Medicinal Products

ADVATE 3000 IU

Generic drug of the therapeutic class: Haemostasis and blood
active ingredients: Octocog alfa
laboratory: Baxter AG

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

Indication

Treatment and prophylaxis of hemorrhagic episodes in patients with hemophilia A (congenital factor VIII deficiency).

ADVATE does not contain von Willebrand factor in pharmacologically active amounts, therefore it is not indicated in von Willebrand disease.

Posology ADVATE 3000 IU Powder and solvent for solution for injection Box of 1 vial of powder + vial of solvent of 5 ml

The treatment should be initiated under the supervision of a doctor experienced in the treatment of hemophilia and with a possibility of immediate intervention in intensive care in case of anaphylaxis.

Dosage

The dosage and duration of the replacement therapy depend on the severity of the factor VIII deficiency,

the location and extent of the bleeding episode, as well as the clinical condition of the patient.

On demand processing

The factor VIII (FVIII) dose is expressed in International Units (IU), reduced to the WHO standard for factor VIII products. Factor VIII coagulant activity in plasma is expressed either as a percentage (relative to normal human plasma) or IU (relative to the International Plasma Factor VIII Standard).

One IU of factor VIII activity corresponds to the amount of factor VIII contained in one ml of normal human plasma. The calculation of the required dose of factor VIII is based on the empirical finding that one IU of factor VIII per kg of body weight increases the plasma coagulant activity of factor VIII by 2 IU / dl. The dose is determined using the following formula:

Number of units (IU) needed = body weight (kg) x desired increase in factor VIII (%) x 0.5.

If any of the following haemorrhagic events occur, the coagulant activity of factor VIII should not fall below the indicated level of plasma clotting activity (as% of normal or IU / dl) during the stated period. Table 1 below can be used as a guide for the determination of dosages during hemorrhagic episodes and surgery:

Table 1: Guide for the Determination of Dosage in Hemorrhagic Episodes and

surgery

Degree of bleeding / type of surgery

Required Factor VIII Level (% or UI / dl)

Frequency of doses (hours) / duration of treatment (days)

Hemorrhage

Start of haemarthrosis, muscle or buccal bleeding.

20 - 40

Repeat the injections every 12 to 24 hours (every 8 to 24 hours in patients under 6 years of age) for at least 1 day, until the end of the bleeding episode, indicated by the disappearance of pain or obtaining healing.

More extensive haemarthrosis, muscular haemorrhage or hematoma.

30 - 60

Repeat injections every 12 to 24 hours (every 8 to 24 hours in patients under 6 years of age) for 3 - 4 days or more until pain and acute disability are resolved.

Life-threatening hemorrhage.

60 - 100

Repeat the injections every 8 to 24 hours (every 6 to 12 hours in patients less than 6 years old) until the vital risk disappears.

Surgery

minor

Of which tooth extraction.

30 - 60

Every 24 hours (every 12 to 24 hours in patients under 6 years of age), at least 1 day, until scarring is achieved.

major

80 - 100

(pre- and postoperative)

Reapply every 8 to 24 hours (every 6 to 24 hours in patients younger than 6 years of age) until satisfactory wound healing, then continue treatment for at least 7 additional days to maintain coagulant activity Factor VIII between 30% and 60% (IU / dl).

The dose and frequency of administration should be tailored to each individual's clinical response. Under certain circumstances (presence of an inhibitor for low titre), larger doses than those calculated using the formula may be necessary.

During treatment, it is advisable to make an appropriate determination of plasma factor VIII levels in order to evaluate the dose to be administered and the frequency of the renewal of injections. In the particular case of major surgery, precise control of the replacement therapy by measuring the plasma clotting activity of factor VIII is essential. Depending on the patient, the response to factor VIII may vary, resulting in different in vivo recovery rates and half-lives.

Prophylaxis

For the long-term prophylaxis of bleeding episodes in patients with severe haemophilia A, the usual dosages are 20 to 40 IU factor VIII per kg body weight at 2 to 3 day intervals. In patients less than 6 years old, the recommended doses are 20 to 50 IU of factor VIII per kg of body weight 3 to 4 times a week.

The appearance of anti-factor VIII inhibitor should be monitored in patients. If the desired level of plasma clotting activity of the desired factor VIII is not achieved or if the bleeding episodes are not controlled following the administration of an appropriate dose, an assay must be performed to determine the presence of a factor VIII inhibitor . In patients with high titres of inhibitor, factor VIII replacement therapy may not be effective and alternative therapeutic alternatives may need to be considered. The management of such patients should be performed by physicians specializing in the treatment of hemophilia (see section Warnings and precautions for use .)

Administration mode

ADVATE should be administered intravenously. If administered by a non-health professional, appropriate training is required.

The rate of administration will be determined according to the comfort level of the patient and up to a maximum of 10 ml / min.

In the interest of the patient, it is recommended that the name and lot number be registered for each administration of ADVATE.

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

Against indications

Hypersensitivity to the active substance, to any of the excipients, or to hamster or mouse proteins.

Advate side effects

at. Summary of the safety profile

In clinical studies with ADVATE, a total of 56 adverse events were reported in 27 of the 234 treated patients. Adverse events that were observed in the largest number of patients were the development of factor VIII inhibitors (5 patients), all of which occurred in previously untreated patients in whom the risk of inhibitor formation was high, headache (5 patients), fever and vertigo (3 patients each). Of the 56 adverse events, none were observed in neonates, 16 were reported in 13 of 32 infants, 7 in 4 of 56 children, 8 in 4 of 31 and 25 of 14 of 94 * adults.

* Newborns (0 to 1 month), infants (1 month to 2 years), children (2 to 12 years), adolescents (12 to 16 years) and adults (over 16 years).

b. Summary Table of Adverse Reactions

Table 2 below shows the frequency of adverse reactions from clinical studies and spontaneous reports.

Frequency was defined according to the following criteria: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10 000, <1/1 000) and very rare (<1 / 10, 000), not known (can not be estimated from the available data). In each frequency group, adverse effects are presented in order of decreasing severity.

Table 2: Frequency of adverse events from clinical studies and reports

spontaneous

MedDRA Standard System Organ Classes

Side effects

Frequency of effects

undesirable

Infections and infestations

Influenza

Rare

Laryngitis

Rare

lymphangitis

Rare

Immune system disorders

Anaphylactic reaction

Not known frequency

Hypersensitivity c

Not known frequency

Affection of the nervous system

Headache

Frequent

Dizziness

Frequent

Memory problems

Rare

tremors

Rare

Migraine

Rare

dysgeusia

Rare

Eye disorders

Inflammation of the eyes

Rare

Vascular disorders

hematoma

Rare

Hot flashes

Rare

Pallor

Rare

Respiratory, thoracic and mediastinal disorders

dyspnoea

Rare

Gastrointestinal disorders

diarrhea

Rare

Abdominal pain

Rare

nausea

Rare

vomiting

Rare

Skin and subcutaneous tissue disorders

itching

Rare

rash

Rare

Hyperhidrosis

Rare

Nappy rash

Rare

General disorders and administration site conditions

pyrexia

Frequent

Peripheral edema

Rare

Chest pain

Rare

Chills

Rare

Abnormal condition

Rare

Tired

Not known frequency

Discomfort

Not known frequency

investigations

Anti-factor VIII antibody positive c

Frequent

Increased alanine aminotransferase

Rare

Decrease in factor VIII

coagulation b

Rare

Decreased hematocrit

Rare

Abnormal biological test

Rare

Injury, poisoning and procedural complications

Post-procedure complication

Rare

Post-procedure hemorrhage

Rare

Reaction on the site of the intervention

Rare

a) Calculated on the basis of the total of individual patients (234).

b) The unexpected decrease in plasma factor VIII coagulant activity occurred in a patient on continuous ADVATE infusion after surgery (10-14 postoperative days). Hemostasis was maintained at all times during this period. Factor VIII activity and clearance returned to normal at D15. Factor VIII inhibitor investigations performed at the end of continuous infusion and at the end of the study were negative.

c) Adverse effect explained in section c.

c. Description of some adverse effects

Inhibitor development

The immunogenicity of ADVATE has been evaluated in previously treated patients. In clinical trials with ADVATE, in 145 pediatric ** patients and adults diagnosed with severe to moderately severe haemophilia A (FVIII ≤ 2%) and previously exposed to factor VIII At least 150 days, one patient developed a low-titre inhibitor (2.4 BU according to the modified Bethesda test) after 26 days of exposure. The follow-up tests for the formation of inhibitors, performed on this patient after leaving the study, were negative. Similarly, in 53 pediatric patients younger than 6 years of age, with severe to moderately severe haemophilia A (FVIII ≤ 2%) and previously exposed to factor VIII concentrates for at least 50 days, no FVIII inhibitor has been detected.

** Pediatric patients: children (0-16 years) and adults (16 years and older)

In patients not previously treated in a current clinical trial, 5 (20%) of the 25 patients who received ADVATE developed factor VIII inhibitors. Of these, 4 had high titres (> 5 BU) and 1 had low titres (≤ 5 BU). The frequency of FVIII inhibitors detected so far is within the expected and previously observed range.

Residual effects specific to residues in the manufacturing process

The immune response of patients to traces of contaminating proteins was analyzed by examining the antibody titers against these proteins, the biological parameters and the reported adverse effects. Of the 182 treated patients, for whom antibody levels against Chinese hamster ovary (CHO) proteins were assessed, 3 cases of statistically significant increase in titre by linear regression analysis and 4 cases of prolonged or temporary peaks were observed. One patient presented both a statistically significant increase in antibodies against CHO cell proteins and a prolonged peak, but this subject did not develop any other sign or symptom of allergic response or hypersensitivity. Of the 182 treated patients, for whom antibodies to murine IgG were evaluated, 10 cases of statistically significant increases in antibodies to murine antigens by linear regression analysis and 2 cases of prolonged or temporary peaks were observed. have been observed. One patient presented both a statistically significant increase and a prolonged peak in antibodies against murine antigens. In four of these patients, isolated cases of urticaria, pruritus, rash and mildly elevated eosinophil counts were observed during repeated, repeated exposures to the product during the study.

hypersensitivity

Allergic-type reactions include anaphylaxis and have occurred in the form of dizziness, paresthesia, rash, flushing, facial swelling, urticaria and pruritus.

d. Pediatric population

In addition to the development of inhibitors in previously untreated pediatric patients (PUPs) and catheter-related complications, no differences in age-related adverse events were observed in clinical studies.

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