Medicinal Products

BENEFIX 3000 IU

Generic drug of the therapeutic class: Haemostasis and blood
Active ingredients: Nonacog alfa
laboratory: Pfizer Limited

Powder and solvent for solution for injection
Box of 1 vial of powder + 5 ml solvent syringe
All forms

Indication

Treatment and prophylaxis of bleeding episodes in patients with hemophilia B (congenital factor IX deficiency).

Dosage BENEFIX 3000 IU Powder and solvent for solution for injection Box of 1 vial of powder + 5 ml solvent syringe

Treatment should be under the supervision of a specialist physician in the management of hemophilia.

Dosage

The dosage and duration of replacement therapy depend on the severity of factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition. The dosage of BeneFIX may be different from that of plasma derived factor IX preparations.

To ensure that the desired factor IX level is achieved, it is necessary to carefully monitor the assay for factor IX plasma activity. The doses to be administered should be calculated and adjusted for this factor IX activity, pharmacokinetic parameters such as half-life and recovery, as well as the clinical status of the patient.

The dose and frequency of administration should always be adapted to each case according to the clinical efficacy. Factor IX preparations rarely need to be administered more than once a day.

The number of factor IX units administered is expressed in International Units (IU), calculated against the WHO standard for factor IX. Plasma activity of factor IX is expressed either as a percentage (relative to normal human plasma) or as International Units (relative to an international factor IX standard in plasma).

On demand processing

An International Unit (IU) of factor IX activity is equivalent to the amount of factor IX present in 1 ml of normal human plasma. The calculation of the dose of BeneFIX required is based on the observation that a unit of factor IX activity per kg of body weight increases the circulating factor IX level by 0.8 IU / dl on average (range 0.4 IU / dl and 1.4 IU / dl) in patients ≥12 years of age (see section 5.2 ).

The required dose is determined using the following formula:

Number of IU of factor IX needed

=

Body weight (in kg)

X

Desired increase in factor IX (% or UI / dl)

X

Inverse of observed recovery

Example: For a recovery of 0.8 IU / dl, the formula is:

Number of IU of factor IX needed

=

Body weight (in kg)

X

Desired increase in factor IX (% or UI / dl)

X

1.3 IU / kg

If the following bleeding episodes occur, the factor IX activity should not decrease below established levels of plasma activity (as a% of a normal level or in IU / dl) and for a corresponding period. The following table can serve as a guide for dosages in case of hemorrhagic accidents and in surgery:

Degree of bleeding / type of surgery

Required factor IX level (%) or (UI / dl)

Frequency of injections (hours) / Duration of treatment (days)

Hemorrhage

Premature haemarthrosis, muscle bleeding or oral cavity

20-40

Repeat every 24 hours, at least for one day, until the bleeding episode is resolved by pain or healing.
Repeat the injection every 24 hours for 3 to 4 days or more until the pain and acute discomfort are gone.

More significant haemarthrosis, muscle bleeding or hematoma

30-60

Life-threatening hemorrhages

60-100

Repeat the injection every 8 to 24 hours until the risk of bleeding stops.

Surgery

Minor: Including tooth extraction

30-60

Every 24 hours, at least for one day, until the haemorrhage stops.

Major:

80-100

(pre- and

postoperative)

Repeat the injection every 8 to 24 hours to a sufficient level of healing then continue the treatment for at least 7 days to maintain a factor IX activity of 30% to 60% (IU / dl)

During treatment, it is advisable to make an appropriate determination of factor IX levels to determine the dose to be administered and the frequency of injections. Precise monitoring of replacement therapy is essential by measuring coagulation activity (plasma factor IX activity), particularly in the case of major surgical procedures. The response of each patient to factor IX may vary, with different levels of in vivo recovery and different half-lives.

Prophylaxis

BeneFIX can be administered as part of a long-term prophylaxis to prevent bleeding episodes in patients with hemophilia B. In a clinical trial in secondary prophylaxis, the average dose for previously treated patients ( PTP) was 40 IU / kg (range: 13 to 78 IU / kg) two to three times a week.

Pediatric population

In pediatric patients under 6 years of age treated with BeneFIX, there is limited data available for on-demand treatment and surgery.

The mean dosage (± standard deviation) for prophylaxis was 63.7 (± 19.1) IU / kg at intervals of 3 to 7 days. In younger patients, shorter injection intervals or higher doses may be necessary. Factor IX consumption in routine prophylaxis in 22 evaluable patients was 4607 (± 1849) IU / kg per year and 378 (± 152) IU / kg per month.

Close monitoring of factor IX plasma activity based on clinical indication and calculation of pharmacokinetic parameters such as recovery and half-life should be performed in order to adjust doses correctly. If doses> 100 IU / kg have had to be used repeatedly for prophylaxis or during the treatment on demand, switching to another factor IX should be considered.

Inhibitor monitoring

The appearance of a factor IX inhibitor should be monitored in patients treated with BeneFIX. If the desired plasma factor IX levels can not be reached or the bleeding is not controlled after a dose calculated according to the above formula, specific biological tests should be performed to detect the presence of an inhibitor. .

In patients with a high level of inhibitor, treatment with factor IX may be ineffective and other treatment options should be considered. Management of these patients should be performed by a hemophilia specialist. See also Warnings and Precautions for Use .

Administration mode

BeneFIX is administered by intravenous infusion after reconstitution of the lyophilizate with sodium chloride solution (0.234%) (see section Instructions for use, handling and disposal ).

BeneFIX should be administered slowly. In most cases, a flow rate ≤4 ml / min was used. The rate of administration should be determined according to the comfort level of the patient.

Continuous infusion has not been approved and is therefore not recommended (see also Warnings and Precautions, Adverse Reactions and Instructions for Use, Handling and Disposal ).

For instructions on reconstitution of the drug before administration, see the section Instructions for use, handling and disposal .

Against indications

Hypersensitivity to the active substance or to any of the excipients listed under Composition .

Known allergic reaction to hamster proteins.

Benefix side effects

Summary of the security profile

The most common side effects are headache, dizziness, nausea, injection site reaction, injection site pain, and skin hypersensitivity reactions. The most significant effects are: anaphylaxis, cellulitis, phlebitis, and neutralizing antibodies. Side effects are uncommon or rare.

Structured list of adverse effects

In uncontrolled open-label clinical trials with BeneFIX in PTPs, 113 adverse events were reported in 25 of 65 patients (38.5%) who received a total of 7573 infusions. Adverse reactions, estimated by infusion, are common (≥1 / 100 to <1/10), infrequent (≥1 / 1000 to <1/100), or rare (≥1 / 10, 000 to <1/1000) ). Adverse reactions based on experience from clinical and post-marketing trials are presented below by organ system class and frequency. In each frequency category, adverse effects are presented in order of decreasing severity.

Immune system disorders

Uncommon: Rare:

Neutralizing antibodies (IX inhibitory factors) *
allergic reactions which may include anaphylaxis, respiratory distress / bronchospasm (dyspnea), hypotension, angioedema, tachycardia, chest tightness, urticaria, urticarial rashes, rash, burning sensation, chills, paresthesia, tingling, flushing, lethargy, agitation, dry cough / sneezing, blurred vision

Nervous system disorders

Rare :

dizziness, headache, dysgeusia

Gastrointestinal disorders

Uncommon: Rare:

nausea
vomiting

General disorders and administration site conditions

Rare :

cellulite, phlebitis, injection site reaction (including burning sensation and tingling at the injection site), discomfort at the injection site

Rare:

pyrexia

* See additional information below.

Description of some adverse effects

Hypersensitivity / allergic reactions

Rare cases of hypersensitivity or allergic reactions have been observed in patients treated with factor IX preparations, including BeneFIX. In some cases, these allergic reactions have evolved into severe anaphylaxis. Allergic reactions occurred concomitantly with the development of a factor IX inhibitor (see also Warnings and Precautions ).

The etiology of allergic reactions with BeneFIX has not yet been determined. These reactions are life-threatening. If allergic or anaphylactic reactions occur, administration of BeneFIX should be discontinued immediately. In case of severe allergic reactions, alternative replacement therapy should be considered. Treatment should depend on the nature and severity of the side effects (see also Warnings and precautions for use ).

Because of its manufacturing process, BeneFIX contains traces of hamster proteins that can cause hypersensitivity reactions.

Inhibitor development

Patients with hemophilia B can develop neutralizing antibodies (inhibitors) against factor IX. The appearance of inhibitors may be manifested by an insufficient clinical response. In this case, it is recommended to contact a center specialized in the treatment of hemophilia. A clinically relevant low-grade inhibitor was detected in one of 65 BeneFIX-treated patients (9 of whom participated in the surgical study only) who had previously received plasma derivatives. Treatment with BeneFIX could be continued in this patient without anamnestic or anaphylactic reaction.

The occurrence of nephrotic syndrome after induction of immune tolerance with high doses of human plasma factor IX has been reported in patients with haemophilia B with factor IX inhibitors and a history of allergic reactions.

Renal infarction

In a clinical trial, an HCV-positive patient developed a renal infarction 12 days after receiving a dose of BeneFIX for a bleeding episode. The relationship between infarction and previous administration of BeneFIX is uncertain. Treatment with BeneFIX has not been interrupted.

Thrombotic events

In post-marketing follow-up, cases of thrombotic events, including life-threatening superior vena cava (SVC) syndrome, have been reported in critically ill neonates receiving BeneFIX by continuous catheter infusion. Peripheral thrombophlebitis and deep vein thrombosis have also been reported. In the majority of cases, BeneFIX was administered as a continuous infusion, which is not a recommended method of administration (see also sections Posology and method of administration and Warnings and precautions for use ).

Inadequate therapeutic response and inadequate factor IX recovery

Inadequate therapeutic response and inadequate factor IX recovery have been reported during post-marketing monitoring of BeneFIX (see also section Dosage and method of administration )

If adverse reactions seemingly related to BeneFIX administration occur, the injection should be slowed or stopped.

Pediatric population

Allergic reactions may occur more frequently in children than in adults.

There is insufficient data to document the incidence of inhibitors in PUPs (see also section 5.1 Pharmacodynamic properties ).

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