally 2000 IU nonacog alfa (recombinant coagulation factor IX). After reconstitution with the accompanying 5 mL (0.234%) sodium chloride solution for injection, each mL of the solution contains approximately 400 IU nonacog alfa.
The potency (IU) is determined using the European Pharmacopoeia one-stage clotting assay. The specific activity of BeneFIX is not less than 200 IU/mg protein.
For the full list of excipients, see section 6.1.
BeneFIX 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection
Powder and solvent for solution for injection
White/almost white powder and clear and colourless solvent.
Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).
BeneFIX can be used for all age groups.
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.
Treatment monitoring
During 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.
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.
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Known allergic reaction to hamster proteins.
No interactions of human coagulation factor IX (rDNA) products with other medicinal products have been reported.
Animal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breastfeeding is not available. Therefore, factor IX should be used during pregnancy and breast-feeding only if clearly indicated.
The effect of BeneFIX on fertility has not been established.
BeneFIX has no influence on the ability to drive or use machines.
Summary of the safety profile
Hypersensitivity 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 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 section 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 reaction.
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, see section 4.4.
Tabulated list of 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), not known (cannot be estimated from the available data). The table lists adverse reactions reported in the clinical trials of previously treated patients and identified in postmarketing use. The frequencies are based on all causality treatment emergent adverse events in pooled clinical trials with 224 subjects.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
* ADR identified post-marketing a including cellulitis b low-titer transient inhibitor formation c including drug hypersensitivity, angioedema, bronchospasm, wheezing, dyspnoea, and laryngospasm d including migraine, sinus headache e including scintillating scotoma and blurred vision f including heart rate increased, sinus tachycardia g including hot flush, feeling hot, skin warm h including blood pressure decreased i superior vena cava (SVC) syndrome in critically ill neonates, while receiving continuous-infusion of BeneFIX through a central venous catheter j including productive cough k including rash macular, rash papular, rash maculopapular l developed in a hepatitis C antibody-positive patient 12 days after a dose of BeneFIX for a bleeding episode. m including injection site pain, infusion site discomfort n including infusion site pruritus, infusion site erythema o including chest pain and chest tightness p This is a verbatim term. No MedDRA 17.1 PT was retrieved. | ||||
| System organ class | Very common ≥ 1/10 | Common ≥ 1/100 to < 1/10 | Unommon ≥ 1/1,000 to < 1/100 | Frequency not known (cannot be estimated from the available data) |
|---|---|---|---|---|
| Infections and infestations | Infusion site cellulitisa | |||
| Blood and lymphatic system disorders | Factor IX inhibitionb | |||
| Immune system disorders | Hypersensitivityc | Anaphylactic reaction* | ||
| Nervous system disorders | Headached | Dizziness; Dysgeusia | Somnolence;tremor | |
| Eye disorders | Visual impairmente | |||
| Cardiac disorders | Tachycardiaf | |||
| Vascular disorders | Phlebitis; flushingg | Hypotensionh | Superior vena cava syndromei,*; deep vein thrombosis*; thrombosis*; thrombophlebitis*; | |
| Respiratory, thoracic and mediastinal disorders | Coughj | |||
| Gastrointestinal disorders | Vomiting; nausea | |||
| Skin and subcutaneous tissue disorders | Rashk; urticaria | |||
| Renal and urinary disorders | Renal infarctl | |||
| General disorders and administration site conditions | Pyrexia | Chest discomforto; infusion site reactionn; infusion site painm | Inadequate therapeutic response* | |
| Investigations | Inadequate factor IX recovery p, * | |||
Description of selected adverse reactions
Hypersensitivity/allergic reactions
If any suspected hypersensitivity reaction takes place that is thought to be related to the administration of BeneFIX see sections 4.2 and 4.4.
Inhibitor development
A clinically relevant, low responding inhibitor was detected in 1 out of 65 BeneFIX patients (including 9 patients participating only in the surgery study) who had previously received plasma-derived products. This patient was able to continue treatment with BeneFIX with no anamnestic rise in inhibitor or anaphylaxis (see section 4.4).
No symptoms of overdose have been reported with recombinant coagulation factor IX products.
Pharmacotherapeutic group: Antihaemorrhagics, blood coagulation factor IX; ATC code: B02BD04
In a randomized, cross-over pharmacokinetic study, BeneFIX reconstituted in 0.234% sodium chloride diluent was shown to be pharmacokinetically equivalent to the previously marketed BeneFIX (reconstituted with sterile water) in 24 previously treated patients (≥12 years) at a dose of 75 IU/kg. In addition, pharmacokinetic parameters were followed up in 23 of the same patients after repeated administration of BeneFIX for six months and found to be unchanged compared with those obtained at the initial evaluation. A summary of pharmacokinetic data is presented in Table 1.
Table 1. Pharmacokinetic Parameter Estimates for BeneFIX (75 IU/kg) at Baseline and Month 6 in Previously Treated Patients with Haemophilia B | ||
|---|---|---|
Abbreviations: AUC∞ = area under the plasma concentration-time curve from time zero to infinity; Cmax = peak concentration; t1/2 = plasma elimination half life; CL = clearance; SD = standard deviation. | ||
| Parameter | Baseline n = 24 Mean ± SD | Month 6 n = 23 Mean ± SD |
| Cmax (IU/dL) | 54.5 ± 15.0 | 57.3 ± 13.2 |
| AUC∞ (IU∙hr/dL) | 940 ± 237 | 923 ± 205 |
| t1/2 (hr) | 22.4 ± 5.3 | 23.8 ± 6.5 |
| CL (mL/hr/kg) | 8.47 ± 2.12 | 8.54 ± 2.04 |
| Recovery (IU/dL per IU/kg) | 0.73 ± 0.20 | 0.76 ± 0.18 |
A population pharmacokinetic model was developed using data collected in 73 patients aged 7 months to 60 years. The parameters estimated using the final 2-compartment model are shown in Table 2. Infants and children had higher clearance, larger volume of distribution, shorter half-life and lower recovery than adolescents and adults. The terminal phase has not been covered unambiguously due to lack of data beyond 24 hours in paediatric subjects < 6 years of age.
| Age Group (years) | Infants <2 | Children 2 to < 6 | Children 6 to < 12 | Adolescents 12 to < 18 | Adults 18 to 60 |
|---|---|---|---|---|---|
| Number of subjects | 7 | 16 | 1 | 9 | 30 |
| Clearance (mL/h/kg) | 13.1 ± 2.1 | 13.1 ± 2.9 | 15.5 | 9.2 ± 2.3 | 8.0 ± 0.6 |
| Vss (mL/kg) | 252 ± 35 | 257 ± 25 | 303 | 234 ± 49 | 225 ± 59 |
| Elimination half life (h) | 252 ± 35 | 15.6 ± 1.2 | 16.3 | 21.5 ± 5.0 | 23.9 ± 4.5 |
| Recovery (IU/dL per IU/kg) | 0.61 ± 0.10 | 0.60 ± 0.08 | 0.47 | 0.69 ± 0.16 | 0.74 ± 0.20 |
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity.
No investigations on carcinogenicity, fertility impairment and foetal development have been conducted.
Powder
Sucrose
Glycine
L-Histidine
Polysorbate 80
Solvent
Sodium chloride solution
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Only the provided infusion set should be used. Treatment failure can occur as a consequence of human coagulation factor IX adsorption to the internal surfaces of some infusion equipment.
Do not use BeneFIX after the expiry date which is stated on the Vial label after EXP:. The expiry date refers to the last day of that month.
The reconstituted product does not contain a preservative and should be used immediately, but no longer than 3 hours after reconstitution. Chemical and physical in-use stability has been demonstrated for 3 hours at temperatures up to 25°C.
Store and transport at 2-30°C. Do not freeze, in order to prevent damage to the prefilled syringe.
BeneFIX 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection
BeneFIX 250 IU, 500 IU, 1000 IU, 2000 IU of powder in a 10 mL vial (type 1 glass) with a stopper (chlorobutyl) and a flip-off seal (aluminium) and 5 mL of clear, colourless solvent in a prefilled syringe (type 1 glass) with a plunger stopper (bromobutyl), a tip-cap (bromobutyl) and a sterile vial adapter reconstitution device, a sterile infusion set, two alcohol swabs, a plaster, and a gauze pad.
BeneFIX is administered by intravenous infusion after reconstitution of the lyophilised powder for injection with the supplied solvent (0.234% w/v sodium chloride solution) in the pre-filled syringe (see also section 3 of the package leaflet for reconstitution instructions).
BeneFIX, when reconstituted, contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of BeneFIX. It is important that the recommendations in section 4.2 be followed closely.
Any unused product or waste material should be disposed of in accordance with local requirements.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
Because the use of BeneFIX by continuous infusion has not been evaluated, BeneFIX should not be mixed with infusion solutions or be given in a drip.
Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium
Wyeth Farma S.A.
Autovia del Norte A-1, Km. 23. Desvio Algete, Km. 1, 28700 San Sebastian de los Reyes, Madrid
Spain
EU: October 2021
USPI: September 2021
status:
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Combined pharmaceutical dose form:
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Clinical Information
IG © 2022+ . Package hl7.fhir.uv.epi-test#0.1.0 based on FHIR 5.0.0. Generated 2024-04-04
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The Gravitate Health project has received funding from the IMI 2 Joint Undertaking under grant agreement No 945334.
This joint undertaking receives support from the EU H2020 research and innovation programme and EFPIA.
