Data Sheet

OCTAPLAS

Solvent/Detergent Treated Human Plasma Solution for Intravenous Infusion

NAME OF DRUG

OCTAPLAS

Solvent/Detergent Treated Human Plasma Solution for Intravenous Infusion

DESCRIPTION

OCTAPLAS is made from pooled plasma from voluntary donors. It contains human plasma proteins. The manufacturing process includes a solvent detergent treatment step using tributyl phosphate and Octoxinol 9 to reduce the potential for virus transmission.

Composition

Each 200 mL bag contains:

PHARMACOLOGY

Pharmacodynamic properties

Pharmacotherapeutic group: Plasma substitutes and plasma protein fractions,
ATC code: B05A A.

OCTAPLAS generally possesses the same clinical activity as normal human fresh frozen plasma (FFP). After solvent/detergent (SD) treatment and subsequent removal of the SD reagents, the plasma protein content and distribution in OCTAPLAS remain at comparable levels to those in FFP, i.e. 45-70 mg/mL.

OCTAPLAS contains coagulation factors in amounts similar to those in FFP. The finished product is tested to ensure that a minimum of 0.5 IU/mL is obtained for coagulation factors V, VIII, XI. OCTAPLAS contains reduced amounts of protein S and alpha2-antiplasmin compared to FFP (see Precautions).

Pharmacokinetic properties

OCTAPLAS has similar pharmacokinetic properties to FFP.

CLINICAL TRIALS

In a prospective, single-blind, randomised study the safety and efficacy of OCTAPLAS was compared to standard FFP in adult patients with coagulopathies due to liver disease (LD) or liver transplantation (LT), or for the management of newly diagnosed Thrombotic Thrombocytopenic Purpura (TTP).

Twenty-eight patients undergoing liver transplantation were randomised to FFP (n=15) or OCTAPLAS (n=13). The median dose administered in both groups was 44 mL/kg. Plasma concentrations of coagulation factors (Fibrinogen, Factors II, V, VII, VIII and protein C) were comparable in the two groups at baseline and both immediately after, and 24 hours after, infusion. Results for clotting tests (INR, APTT) were also comparable between treatment groups. Transfusion requirements were similar.

Twenty-four patients with liver disease who were undergoing invasive procedures (mainly liver biopsy), were randomised to receive FFP (n=13) or OCTAPLAS (n=11). The median dose administered was 13 and 12 mL/kg respectively. The two products produced similar increments in plasma concentrations of coagulation factors (II, VII, and protein C). All subjects underwent the procedures without complications.

Three subjects with TTP underwent repeated plasma exchange with OCTAPLAS. All subjects achieved a platelet count of 50 ?10⁹ / L by day 3, and remained in remission after 1 year.

In another prospective, open, multi-centre study involving 100 patients the restoring effects of OCTAPLAS on depleted coagulation factors was investigated when used in large volumes for plasma exchange (PEX). Patients underwent between 1 to 28 courses of PEX, summing up to a total of 215 exposures. After an initial two-third exchange with 4% diluted albumin, the last third of the exchange was made with OCTAPLAS at an average amount of 1,735 + 755 mL per exchange. For data evaluation purposes, patients were allocated to 1 of 3 groups depending on the volume of plasma exchanged (Group 1: < 50 % exchange, Group 2: 50 -100 % exchange, Group 3: > 100 % exchange).

Following the initial infusion of albumin, a drop of coagulation factor levels was observed. After completion of the final one third of the PEX with OCTAPLAS, coagulation factor levels were restored compared to those observed following the initial two thirds with albumin, as can be seen in the following table.

Table Reduction of Coagulation Parameters in PEX Procedures.

INDICATIONS

Indications for OCTAPLAS are identical to those for FFP:

• Complex deficiencies of coagulation factors such as coagulopathy due to severe hepatic failure or massive transfusion.
• Substitution therapy in coagulation factor deficiencies, in emergency situations, when a specific coagulation factor concentrate, e.g. factor V or factor XI, is not available or when a precise laboratory diagnosis is not possible.
• Reversal of life-threatening bleeding due to warfarin effect, in conjunction with vitamin K dependant concentrates
• Thrombotic thrombocytopenic purpura (TTP), usually in conjunction with plasma exchange.
• Haemorrhage due to coagulation abnormalities resulting from intensive plasma exchange procedures.

CONTRAINDICATIONS

Contraindications for OCTAPLAS are identical to those for FFP:

• IgA deficiency with documented antibodies against IgA.
• Severe deficiencies of protein S

WARNINGs

Administration of OCTAPLAS must be based on ABO-blood group compatibility. In emergency cases, OCTAPLAS Blood Group AB can be regarded as universal plasma since it can be given to all patients.

When medicinal products prepared from human blood or plasma are administered, infectious diseases due to transmission of infective agents cannot be totally excluded. This also applies to pathogens of hitherto unknown nature.

The risk of transmission of infective agents is however reduced by:

Selection of donors by a medical interview and screening of individual donations and plasma pools for the three major pathogenic viruses HIV, HCV, HBV.

Testing of each plasma pool for HCV genomic material.

Inactivation/removal procedures included in the production process that have been validated using model viruses and are considered effective for HIV, HCV and HBV. The viral inactivation/removal procedures may be of limited value against non-enveloped viruses such as HAV and Parvovirus B19. Transmission of Parvovirus B19 has been reported after the use of S/D-treated plasma in spite of the presence of neutralising antibodies.

Parvovirus B19 may seriously affect seronegative pregnant women or immuno-compromised individuals or patients with increased red cell turn over, therefore OCTAPLAS should only be administered to these patients if strongly indicated.

A maximum of 1520 single donations are used for the manufacture of each batch of OCTAPLAS.

OCTAPLAS is produced from plasma pools containing a specified minimum antibody level which has been shown to have neutralising effect against HAV.

A possible risk of infection by non-enveloped viruses should be weighed against the benefit of the inactivation of lipid-enveloped viruses such as HIV, HBV and HCV by the SD treatment.

Appropriate vaccination (e.g. against HAV and HBV) for patients in regular receipt of medicinal products derived from human blood or plasma should be considered.

In the interest of patients, it is recommended that the name and batch number of OCTAPLAS be registered before administration.

Patients should be observed for at least 20 minutes after the administration.

In case of anaphylactic reaction or shock, the infusion must be stopped immediately. Treatment should follow the guidelines for shock therapy, (see Adverse Reactions).

PRECAUTIONS

OCTAPLAS should be used with caution under the following conditions:

• IgA deficiency
• Plasma protein allergy
• Previous reactions to FFP
• Manifest or latent cardiac decompensation
• Pulmonary oedema

OCTAPLAS should not be used as volume expander.

OCTAPLAS should not be used in cases of bleeding caused by von Willebrand's Disease (vWD) or other coagulation factor deficiencies where a specific factor concentrate is available for use.

OCTAPLAS contains reduced concentrations of plasmin inhibitor (PI) compared to normal plasma. In clinical situations where large volumes of OCTAPLAS are infused (e.g. during liver transplantation), patient PI concentrations may be reduced, predisposing the patient to the development of hyperfibrinolysis and bleeding. Consideration should be given to the use of appropriate antifibrinolytic treatment. OCTAPLAS should not be used to correct hyperfibrinolysis caused by PI deficiency, as dilution with OCTAPLAS will further reduce PI levels.

OCTAPLAS contains reduced concentrations of protein S compared to normal plasma. In clinical situations where large volumes of OCTAPLAS are infused (e.g. plasma exchange for TTP or during liver transplantation), patient plasma protein S concentrations may be reduced, predisposing the patient to the development of deep venous thrombosis (DVT). Consideration should be given to the use of prophylactic measures against DVT in such patients, especially for those with other risk factors. OCTAPLAS should not be used to treat patients with protein S deficiency.

Data on the use of OCTAPLAS in premature babies are very limited; therefore, the product should only be administered to these individuals if the likely benefits clearly outweigh potential risks.

Carcinogenesis, mutagenesis, impairment of fertility

No carcinogenicity, mutagenicity or reproductive toxicity studies have been conducted with OCTAPLAS.

Use in Pregnancy

The safety of OCTAPLAS for use in human pregnancy has not been established in controlled clinical trials. The product should not be administered to pregnant woman unless alternative therapies are regarded inappropriate, due to the potential risk of parvovirus B19 transmission, (see Warnings).

Use in Lactation

The product should not be administered to lactating woman unless alternative therapies are regarded inappropriate, due to the potential risk of parvovirus B19 transmission, (see Warnings).

Interaction with other drugs

During clinical trials, OCTAPLAS has been administered in association with various concomitant medications, and no interactions have been identified.

Incompatibilities are identical to those of FFP:

• OCTAPLAS must not be mixed with other drugs as inactivation and precipitation may occur. The product can be mixed with red blood cells and platelets.
• To avoid the possibility of clot formation, solutions containing calcium must not be administered by the same intravenous line as OCTAPLAS.
• Interactions with other drugs are unknown.

Effects on ability to drive and use machines

After ambulant infusion, the patient should rest for one hour. There is no indication that OCTAPLAS may impair the ability to drive or to operate machines.

ADVERSE REACTIONS

The following adverse reactions were reported with OCTAPLAS during clinical trials (as per CIOMS frequency categories):

Common (≥1% and < 10 %):

Cutaneous manifestation (rash, rash erythematous and urticaria).

Uncommon (≥ 0.1 % and < 1%):

Chills/shivering with or without fever.

Isolated fever.

Nausea with or without vomiting.

Local oedema.

Pulmonary manifestation.

Rare (≥ 0.01 % and < 0.1 %):

Hypocalcemia.

Anaphylactoid reaction.

The following adverse reactions are known to be associated with FFP and therefore may also occur with OCTAPLAS:

• Acute mild allergic reactions (e.g. urticaria (hives), fever, chills, nausea, vomiting, and abdominal or back pain) due to hypersensitivity to infused proteins are common.
• Acute severe allergic (anaphylactic or anaphylactoid) reactions (characterised by e.g. flushing of the skin, hypotension, substernal pain, bronchospasms, dyspnoea, and cardio-respiratory collapse) due to hypersensitivity to infused proteins or anti-IgA are rare.
• Rarely, high infusion rates may cause cardiovascular effects as a result of citrate toxicity (fall in ionised calcium), especially in patients with liver function disorders.
• In the course of plasma exchange, symptoms attributable to citrate toxicity (e.g. fatigue, paresthesia, tremor, and hypocalcemia) are uncommon.
• Rarely, incompatibility between antibodies in FFP and antigens of recipient red blood cells can result in immediate or delayed type haemolytic transfusion reactions. Therefore, administration of OCTAPLAS must be based on ABO-blood group compatibility.
• Rarely, potent anti-leukocyte antibodies may be present which, as a consequence of leukocyte aggregation in pulmonary vessels, can provoke an acute pulmonary injury, a syndrome known as transfusion-related acute lung injury characterised by chills, fever, a non-productive cough, and dyspnoea.
• Rarely, potent specific platelet antibodies may be present which can induce a passive post-transfusional purpura (PTP) characterised by dyspnoea, rash, fever, generalised purpura, and marked thrombocytopenia.
• Since the product does not contain whole cells (red blood cells, leukocytes and platelets) the risk of immunisation is reduced.
• Infusion of OCTAPLAS may give rise to specific coagulation factor antibodies.

Emergency measures for adverse reactions

Depending on type and severity of adverse reactions, the infusion may be discontinued and appropriate reanimation must be applied, as defined in general guidelines for shock therapy:

The following guidance applies to specific adverse reactions, which may be associated with OCTAPLAS:

DOSAGE AND ADMINISTRATION

Dosage

The dosage depends upon the clinical situation and underlying disorder, but 12-15 mL OCTAPLAS/kg body weight is a generally accepted starting dose (this should increase the patient's plasma coagulation factor levels by approximately 25 %). It is important to monitor the response, both clinically and with the measurement of prothrombin time (PT), partial thromboplastin time (PTT) and/or specific coagulation factor assays.

Dosage for coagulation factor deficiencies

An adequate haemostatic effect in minor and moderate haemorrhages or surgery in coagulation factor deficient patients is normally achieved after the infusion of 5-20 mL OCTAPLAS/kg body weight (this should increase the patient's plasma coagulation factor levels by approximately 10-33 %).

In the event of major haemorrhage or surgery the expert advice of a haematologist should be sought.

Dosage for TTP and haemorrhages in intensive plasma exchange

In TTP patients the whole plasma volume exchanged should be replaced with OCTAPLAS.

For the treatment of haemorrhages in intensive plasma exchange procedures the expert advice of a haematologist should be sought.

Administration

Administration of OCTAPLAS must be based on ABO-blood group compatibility. In emergency cases, OCTAPLAS blood group AB can be regarded as universal plasma since it can be given to all patients.

OCTAPLAS must be administered by intravenous infusion immediately after thawing (see Instructions for Use and Handling) using an infusion set with a filter. An aseptic technique must be used throughout the infusion.

Due to the risk of citrate toxicity, the infusion rate should not exceed 0.020-0.025 mmoL citrate/kg body weight/min equal to ≤1 mL OCTAPLAS/kg body weight/min. Toxic effects of citrate can be minimised by giving calcium gluconate i.v. into another vein.

OVERDOSAGE

• High dosages or infusion rates may induce hypervolaemia, pulmonary oedema and/or cardiac failure.
• High infusion rates may cause cardiovascular effects as a result of citrate toxicity (fall in ionised calcium), especially in patients with liver function disorders.

PRESENTATION

Incompatibilities

OCTAPLAS should not be mixed with other medicinal products as inactivation and precipitation may occur.

Storage

The shelf-life of OCTAPLAS is four years when stored at ≤ -18 °C (Deep Freeze) and protected from light.

Once the bag has been opened, the product must be used immediately, within one hour after thawing.

Instructions for use and handling

OCTAPLAS should be transported and stored at ≤ -18 °C and protected from light.

Do not use after the expiry date given on the label.

Thaw OCTAPLAS in the outer wrapper in a water bath between +30°C to +37°C. Ensure that there is good water circulation in the bath. It is important to prevent water from contaminating the entry port. Temperature in the water bath must never exceed +37 °C and should not be lower than +30 °C. Allow the content of the bag to warm to approximately +37 °C before infusion. The temperature of OCTAPLAS must not exceed +37 °C. The thawing procedure should not take more than 30 minutes.

Remove the outer wrapper and examine the bag for cracks or leaks.

Avoid shaking.

Do not use solutions, which are cloudy or have deposits.

OCTAPLAS contains no antimicrobial agent. Storage of OCTAPLAS for more than one hour after thawing may result in loss of activity of coagulation factors. To obtain the best yield of coagulation factors, OCTAPLAS should be used immediately, within one hour after thawing. OCTAPLAS stored for more than one hour after thawing should not be used to correct deficiencies especially of the labile coagulation factors.

Thawed OCTAPLAS must not be refrozen, any remaining contents must be discarded. Keep out of reach of children.

Pack

The primary pack is a 200 mL sterile, pyrogen-free, plasticised polyvinyl chloride blood bag, which is over-wrapped with a polyamide/polyethylene film.

OCTAPLAS is supplied in bags of 200 mL.

Medicine Classification

Prescription Medicine

NAME AND ADDRESS OF SPONSOR

Octapharma New Zealand Ltd
c/- Minter Ellison Rudd Watts
Lumley Centre
88 Shortland St
Auckland
New Zealand

Octapharma Australia Pty. Ltd.
Jones Bay Wharf
42/26-32 Pirrama Road
Pyrmont NSW 2009
Australia

Date of Preparation

31 October 2005