OCTAPLASMA Solution for infusion Ref.[27992] Active ingredients: Human plasma protein fraction

General

Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections.

When medicinal products prepared from human plasma are administered, infectious disease due to the transmission of infective agents cannot be totally excluded. Like other plasma products, OCTAPLASMA carries the possibility for transmission of blood-borne viral agents, and theoretically, the variant Creutzfeldt-Jakob disease (vCJD) agent. This applies also to pathogens of hitherto unknown origin.

To reduce the risk of transmission of infective agents, stringent controls are applied to the selection and screening of donors for hepatitis B, hepatitis C and HIV infection. The plasma pools are also tested for HBsAg, anti-HIV 1/2, HBV-NAT, HIV-NAT, HCV-NAT, HAV-NAT, HEV-NAT and parvovirus B19-NAT and only those found negative or below a given cut-off limit (parvovirus B19) are used for manufacturing.

S/D treatment is not effective against non-enveloped viruses, including parvovirus B19 and HAV.

Transmission of HAV may occur following transfusion with OCTAPLASMA. It is, however greatly reduced by accepting only plasma pools found negative for HAV by a NAT test and by the presence of justified limits for neutralizing antibodies towards HAV.

Transmission of parvovirus B19 may occur following transfusion of OCTAPLASMA. However plasma pools are tested for the presence of justified limits for neutralizing antibodies towards parvovirus B19 and the parvovirus B 19 – NAT. This combination may limit the risk of infection, although no laboratory or clinical studies have been performed to show that it is sufficient to prevent infection.

However, as with FFP, the transmission of parvovirus B19 or HAV by OCTAPLASMA cannot be totally excluded. In immunocompromised patients, in patients with haematological disorders of high red cell turnover and in pregnant women, parvovirus B19 infections could lead to aplastic crises and hydrops fetalis with subsequent foetal loss, respectively. Therefore, OCTAPLASMA should only be administered to these patients if strongly indicated. A possible risk of infection should be weighed against the benefit of the inactivation of enveloped viruses such as HIV, HBV and HCV. Appropriate vaccination (e.g. against HAV) for patients in regular receipt of OCTAPLASMA should be considered. Infusion of OCTAPLASMA may give rise to specific coagulation factor antibodies.

Five cases of possible transmission of vCJD, or the causative agent of this disease, by nonleukocyte-depleted red blood cell concentrates (n=4) and a low-purity coagulation factor concentrate to a haemophiliac (n=1) have been reported in the literature [1, 2, 3, 4, 5]. The possibility of transmission of the vCJD agent by S/D plasma cannot be completely ruled-out. At present, the vCJD agent cannot be routinely detected in blood. However, the hypothesis of the Blymphocytes and follicular dendritic cells, in particular, acting as potential blood borne carriers of the prion protein and their role in neuroinvasion, suggests that leukocyte depletion during processing of blood products and plasma-derivatives will reduce the possibility of transmitting vCJD ⁶. Thus, leukocyte depletion of cellular blood components has been adopted by some countries as a measure to reduce the hypothetical risk of vCJD transmission. OCTAPLASMA undergoes multiple size exclusion filtration steps resulting in complete leukocyte removal without activating the leukocytes, and both this particular measure and the down-stream processing have demonstrated a potential to clear prions using an animal model of the agent causing vCJD ⁷. Additionally, a column has been included into the production process of OCTAPLASMA in order to specifically remove prions. This safety measure is considered effective for removing the infectious agent causing vCJD, if present in plasma ⁸. No animal material is used in the production of OCTAPLASMA.

Individuals who receive infusion of blood or plasma products may develop signs and/or symptoms of some viral infections. In the interest of the patient, it is recommended that, whenever possible, every time that OCTAPLASMA is administered to them, the name and batch number of the product is recorded.

Cardiovascular

High dosages of OCTAPLASMA or high infusion rates may induce hypervolaemia, pulmonary oedema, and/or cardiac failure. High infusion rates may cause symptoms attributable to citrate toxicity (fall in ionised calcium) e.g. fatigue, paresthaesia, tremor and hypocalcaemia, especially in patients with liver function disorders.

Gastrointestinal

The infusion should be discontinued if subjective complaints (e.g. nausea) cannot be mitigated by a reduction of the infusion rate.

Hematologic

OCTAPLASMA should not be used to correct hyperfibrinolysis caused by a deficiency of the plasmin inhibitor, alpha2-antiplasmin, as dilution with S/D treated plasma (which contains low levels of alpha2-antiplasmin) may further reduce alpha2-antiplasmin levels. 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.

An increased incidence of thromboembolic events has been described in patients receiving large volumes of S/D treated plasma. In patients considered at risk for such complications, OCTAPLASMA should only be used if the benefit exceeds the risk of thromboembolic events. Appropriate protection against thromboembolism should be employed when indicated, and patients should be monitored for thromboembolic events ⁹.

In extensive plasma exchange procedures, OCTAPLASMA should only be used to correct the coagulation abnormality when abnormal haemorrhage occurs.

Immune

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

Anaphylactic Reactions

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

Special Populations

Pregnant Women

The safety of OCTAPLASMA for use in human pregnancy and during lactation 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. 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. 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, OCTAPLASMA should be used during pregnancy and lactation only if the benefit outweighs the potential risk.

Nursing Women

See Pregnant Women section above.

Pediatrics (<16 years of age)

OCTAPLASMA was evaluated in 50 pediatric patients (age range 0-16 years) in a postmarketing study. The product should only be administered to these individuals if the likely benefits clearly outweigh potential risks.

Geriatrics (>65 years of age)

No data are available.

Monitoring and Laboratory Tests

It is important to monitor the response of the patients coagulation factor levels, both clinically and with measurement of prothrombin time (PT), partial thromboplastin time (PTT) and/or specific coagulation factor assays.

Adverse Drug Reaction Overview

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

Table 1 provides an overview on ADRs that have rarely been reported during the use of OCTAPLASMA 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.

Table 1. Adverse Reactions that were reported for OCTAPLASMA 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 ¹⁰, has not been observed with OCTAPLASMA.

The following adverse reactions have not been reported with OCTAPLASMA but were observed with FFP and therefore may also occur with OCTAPLASMA:

• 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 Table 2 the different measures are specified for the different clinical symptoms.

Table 2. Symptoms and Treatment of Adverse Reaction:

The following guidance (see Table 3) applies to specific adverse reactions, which may be associated with OCTAPLASMA:

Table 3. 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 OCTAPLASMA 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 OCTAPLASMA.

For a comprehensive overview of all clinical studies performed with OCTAPLASMA please refer to Table 6 under PART II: CLINICAL TRIALS.

Relative Frequency of Adverse Drug Reactions

The frequency of adverse drug reactions observed in clinical studies is shown in Table 4 below. The safety information derives from about 230 patients enrolled in 6 clinical studies.

Table 4. Overview of OCTAPLASMA 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.

OCTAPLASMA 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.

Post-Market Adverse Drug Reactions

Since the introduction of OCTAPLASMA in Europe in 1992, more than 9.3 million units of OCTAPLASMA have been infused into approximately 3.1 million patients. For more detailed information of reported adverse reactions please refer to Table 1 PART I: ADVERSE REACTIONS, Adverse Drug Reaction Overview.

Overview

No formal studies of drug interactions have been performed and interactions with other drugs are unknown.

OCTAPLASMA must not be mixed with other drugs as inactivation and precipitation may occur. To avoid the possibility of clot formation, solutions containing calcium must not be administered by the same intravenous line as OCTAPLASMA.

Due to the risk of activation/inactivation of OCTAPLASMA, the concomitant administration of other blood products should be avoided as much as possible, except for emergency situations. However, the product can be mixed with red blood cells and platelets.

OCTAPLASMA administration may impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella and varicella for at least six weeks, and possibly up to three months. In some cases, where large doses are given, this period may be as long as one year.

Drug-Drug Interactions

Interactions with other drugs have not been established. During clinical trials, OCTAPLASMA has been administered in association with various concomitant medications, and no interactions have been identified.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interference with serological testing

Passive transmission of plasma components from OCTAPLASMA (e.g. β-human chorionic gonadotropin; β-HCG) may result in misleading laboratory results in the recipient. For example, a false-positive pregnancy test result has been reported following passive transmission of ßHCG.