Human Prothrombin Complex

Registered South African indications:

• 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

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to residues of the manufacturing process
• Patients with known allergy to heparin or history of heparin induced thrombocytopenia
• Individuals who have IgA deficiency with known antibodies against IgA

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

Coagulation disorder management

• 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), human prothrombin complex should only be used when rapid correction of prothrombin complex levels is necessary, such as in cases of major bleeding or emergency surgery. In other situations, reduction of the vitamin K antagonist dose and/or administration of vitamin K is usually sufficient
• Patients receiving a vitamin K antagonist may have an underlying hypercoagulable state, and infusion of human prothrombin complex may exacerbate this condition. In cases of congenital deficiency of any of the vitamin K-dependent factors, a specific coagulation factor product should be used when available
• If allergic or anaphylactic-type reactions occur, the infusion should be stopped immediately. In the event of shock, standard medical treatment should be initiated without delay

Viral safety

• Standard measures to prevent infections resulting from the use of human prothrombin complex, a medicine prepared from human blood or plasma are implemented. These measures are considered effective for enveloped viruses such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV), but may be of limited effectiveness against non-enveloped viruses such as hepatitis A virus (HAV) and parvovirus B19
• It is strongly recommended that, whenever possible, the name and batch number of the human prothrombin complex product be recorded each time it is administered to ensure traceability between the patient and the specific product batch
• Appropriate vaccination (e.g. against HBV and HAV) should be considered for patients receiving regular treatment with medicinal products derived from human blood or plasma, such as human prothrombin complex

Risk of thrombosis and disseminated intravascular coagulation (DIC)

• There is a risk of thrombosis or disseminated intravascular coagulation (DIC) when patients are treated with human prothrombin complex, particularly with repeated dosing. Patients receiving human prothrombin complex should be closely monitored for signs or symptoms of intravascular coagulation or thrombotic events.
• Due to the risk of thromboembolic complications, careful monitoring is recommended when administering human prothrombin complex to the following patient groups:
  • patients with a history of coronary heart disease,
  • patients with liver disease,
  • peri- or postoperative patients,
  • neonates, or
  • patients at risk of thromboembolic events or disseminated intravascular coagulation

Additional precautions and considerations

• In each of these situations, the potential benefit of treatment should be weighed against the risk of associated complications
• In patients with disseminated intravascular coagulation (DIC), substitution of the coagulation factors of the prothrombin complex may be necessary under certain circumstances. However, this substitution should only be undertaken after the consumptive coagulopathy has been resolved through appropriate measures
• Reversal of vitamin K antagonists exposes patients to the thromboembolic risks associated with the underlying disease. Therefore, resumption of anticoagulation therapy should be carefully considered as soon as clinically appropriate
• No data are available regarding the use of human prothrombin complex in cases of perinatal bleeding due to vitamin K deficiency in neonates
• Human prothrombin complex contains 75–125 mg sodium per vial. This should be taken into consideration in patients on a controlled sodium diet

Effects on ability to drive and use machines

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

Forms avail. in SA and covered in this monograph: inf

South African registered indications and dosages

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 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 human prothrombin complex. 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 (International Normalised Ratio)), 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	Approximate dose* (ml human prothrombin complex/kg body weight)
2 - 2.5	0.9 – 1.3
2.5 - 3	1.3 – 1.6
3 - 3.5	1.6 – 1.9
> 3.5	> 1.9

* Multiple doses are allowed if the INR is not corrected to the desired level with a previous dose.

• IV: Max dose: Single dose should not exceed 3000 IU (120ml human prothrombin complex); Monitor INR after each dose; Correction of the vitamin K antagonist induced impairment of haemostasis persists for approximately 6-8hrs; However, the effects of vitamin K, if administered simultaneously, are usually achieved within 4-6hrs; Repeat treatment with human prothrombin complex is not usually required when vitamin K has been administered

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As these recommendations are empirical and recovery and the duration of effect may vary, monitoring of INR during treatment is mandatory.

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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

• IV: 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 is 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 IU (relative to the international standard for the specific coagulation factor). One IU of a coagulation factor activity is equivalent to the quantity in 1ml of normal human plasma

For example

The calculation of the required dosage of factor X is based on the empirical finding that 1 (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

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Applicable to all indications

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

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See Additional prescribing points for method of administration

No specific paediatric information available. See adult dosages

Pregnancy

South African recommendations

• Caution
• The safety of human prothrombin complex for use in human pregnancy has not been established

Breastfeeding

South African recommendations

• Caution
• The safety of human prothrombin complex for use in human pregnancy has not been established

Fertility

South African recommendations

• No information available

South African recommendations

• Caution; no information available

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  Because of the risk of thromboembolic complications, close monitoring should be exercised when administering to patients with liver disease
• Severe: Caution
  Severe hepatic insufficiency also results in markedly reduced levels of the vitamin K dependent coagulation factors and a clinical bleeding tendency

South African recommendations

• Caution; no information available

Immune System Disorders

Rare (≥ 1/10 000 to < 1/1 000)

• Hypersensitivity or allergic type of reactions, which may include:
  • Angioedema
  • Injection site reactions
  • Chills
  • Flushing
  • Urticaria
  • Headache
  • Changes in blood pressure
  • Anxiety
  • Nausea
  • Vomiting
  • Sweating
  • Tachycardia
  • Dyspnoea
  • Bronchospasm

In some cases, these reactions may progress to severe anaphylaxis

Vascular Disorders
Not known

• Thromboembolic episodes following the administration of human prothrombin complex

Investigations

Rare (≥ 1/10 000 to < 1/1 000)

• Transient increase in liver transaminases

Post-marketing Reported Adverse Reactions

Immune System Disorders
Not known

• Anaphylactic shock
• Anaphylactic reaction
• Hypersensitivity
• Thrombocytopenia type II (heparin-induced)

Nervous System Disorders
Not known

• Tremor

Cardiac Disorders
Not known

• Cardiac arrest
• Tachycardia

Vascular Disorders
Not known

• Thromboembolic events including:
  • Myocardial infarction
  • Cerebral infarction
  • Ischaemic stroke
  • Pulmonary embolism
  • Deep vein thrombosis
  • Peripheral thrombosis
  • Ischaemia
• Circulatory collapse
• Hypotension
• Hypertension

Respiratory, Thoracic and Mediastinal Disorders
Not known

• Dyspnoea
• Respiratory failure

Gastrointestinal Disorders
Not known

• Nausea

Skin and Subcutaneous Tissue Disorders
Not known

• Urticaria
• Rash

General Disorders and Administration Site Conditions
Not known

• Fever
• Chills

Laboratory and Diagnostic
Rare

• Therapy failure due to the formation of circulating antibodies against human prothrombin complex factors.

• Vitamin K antagonists (See Additional prescribing points)

Other interactions

• Interference with biological testing  (See Additional prescribing points)

• Plasma levels of the coagulation factors
• Prothrombin complex levels
• Prothrombin time
• International Normalised Ratio (INR)

Specific cases may require

• Coagulation assays (specific coagulation factor assays and/or global tests for prothrombin complex levels)

Additional observations

• Signs or symptoms of intravascular coagulation or thrombosis (because of the risk of thromboembolic complications)
• Clinical condition of the patient

Interaction with vitamin K antagonist treatment

• The human prothrombin complex products neutralise the effect of vitamin K antagonist treatment. 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 the human prothrombin complex the heparin as a constituent of the the human prothrombin complex must be taken into account

Method of administration

• Human prothrombin complex 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
• Please read all the instructions found in the product information and follow them carefully
• 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 human prothrombin complex 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. Remove the protective cover from the short end of the double-ended needle, making sure not to touch the exposed tip of the needle. Then perforate the centre of the water vial rubber stopper with the vertically held needle. In order to withdraw the fluid from the water vial completely, the needle must be introduced into the rubber stopper in such a way that it just penetrates the stopper and is visible in the vial
4. Remove the protective cover from the other, long end of the double-ended needle, making sure not to touch the exposed tip of the needle. Hold the water vial upside-down above the upright powder vial and quickly perforate the centre of the powder vial rubber stopper with the needle. The vacuum inside the powder vial draws in the water
5. Remove the double-ended needle with the empty water vial from the powder vial, then slowly rotate the powder vial until it is completely dissolved. Human prothrombin complex dissolves quickly at room temperature to a colourless to slightly blue solution

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. After the powder has been reconstituted in the manner described above, remove the protective cover from the filter needle and perforate the rubber stopper of the powder vial
2. Remove the cap of the filter needle and attach a 20 ml syringe
3. Turn the vial with the attached syringe upside-down and draw up the solution into the syringe
4. Disinfect the intended injection site with an alcohol swab
5. After removing the filter, inject the solution intravenously at a slow speed: Initially 1 ml per minute, not faster than 2 - 3 ml per minute

The filter needle is for single use only. Always use a filter needle when drawing up the preparation into a syringe. No blood must flow into the syringe due to the risk of formation of fibrin clots.

Storage instructions

• Powder and solvent: Store at or below 25 °C. Do not freeze. Store in the original package in order to protect from light
• Reconstituted solution: can be stored for 8 hours at or below 25 °C

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. The 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. 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.