Human plasma protein fraction

The safety of human plasma protein fraction for use in human pregnancy has not been established in controlled clinical trials.

A study of the embryotoxic and teratogenic properties of TNBP and Octoxynol was carried out in rats and rabbits at dose levels of 50 to 900 μg/kg BM/day for TNBP and 250 to 4,500 μg/kg BM/day for Octoxynol.

Pre-natal development was not affected in the rats, although in the high-dose group in the rabbit, the resorption rate was slightly increased and body weight of the foetus was moderately and significantly decreased.

Although no harmful effects on mother, embryo, foetus, or child are to be expected, human plasma protein fraction should be used during pregnancy only if the benefit outweighs the potential risk.

The safety of human plasma protein fraction for use during lactation has not been established in controlled clinical trials.

Although no harmful effects on mother, embryo, foetus, or child are to be expected, human plasma protein fraction should be used during pregnancy and lactation only if the benefit outweighs the potential risk.

No test was made of the fertility and breeding efficiency, or the peri- and post-natal development since there was no evidence of any effect on the reproductive organs by the substances. In rats, some malformations occurred, but these were of a type commonly occurring in control animals of this species. No malformations were seen in the rabbits.

Adverse Drug Reaction Overview

High dosages of human plasma protein fraction or increased infusion rates may induce hypervolaemia, pulmonary oedema and/or cardiac failure. In the course of plasma exchange, symptoms attributable to citrate toxicity (e.g. fatigue, paresthaesia, tremor and hypocalcaemia) may occur.

Administration of human plasma protein fraction must be based on ABO-blood group specificity, otherwise incompatibility reactions between antibodies contained in human plasma protein fraction and antigens on the recipient’s red blood cells can result in immediate or delayed type haemolytic transfusion reactions.

The folowing table provides an overview on ADRs that have rarely been reported during the use of human plasma protein fraction during its post-approval use. As these reactions are reported voluntarily from a population of uncertain size, a reliable estimation of frequency cannot be established.

Adverse Reactions that were reported for human plasma protein fraction during its Post-Marketing Use:

Transfusion-related acute lung injury (TRALI), which is a severe and rather frequent adverse reaction known from the use of FFP, has not been observed with human plasma protein fraction.

The following adverse reactions have not been reported with human plasma protein fraction but were observed with FFP and therefore may also occur with human plasma protein fraction:

• Rarely (<1/1000), 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 characterized by chills, fever, a non-productive cough, and dyspnea.
• Rarely (<1/1000), potent specific platelet antibodies may be present which can induce a passive post-transfusion purpura (PTP) characterized by dyspnea, rash, fever, generalized purpura, and marked thrombocytopenia.

Management of Severe Adverse Reactions

The infusion should be discontinued if subjective complaints (e.g. nausea) cannot be mitigated by a reduction of the infusion rate. In case of skin reactions or tachycardia accompanied by a drop in blood pressure, or in case of respiratory problems with or without shock, infusion should be stopped immediately.

In the table below the different measures are specified for the different clinical symptoms.

Symptoms and Treatment of Adverse Reaction:

The following guidance applies to specific adverse reactions, which may be associated with human plasma protein fraction:

Guidance for Specific Adverse Reactions:

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Six clinical studies with human plasma protein fraction have been conducted by Octapharma. In total, 229 patients have been enrolled, and the patients were exposed to a total number of about 1,200 treatment courses with human plasma protein fraction.

Relative Frequency of Adverse Drug Reactions

The frequency of adverse drug reactions observed in clinical studies is shown in the table below. The safety information derives from about 230 patients enrolled in 6 clinical studies.

Overview of human plasma protein fraction Adverse Reactions Observed in Clinical Studies:

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Please refer to Table 4 above.

Abnormal Hematologic and Clinical Chemistry Findings

High infusion rates may cause symptoms attributable to citrate toxicity (fall in ionised calcium) e.g. hypocalcaemia, fatigue, paresthaesia, and tremor, especially in patients with liver function disorders.

Human plasma protein fraction contains low levels of alpha2-antiplasmin and should therefore not be used to correct hyperfibrinolysis caused by a deficiency of the plasmin inhibitor. Special attention must be paid to signs of excessive bleeding tendency in patients likely to require massive transfusions e.g. in liver transplantation or other conditions with complex disturbances of haemostasis.