Medicinal Products

BENEFIX 250 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 Bottle of powder + 5 ml solvent bottle
All forms

Indication

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

Dosage BENEFIX 250 IU Powder and solvent for solution for injection Box of 1 vial of powder + vial of solvent of 5 ml

Treatment should be initiated 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 plasma activity of factor IX. 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. 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).

An International Unit (IU) of factor IX activity corresponds 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 adult patients (≥ 15 years). Dosages should be adjusted according to the pharmacokinetic parameters that should be evaluated regularly in each patient.

The required dose is determined using the following formula:

Number of IU = factor IX needed

Body weight

(in kg)

X desired factor IX increase (% or UI / dl)

X Inverse of observed recovery

For a recovery of 0.7 IU / dl (average increase in factor IX), the required dose is:

Number of IU = factor IX needed

Body weight

(in kg)

X desired factor IX increase (% or UI / dl)

X 1.4 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 the event of hemorrhagic accidents and surgery.

Degree of hemorrhage / type of

Factor IX level

Frequency of injections

surgery

required (%) or (UI / dl)

(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.

More significant haemarthrosis, muscle bleeding or hematoma

30-60

Repeat the injection every 24 hours for 3 to 4 days or more until the pain and acute discomfort are gone.

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.

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. In 4 of the younger patients, shorter injection intervals or higher doses may be required.

Pediatric patients

There is insufficient data to support the use of BeneFIX in children under 6 years of age. In clinical studies, 57% of pediatric patients increased their doses either because of a lower than expected recovery, or to obtain a sufficient therapeutic response, or for both reasons. Some of these patients used an average dose> 50 IU / kg. Therefore, close monitoring of plasma factor IX activity and calculation of pharmacokinetic parameters such as recovery and half-life should be performed according to the clinical response, in order to correctly adjust the doses. 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.

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 Special warnings and precautions for use .

Administration mode

BeneFIX is administered by intravenous infusion after reconstitution of the lyophilizate with sterile water for injection (see section Special precautions for disposal and other handling ).

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 sections 4.4 Special warnings and precautions for use, Adverse reactions and Special precautions for disposal and other handling ).

Against indications

Hypersensitivity to the active substance or to any of the excipients.
Known allergic reaction to hamster proteins.

Benefix side effects

So far, no adverse events in association with BeneFIX have been reported with frequency between ≥1 / 100 and <1/10 (common). The frequency of adverse reactions reported in association with BeneFIX would be categorized as uncommon (≥1 / 1000 to <1/100) or uncommon (≥1 / 10000 to <1/1000). Among these, the most significant are: anaphylaxis, cellulitis, phlebitis and neutralizing antibodies (inhibitors).

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. Frequencies were estimated by infusion and are divided using the following categories: infrequent (≥1 / 1000 to <1/100); rare (≥1 / 10000 to <1/1000).

Nervous system disorders

Rare :

dizziness, headache, change in taste, dizziness.

Gastrointestinal disorders

Rare :

nausea

Rare:

vomiting

General disorders and administration site reactions

Rare :

cellulitis, phlebitis, injection site reaction (burning and tingling at the infusion site), discomfort at the injection site

Rare:

pyrexia

Immune system disorders

Rare :

Neutralizing antibodies (IX inhibitory factors) *

Rare:

hypersensitivity / allergy reactions; such reactions may include anaphylaxis *, respiratory distress / bronchospasm (dyspnea), hypotension, angioedema, tachycardia, chest tightness, urticaria, hives, rash, burning sensation jaw and skull, chills (feeling cold), tingling, flushing, lethargy, restlessness, dry cough / sneezing

* See additional information below.

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 have occurred concomitantly with the development of a factor IX inhibitor (see also section 4.4 Special warnings and precautions for use ).

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 adverse effects (see also section 4.4 Special 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 occurrence of inhibitor 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. There is insufficient data to document the occurrence of inhibitors in PUPs.

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.

Kidney

In one clinical trial, an HIV-positive hepatitis C patient developed 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 special 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.

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