OCTAPLEX 500 IU POWDER AND SOLVENT FOR SOLUTION FOR INFUSION

Active substance: PROTEIN S

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Octaplex 500 IU powder and solvent for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Octaplex is presented as a powder and solvent for solution for infusion containing
human prothrombin complex. Octaplex nominally contains:
Name of ingredient

Octaplex
Quantity per vial

Octaplex
Quantity after reconstitution with
20 ml of Water for Injections
(IU/ml)

(IU)
Active substances
Human coagulation factor II
Human coagulation factor
VII
Human coagulation factor IX
Human coagulation factor X
Further active ingredients
Protein C
Protein S

280 - 760
180 - 480

14 - 38
9 - 24

500
360 - 600

25
18 - 30

260 - 620
240 - 640

13 - 31
12 - 32

The total protein content per vial is 260 - 820 mg. The specific activity of the product
is 0.6 IU/mg proteins, expressed as factor IX activity.



Excipients known to have a recognised action or effect: sodium (75 - 125 mg per
vial), heparin (100 - 250 IU per vial, corresponding to 0.2 - 0.5 IU/IU FIX)).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Powder and solvent for solution for infusion.
The powder is of bluish-white colour.
The solvent is a clear and colourless liquid.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
-

-

4.2

Treatment of bleeding and perioperative prophylaxis of bleeding in acquired
deficiency of the prothrombin complex coagulation factors, such as deficiency caused
by treatment with vitamin K antagonists, or in case of overdose of vitamin K
antagonists, when rapid correction of the deficiency is required.
Treatment of bleeding and perioperative prophylaxis in congenital deficiency of the
vitamin K dependent coagulation factors II and X when purified specific coagulation
factor product is not available.

Posology and method of administration
Posology
Only general dosage guidelines are given below. Treatment should be initiated under
the supervision of a physician experienced in the treatment of coagulation disorders.
The dosage and duration of the substitution therapy depend on the severity of the
disorder, on the location and extent of the bleeding and on the patient’s clinical
condition.
The amount and the frequency of administration should be calculated on an individual
patient basis. Dosage intervals must be adapted to the different circulating half-life of
the different coagulation factors in the prothrombin complex (see section 5.2).
Individual dosage requirements can only be identified on the basis of regular
determinations of the individual plasma levels of the coagulation factors of interest,
or on global tests of the prothrombin complex levels (prothrombin time, INR), and
continuous monitoring of the clinical condition of the patient.
In case of major surgical interventions precise monitoring of the substitution therapy
by means of coagulation assays is essential (specific coagulation factor assays and/or
global tests for prothrombin complex levels).
Bleeding and perioperative prophylaxis of bleeding during vitamin K antagonist
treatment:
The dose will depend on the INR before treatment and the targeted INR. In the
following table approximate doses (ml/kg body weight of the reconstituted product)
required for normalisation of INR (≤ 1.2 within 1 hour) at different initial INR levels
are given.

Initial INR

2 – 2.5

2.5 – 3

3 – 3.5

> 3.5

Approximate dose*
(ml Octaplex/kg body
weight)

0.9 –1.3

1.3 – 1.6

1.6 – 1.9

> 1.9

*The single dose should not exceed 3.000 IU (120 ml Octaplex).

The correction of the vitamin K antagonist induced impairment of haemostasis
persists for approximately 6-8 hours. However, the effects of vitamin K, if
administered simultaneously, are usually achieved within 4-6 hours. Thus, repeated
treatment with human prothrombin complex is not usually required when vitamin K
has been administered.
As these recommendations are empirical and recovery and the duration of effect may
vary, monitoring of INR during treatment is mandatory.
Bleeding and perioperative prophylaxis in congenital deficiency of the vitamin K
dependent coagulation factors II and X when specific coagulation factor product
is not available:
The calculated required dosage for treatment is based on the empirical finding that
approximately 1 IU of factor II or X per kg body weight raises the plasma factor II or
X activity by 0.02 and 0.017 IU/ml, respectively.
The dose of a specific factor administered is expressed in International Units (IU),
which are related to the current WHO standard for each factor. The activity in plasma
of a specific coagulation factor is expressed either as a percentage (relative to normal
plasma) or in International Units (relative to the international standard for the specific
coagulation factor).
One International Unit (IU) of a coagulation factor activity is equivalent to the
quantity in one ml of normal human plasma.
For example, the calculation of the required dosage of factor X is based on the
empirical finding that 1 International Unit (IU) of factor X per kg body weight raises
the plasma factor X activity by 0.017 IU/ml. The required dosage is determined using
the following formula:

Required units = body weight (kg) x desired factor X rise (IU/ml) x 59
where 59 (ml/kg) is the reciprocal of the estimated recovery.
Required dosage for factor II:
Required units = body weight (kg) x desired factor II rise (IU/ml) x 50
If the individual recovery is known that value should be used for calculation.
Method of administration
For instructions on reconstitution of the medicinal product before administration, see
section 6.6. Octaplex should be administered intravenously. The infusion should start
at a speed of 1 ml per minute, followed by 2-3 ml per minute, using an aseptic
technique.

4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.
Known allergy to heparin or history of heparin induced thrombocytopenia.

4.4

Special warnings and precautions for use

The advice of a specialist experienced in the management of coagulation disorders should be
sought.
In patients with acquired deficiency of the vitamin K dependent coagulation factors (e.g. as
induced by treatment with vitamin K antagonists), Octaplex should only be used when rapid
correction of prothrombin complex levels is necessary, such as major bleeding or emergency
surgery. In other cases, reduction of the dose of the vitamin K antagonist and/or
administration of vitamin K is usually sufficient.
Patients receiving a vitamin K antagonist may have an underlying hypercoaguable state and
infusion of prothrombin complex concentrate may exacerbate this.
In congenital deficiency of any of the vitamin K dependent factors, specific coagulation factor
product should be used when available.
If allergic or anaphylactic-type reactions occur, the infusion should be stopped immediately.
In case of shock, standard medical treatment for shock should be implemented.
Standard measures to prevent infections resulting from the use of medicinal products prepared
from human blood or plasma include selection of donors, screening of individual donations
and plasma pools for specific markers of infection and the inclusion of effective
manufacturing steps for the inactivation/removal of viruses.
Despite this, when medicinal products prepared from human blood or plasma are
administered, the possibility of transmitting infective agents cannot be totally excluded. This
also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and
HCV. The measures taken may be of limited value against non-enveloped viruses such as
HAV and parvovirus B19. Parvovirus B19 infection may be serious for pregnant women
(foetal infection) and for individuals with immunodeficiency or increased erythropoiesis (e.g.
haemolytic anaemia).
It is strongly recommended that every time Octaplex is administered to a patient, the name
and batch number of the product are recorded in order to maintain a link between the patient
and the batch of the product.
Appropriate vaccination (hepatitis A and B) is recommended for patients in regular/repeated
receipt of human plasma-derived prothrombin complex products.
There is a risk of thrombosis or disseminated intravascular coagulation when patients, with
either congenital or acquired deficiency are treated with human prothrombin complex
particularly with repeated dosing. Patients given human prothrombin complex should be
observed closely for signs or symptoms of intravascular coagulation or thrombosis. Because
of the risk of thromboembolic complications, close monitoring should be exercised when
administering human prothrombin complex to patients with a history of coronary heart
disease, to patients with liver disease, to peri- or postoperative patients, to neonates, or to
patients at risk of thromboembolic events or disseminated intravascular coagulation. In each
of these situations, the potential benefit of treatment should be weighed against the risk of
these complications.
No data are available regarding the use of Octaplex in case of perinatal bleeding due to
vitamin K deficiency in the new-born.

Octaplex contains 75 - 125 mg sodium per vial. To be taken into consideration by patients on
a controlled sodium diet.

4.5

Interaction with other medicinal products and other forms of interaction
Human prothrombin complex products neutralise the effect of vitamin K antagonist
treatment, but no interactions with other medicinal products are known.
Interference with biological testing:
When performing clotting tests which are sensitive to heparin in patients receiving
high doses of human prothrombin complex, the heparin as a constituent of the
administered product must be taken into account.

4.6

Fertility, pregnancy and lactation

The safety of human prothrombin complex for use in human pregnancy and during
lactation has not been established.
Animal studies are not suitable to assess the safety with respect to pregnancy,
embryonal/foetal development, parturition or postnatal development. Therefore,
human prothrombin complex should be used during pregnancy and lactation only if
clearly indicated.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.

4.8

Undesirable effects
Immune system disorders:

Replacement therapy may rarely (≥ 1/10,000 to < 1/1,000) lead to the
formation of circulating antibodies inhibiting one or more of the human prothrombin
complex factors. If such inhibitors occur, the condition will manifest itself as a poor
clinical response.

Allergic or anaphylactic-type reactions and an increase in body temperature
have not been observed in clinical studies with Octaplex but may rarely occur (≥
1/10,000 to < 1/1,000).

General disorders and administration site conditions:

Increase in body temperature has not been observed but may rarely occur (≥
1/10,000 to < 1/1,000).
Vascular disorders:

There is a risk of thromboembolic episodes following the administration of
human prothrombin complex (see section 4.4).
Nervous system disorders:


Headache may rarely occur (≥ 1/10,000 to < 1/1,000).

Investigations:

A transient increase in liver transaminases has been rarely observed (≥
1/10,000 to < 1/1,000).
Others:
Octaplex contains heparin. Therefore, a sudden, allergy induced reduction of the
blood platelet count below 100.000/µl or 50 % of the starting count may be rarely
observed (thrombocytopenia type II). In patients not previously hypersensitive to
heparin, this decrease in thrombocytes may occur 6 - 14 days after the start of
treatment. In patients with previous heparin hypersensitivity this reduction may
happen within a few hours.
The treatment with Octaplex must be stopped immediately in patients showing this
allergic reaction. These patients must not receive heparin containing medicinal
products in the future.
For safety with respect to transmissible agents, see 4.4.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via www.mhra.gov.uk/yellowcard.

4.9

Overdose
The use of high doses of human prothrombin complex products has been associated
with instances of myocardial infarction, disseminated intravascular coagulation,
venous thrombosis and pulmonary embolism. Therefore, in case of overdose, the risk
of development of thromboembolic complications or disseminated intravascular
coagulation is enhanced.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antihemorrhagics, blood coagulation factors IX, II, VII, and X in
combination, ATC code: B02BD01.
The coagulation factors II, VII, IX and X, which are synthesised in the liver with the help of
vitamin K , are commonly called the Prothrombin Complex.
Factor VII is the zymogen of the active serine protease factor VIla by which the extrinsic
pathway of blood coagulation is initiated. The tissue factor-factor VIla complex activates
coagulation factors X and IX, whereby factor IXa and Xa are formed. With further activation
of the coagulation cascade prothrombin (factor II) is activated and transformed to thrombin.
By the action of thrombin, fibrinogen is converted to fibrin, which results in clot formation.
The normal generation of thrombin is also of vital importance for platelet function as a part of
the primary haemostasis.
Isolated severe deficiency of factor VII leads to reduced thrombin formation and a bleeding
tendency due to impaired fibrin formation and impaired primary haemostasis. Isolated
deficiency of factor IX is one of the classical haemophilias (haemophilia B). Isolated
deficiency of factor II or factor X is very rare but in severe form they cause a bleeding
tendency similar to that seen in classical haemophilia.
Acquired deficiency of the vitamin K dependent coagulation factors occurs during treatment
with vitamin K antagonists. If the deficiency becomes severe, a severe bleeding tendency
results, characterised by retroperitoneal or cerebral bleeds rather than muscle and joint
haemorrhage. Severe hepatic insufficiency also results in markedly reduced levels of the
vitamin K dependent coagulation factors and a clinical bleeding tendency which, however, is
often complex due to a simultaneous ongoing low-grade intravascular coagulation, low
platelet levels, deficiency of coagulation inhibitors and disturbed fibrinolysis.
The administration of human prothrombin complex provides an increase in plasma levels of
the vitamin K dependent coagulation factors, and can temporarily correct the coagulation
defect of patients with deficiency of one or several of these factors.

5.2

Pharmacokinetic properties

The plasma half-life ranges are:
Coagulation factor
Factor II
Factor VII
Factor IX
Factor X

half-life
48 - 60 hours
1.5- 6 hours
20 - 24 hours
24 - 48 hours

Octaplex is administered intravenously and therefore immediately available in the organism.

5.3

Preclinical safety data
There are no preclinical data considered relevant to clinical safety beyond data
included in other sections of the SPC.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Powder:
Heparin: 0.2 – 0.5 IU/IU FIX
Tri-sodium citrate dihydrate
Solvent:
Water for Injections

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products.

6.3

Shelf life
2 years
Chemical and physical in-use stability has been demonstrated for up to 8 hours
at +2°C to +25°C.
From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not be longer
than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled
and validated aseptic conditions.

6.4

Special precautions for storage
Do not store above 25°C.
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5

Nature and contents of container
One package of Octaplex contains:
Powder in a vial (type I glass) with a stopper (halobutyl rubber) and a flip off
cap (aluminium)
- 20 ml of Water for Injections in a vial (type I or type II glass) with a stopper
(halobutyl rubber) and a flip off cap (aluminium)
1 transfer set Mix2Vial™.

6.6

Special precautions for disposal

Please read all the instructions and follow them carefully!
During the procedure described below, aseptic technique must be maintained!
The product reconstitutes quickly at room temperature.
The solution should be clear or slightly opalescent. Do not use solutions that are
cloudy or have deposits. Reconstituted products should be inspected visually for
particulate matter and discoloration prior to administration.
After reconstitution the solution must be used immediately.
Any unused product or waste material should be disposed of in accordance with local
requirements.
Instructions for reconstitution:
1. If necessary, allow the solvent (Water for Injections) and the powder in the closed
vials to reach room temperature. This temperature should be maintained during
reconstitution.
If a water bath is used for warming, care must be taken to avoid water coming into
contact with the rubber stoppers or the caps of the vials. The temperature of the
water bath should not exceed 37°C.
2. Remove the caps from the powder vial and the water vial and clean the rubber
stoppers with an alcohol swab.
3. The Mix2vial™ is depicted in Fig. 1. Place the solvent vial on an even surface and
hold it firmly. Take the Mix2Vial™ and turn it upside down. Place the blue part of
the Mix2Vial™ on top of the solvent vial and press firmly down until it snaps
(Fig. 2+3).

4. Place the powder vial on an even surface and hold it firmly. Take the
solvent vial with the attached Mix2Vial™ and turn it upside down. Place
the transparent part on top of the powder vial and press firmly down
until it snaps (Fig. 4). The solvent flows automatically into the powder
vial.

5. With both vials still attached, gently swirl the powder vial until the
product is dissolved.
Octaplex dissolves quickly at room temperature to a colourless to
slightly blue solution. Unscrew the Mix2Vial™ into two parts (Fig. 5).
Dispose the empty solvent vial with the blue part of the Mix2Vial™.

If the powder fails to dissolve completely or an aggregate is formed, do not use the
preparation.
Instructions for infusion:
As a precautionary measure, the patients pulse rate should be measured before and
during the infusion. If a marked increase in the pulse rate occurs the infusion speed
must be reduced or the administration must be interrupted.
1. Attach a 20 ml syringe to the transparent part of the Mix2Vial™. Turn the vial
upside down and draw the solution into the syringe. Once the solution has been
transferred, firmly hold the plunger of the syringe (keeping it facing down) and
remove the syringe from the Mix2Vial™. Dispose the Mix2Vial™ and the empty
vial.
2. Disinfect the intended injection site with an alcohol swab.
3. Inject the solution intravenously at a slow speed: Initially 1 ml per minute, not
faster than 2 - 3 ml per minute.
No blood must flow into the syringe due to the risk of formation of fibrin clots. The
Mix2Vial™ is for single use only.

7

MARKETING AUTHORISATION HOLDER
Octapharma Limited
The Zenith Building
26 Spring Gardens
Manchester M2 1AB
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 10673/0027

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION

27/07/2008

10

DATE OF REVISION OF THE TEXT
26/07/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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