Octaplasma Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

PART I: HEALTH PROFESSIONAL INFORMATION ................................................................. 4

1 INDICATIONS ................................................................................................................. 4

1.1 Pediatrics ............................................................................................................... 4

1.2 Geriatrics ............................................................................................................... 4

2 CONTRAINDICATIONS .................................................................................................. 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ........................................................ 5

4 DOSAGE AND ADMINISTRATION ................................................................................ 5

4.1 Dosing Considerations ........................................................................................... 5

4.2 Recommended Dose and Dosage Adjustment ....................................................... 5

4.4 Administration ........................................................................................................ 5

4.5 Missed Dose .......................................................................................................... 6

5 OVERDOSAGE ............................................................................................................... 7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ......................... 7

7 WARNINGS AND PRECAUTIONS ................................................................................. 7

7.1 Special Populations ............................................................................................. 10

7.1.1 Pregnant Women ...........................................................................................10

7.1.2 Breast-feeding ................................................................................................10

7.1.3 Pediatrics .......................................................................................................10

7.1.4 Geriatrics .......................................................................................................10

8 ADVERSE REACTIONS ............................................................................................... 10

8.1 Adverse Reaction Overview ................................................................................. 10

8.2 Clinical Trial Adverse Reactions........................................................................... 12

8.3 Less Common Clinical Trial Adverse Reactions ................................................... 14

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ........................................................................................................... 14

8.5 Post-Market Adverse Reactions ........................................................................... 14

9 DRUG INTERACTIONS ................................................................................................ 15

9.2 Drug Interactions Overview .................................................................................. 15

9.4 Drug-Drug Interactions ......................................................................................... 16

9.5 Drug-Food Interactions ........................................................................................ 16

9.6 Drug-Herb Interactions ......................................................................................... 16

9.7 Drug-Laboratory Test Interactions ........................................................................ 16

10 CLINICAL PHARMACOLOGY ...................................................................................... 16

10.1 Mechanism of Action ...................................................................................... 16

10.2 Pharmacodynamics ........................................................................................ 16

10.3 Pharmacokinetics ........................................................................................... 17

11 STORAGE, STABILITY AND DISPOSAL ..................................................................... 18

12 SPECIAL HANDLING INSTRUCTIONS ........................................................................ 18

PART II: SCIENTIFIC INFORMATION ..................................................................................... 19

13 PHARMACEUTICAL INFORMATION ........................................................................... 19

14 CLINICAL TRIALS ........................................................................................................ 21

14.1 Trial Design and Study Demographics ........................................................... 21

14.2 Study Results .................................................... Error! Bookmark not defined.

16 NON-CLINICAL TOXICOLOGY .................................................................................... 24

PATIENT MEDICATION INFORMATION ................................................................................. 25

Part 1: Healthcare Professional Information

1 Indications

OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) is indicated for:

• Complex deficiencies of coagulation factors such as consumption coagulopathy e.g. disseminated intravascular coagulation (DIC) or coagulopathy due to severe hepatic failure, massive transfusion, or repeated large volume plasma exchange (especially in patients with impaired liver function).
• OCTAPLASMA may be used for emergency substitution therapy in coagulation factor deficiencies, when situations, e.g. haemorrhage, do not allow a precise laboratory diagnosis, or when a specific coagulation factor concentrate is not available.
• Rapid reversal of effects of oral anticoagulants when vitamin K is insufficient in emergency situations, or in patients with impaired liver function.

The efficacy in patients with Thrombotic Thrombocytopenic Purpura has not been studied sufficiently, therefore, the clinical experience in these patients is limited.

OCTAPLASMA should be administered under the supervision of a qualified health professional who is experienced in the use of anticoagulation agents and in the management of coagulation disorders. Appropriate management of therapy and complications is only possible when adequate diagnostic and treatment facilities are readily available.

1.1 Pediatrics

Pediatrics (< 20 years of age): OCTAPLASMA was evaluated in 91 pediatric patients (age range 0-20 years) in two post-marketing studies. (See 14 Clinical Trials, Table 9 and Table 10Error! Reference source not found.). The product should only be administered to these individuals if the likely benefits clearly outweigh potential risks.

1.2 Geriatrics

No data are available.

2 Contraindications

Contraindications for OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) are as follows:

• OCTAPLASMA is contraindicated in patients with IgA deficiency with documented antibodies against IgA as it may cause anaphylactic and anaphylactoid reactions.
• OCTAPLASMA is contraindicated in patients with severe deficiency of protein S as it may result in an increased risk of developing blood clots.
• OCTAPLASMA is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.

3 Serious Warnings and Precautions Box

• This product is prepared from large pools of human plasma, which may contain the causative agents of hepatitis and other viral diseases. The physician should discuss the risks and benefits of this product with the patient before prescribing or administering to the patient (see Warnings and Precautions).

4 Dosage and Administration

4.1 Dosing Considerations

The dosage depends upon the clinical situation and underlying disorder. The volume and frequency of plasma exchanges vary depending on the individual patient, the clinical situation, and the preferred regimen of treatment. In the event of major haemorrhage or surgery, the expert advice of a haematologist should be sought.

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. Due to the risk of citrate toxicity, the infusion rate should not exceed 0.020-0.025 mmol citrate/kg body weight/min, which equals to 1 mL OCTAPLASMA/kg body weight/min. Toxic effects of citrate can be minimised by giving calcium gluconate i.v. into another vein. Patients should be observed for at least 20 minutes after the administration.

4.2 Recommended Dose and Dosage Adjustment

The volume and frequency of plasma exchanges vary depending on the individual patient, the clinical situation, and the preferred regimen of treatment. The volume of the plasma exchange in most therapeutic procedures is usually equivalent to the plasma volume of the patient. A part of the exchanged plasma volume should be replaced with OCTAPLASMA in order to prevent haemostatic disorders associated with a decreased level of coagulation factors (especially in patients with impaired liver function).

The dosage depends upon the clinical situation and underlying disorder, but 12-15 mL OCTAPLASMA/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 measurement of prothrombin time (PT), partial thromboplastin time (PTT) and/or specific coagulation factor assays.

An adequate haemostatic effect in minor and moderate haemorrhages or surgery is normally achieved after the infusion of 5-20 mL OCTAPLASMA/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.

4.4 Administration

Administration of OCTAPLASMA must be based on ABO-blood group specificity. In emergency cases, OCTAPLASMA blood group AB can be regarded as universal plasma since it can be given to all patients. OCTAPLASMA must be administered by intravenous infusion after thawing using an infusion set with a filter. Aseptic technique must be used throughout the infusion.

There are several options for thawing frozen OCTAPLASMA:

• Using a water bath:

  Thaw in the outer wrapper for not less than 30 minutes in a circulating water bath at +30 °C to +37 °C. An overwrap bag may be used to provide further protection of contents if appropriate. Prevent water from contaminating the entry port. The minimum thawing time is 30 minutes at 37 °C. Temperature in the water bath must never exceed +37 °C and should not be lower than +30 °C. The thawing time depends on the number of bags in the water bath. If more plasma bags are thawed in parallel, the thawing time can be prolonged but should not be longer than 60 minutes.

• Using a dry tempering system such as the SAHARA-III:

  Place the OCTAPLASMA bags on the agitation plate according to the manufacturer instructions and thaw plasma using the fast tempering function. When +37 °C blood component temperature is indicated on the temperature display terminate the tempering process and remove the bags.

Other thawing systems for frozen OCTAPLASMA can be used on the condition that the methods are validated for that purpose.

Allow the content of the bag to warm to approximately +37 °C before infusion. The temperature of OCTAPLASMA must not exceed +37 °C. Remove the outer wrapper and examine the bag for cracks or leaks.

Avoid shaking.

Do not use solutions that are cloudy or have deposits.

Precautions:

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.

Special Precautions for Storage:

Protect from light.

Thawed OCTAPLASMA must not be refrozen. Unused product must be discarded.

4.5 Missed Dose

Not applicable because OCTAPLASMA is administered in a hospital setting by health care professionals.

5 Overdose

Overdose may lead to hypervolaemia and thereby pulmonary oedema and/or cardiac failure. In such cases, OCTAPLASMA transfusion should be stopped immediately. General measures such as the administration of furosemide can be considered, if clinically appropriate.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of biologic products, including biosimilars, healthcare professionals should record both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 1 - Dosage Forms, Strengths, and Composition and Packaging

Description

OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) is supplied frozen in bags of 200 mL containing 45-70 mg/mL Human Plasma Proteins.

Nature and Contents of Container

Each 200 mL of OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) contains Human plasma proteins (9.0-14.0 g), Sodium citrate dihydrate (0.88-1.48 g), Sodium dihydrogenphosphate dihydrate (0.06-0.24 g), Glycine (0.80-1.20 g), TNBP (< 2.0 mcg/mL), Octoxynol (< 5.0 mcg/mL).

7 Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box.

This product is prepared from large pools of human plasma. Thus, there is a possibility it may contain causative agents of viral or other undetermined diseases.

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 B19–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 non-leukocyte-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. 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 B-lymphocytes 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. 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. 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. 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. OCTAPLASMA should be used with caution in patients with pulmonary oedema, and manifest or latent cardiac decompensation. 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.

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.

OCTAPLASMA should be used with caution in patients with IgA deficiency, plasma protein allergy or previous reaction to FFP or OCTAPLASMA.

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

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.

7.1 Special Populations

7.1.1 Pregnancy

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.

7.1.2 Breastfeeding

It is unknown if OCTAPLASMA is excreted in human milk. Precaution should be exercised because many drugs can be excreted in human milk.

7.1.3 Pediatrics

OCTAPLASMA was evaluated in 91 pediatric patients (age range 0-20 years) in two post-marketing studies. The product should only be administered to these individuals if the likely benefits clearly outweigh potential risks.

7.1.4 Geriatrics

No data are available.

8 Adverse Reactions

8.1 Adverse Reaction Overview

The most common adverse reactions observed in clinical studies with OCTAPLASMA were urticaria, pruritus, nausea, pyrexia and citrate toxicity. Each of them happened in 2 subjects out of 152 (1.3%).

No serious adverse reactions were seen in the prospective interventional clinical studies with OCTAPLASMA.

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.

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 Reactions

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

Table 3: Guidance for Specific Adverse Reactions

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug. Eight prospective interventional clinical studies were performed with OCTAPLASMA. Two studies conducted before 2000 that had no adverse reactions reported and one study in healthy volunteers were excluded. This resulted in a sub-population of 152 patients treated with OCTAPLASMA from 5 studies (03PLASIV90, 19/PLAS/IV/91, LAS-1-03-UK, LAS-212 and LAS-213).

For a comprehensive overview of all clinical studies performed with OCTAPLASMA please refer to Table 9 and Table 10Error! Reference source not found. under Part 2: Scientific Information: Clinical Trials.

Three of the above mentioned 5 studies (03PLASIV90, 19/PLAS/IV/91, LAS-1-03-UK) were in adults (N=61).

Table 4 - Clinical Trial Adverse Reactions - Adults

03PLASIV90 an open-labelled prospective study assessed the effects of OCTAPLASMA in 11 adult patients with hereditary or acquired coagulation factor deficiency. In total, 3 adverse reactions were observed in 2 out of the 11 patients. In 1 patient a severe anaphylactoid reaction was observed, in another patient pruritus and urticaria were reported. No serious or unexpected adverse reactions occurred, and no patient dropped out of the study for safety reasons. No adverse laboratory findings or evidence of a seroconversion was reported during the follow-up period.

19/PLAS/IV/91 an open, parallel group study was performed in severely ill surgical patients who were allocated to receive either a single infusion of OCTAPLASMA (n=20) or no plasma treatment (n=26) during open-heart surgery. In terms of safety, only 1 case of a transient increase in temperature in an asthmatic patient was reported for OCTAPLASMA. No abnormal liver function tests or evidence of a seroconversion were noted in the 16 patients, who were followed up for 6 months after exposure to OCTAPLASMA.

LAS-1-03-UK a prospective, single-blind, randomized study was designed to investigate the safety and efficacy of OCTAPLASMA compared with standard FFP in adult patients with coagulopathies due to liver disease (LD) or liver transplantation (LTX), or for the management of newly diagnosed thrombotic thrombocytopenic purpura (TTP). In total, 55 patients were included. Thereof, 3 patients were suffering from TTP and all received OCTAPLASMA. Of the 24 patients with LD, 11 were treated with OCTAPLASMA, and out of the 28 LTX patients, 13 received OCTAPLASMA. Two deaths (1 in each treatment group) were recorded in the immediate post-study period. Both patients had severe LD, and died as a result of worsening of this disease. Only in 1 patient the reported adverse reactions (nausea and pruritus) were considered to be related to OCTAPLASMA treatment.

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Two of the above mentioned 5 studies (LAS-212 and LAS-213) were in pediatrics (N=91).

Table 5 - Clinical Trial Adverse Reactions - Pediatrics

LAS-212 was a prospective, open-label, multicenter, single arm, postmarketing study in pediatric patients requiring replacement of multiple coagulation factors. Fifty pediatrics between 0 weeks and 16 years of age were enrolled into the study and received at least 1 infusion episode of OCTAPLASMA. Thirty-seven patients were aged 2 or under and 13 were children or adolescents over 2. There were 2 unrelated TE or TEEs reported in 2 patients, these were SAEs of portal vein thrombosis and intracardiac thrombus. No adverse reactions were reported during the study.

LAS-213 was a prospective, open-label, multicenter, single-arm, postmarketing study pediatrics who underwent therapeutic plasma exchange (TPE). A total of 102 TPE procedures were performed in 41 subjects aged 2 to 20. Overall, a total of 135,137 mL of OCTAPLASMA was administered. No thrombotic or thromboembolic events were found in any study subject.

In total, 8 adverse reactions were found in 4 subjects. These included 5 adverse reactions in three adolescents and 3 adverse reactions in one young adult. Adverse reactions in adolescents included citrate toxicity (2 in 2 subjects), and headache, pyrexia, and urticaria (each reported in 1 subject), while adverse reactions found in young adults included inflammatory marker (C-reactive protein, procalcitonin) increased, myalgia, and nausea (each reported in 1 subject). Most (7/8) adverse reactions were mild in intensity and recovered/resolved by end of study. No treatment-related serious adverse events were reported.

8.3 Less Common Clinical Trial Adverse Reactions

Please refer to 8.2, Table 4 above.

8.3.1 Less common Clinical Trial Adverse Reactions – Pediatrics

Please refer to 8.2.1, Table 5 above.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

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.

8.5 Post-Market Adverse Reactions

Since the introduction of OCTAPLASMA in Europe in 1992, more than 13.9 million units of OCTAPLASMA have been infused into approximately 4.6 million patients. For more detailed information of reported adverse reactions please refer to Table 6.

Table 6 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 6 : Adverse Reactions that were reported for OCTAPLASMA during its Post-Marketing Use

9 Drug Interactions

9.2 Drug Interactions 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.

9.3 Drug-Behaviour Interactions

The interaction of OCTAPLASMA with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4 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.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

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 ß-HCG.

10 Clinical Pharmacology

10.1 Mechanism of Action

OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) is a virus inactivated frozen human plasma and is assumed to be active on a species-specific basis.

10.2 Pharmacodynamics

The total protein concentration is 45-70 mg/mL. The protein distribution is within the normal range of human plasma, please refer to Table 7 below. Protein S and Plasmin inhibitor levels have been found to be below the range for normal human plasma. The final product release limits are ≥ 0.4 IU/ml and ≥ 0.2 U/ml, respectively.

After S/D treatment and subsequent removal of S/D reagents, the plasma protein content and distribution in OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) remain at comparable levels to those in normal fresh frozen plasma (see Table 7).

Table 7: Plasma Protein Levels in OCTAPLASMA Compared to Single-Donor Fresh-Frozen Plasma

Parameters

OCTAPLASMA (n=12)

Mean (min-max)

Reference ranges

FFP

Total protein [mg/mL]

55 (54-57)

48-64

Albumin [mg/mL]

32 (30-34)

28-41

Fibrinogen [mg/mL]

2.5 (2.4-2.6)

1.45-3.85

IgG [mg/mL]

9.65 (9.15-10.10)

6.60-14.50

IgA [mg/mL]

2.00 (1.80-2.05)

0.75-4.20

IgM [mg/mL]

1.25 (1.20-1.30)

0.40-3.10

Factor V [IU/mL]

0.78 (0.75-0.84)

0.54-1.45

Factor VII [IU/mL]

1.08 (0.90-1.17)

0.62-1.65

Factor X [IU/mL]

0.78 (0.75-0.80)

0.68-1.48

Factor XI [IU/mL]

0.99 (0.91-1.04)

0.42-1.44

Protein C [IU/mL]

0.85 (0.81-0.87)

0.58-1.64

Protein S [IU/mL]

0.64 (0.55-0.71)

0.56-1.68

Plasmin inhibitor [IU/mL]

0.23 (0.20-0.27)

0.72-1.32

12 consecutive batches OCTAPLASMA were investigated; mean (minimum-maximum) values are presented; FFP, single-donor fresh-frozen plasma

10.3 Pharmacokinetics

During one clinical study (PLAS_IV_90) pharmacokinetic data of coagulation factors after treatment with OCTAPLASMA reconstituted as lyophylisate have been collected from eight patients suffering from hereditary coagulation factor deficiencies. All patients received a single OCTAPLASMA infusion of an average of 580 mL (range 400 to 1,600 mL). The dose administered was expected to achieve and maintain a plasma concentration of 10% to 20% of normal of the deficient coagulation factor. The pharmacokinetic results are shown in Table 8 (see 14 Clinical Trials).

Table 8: Pharmacokinetic results

Vd volume of distribution; CL clearance; MRT mean residence time; T ½ half life; IU international unit.

These pharmacokinetics parameters after OCTAPLASMA administration were within the kinetic profile of coagulation factors after administration of FFP. No pharmacokinetic results are available for the remaining coagulation factors.

Absorption

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

Distribution, Metabolism and Excretion

OCTAPLASMA is a virus inactivated frozen human plasma and is assumed to be active on a species-specific basis. Human plasma may cause severe toxic reactions in animals and is not tolerated at dosages approaching those generally used in humans. Routine pharmacology testing in laboratory animals is not considered to add any relevant information for the safety and efficacy of OCTAPLASMA in the clinical use.

Two contaminants derived from the manufacturing process, namely Tri(n-butyl)phosphate (TNBP) and Octoxynol, might be present in the final product. A program of studies has been carried out to assess the pharmacokinetic profile of TNBP and Octoxynol. After i.v. administration in rats, TNBP disappeared rapidly from the plasma with an elimination half-life of approximately 20 min. TNBP was not found at any time in the urine and only very small amounts were detectable in the faeces. Concomitantly administered Octoxynol could not be detected in the plasma, the urine or the faeces.

Special Populations and Conditions

No specific pharmacokinetic studies have been performed in patients at increased risk, such as elderly subjects or patients with renal or hepatic impairment.

10.4 Immunogenicity

Treatment with plasma may rarely lead to the formation of circulating antibodies inhibiting one or more proteins mostly coagulation factors. No clinical trials were performed to evaluate the occurrence of inhibitor formation.

11 Storage, Stability, and Disposal

The shelf life of OCTAPLASMA is 48 months when stored at ≤ -18 °C.

Protect from exposure to light.

After thawing, OCTAPLASMA can be stored for up to 5 days at +2 to 8 °C or for up to 8 hours at room temperature (+20 to 25°C) before use. Do not use solutions that are cloudy or have deposits.

Thawed OCTAPLASMA must not be refrozen. Unused product must be discarded.

12 SPECIAL HANDLING INSTRUCTIONS

Any unused product or waste material should be disposed of in accordance with local requirements for blood products.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: OCTAPLASMA, Solvent Detergent (S/D) Treated Human Plasma

Chemical name: Human Plasma

Molecular formula and molecular mass: not applicable

Structure/structural formula: not applicable

Physicochemical properties: The total protein concentration is 45-70 mg/mL. The protein distribution is within the normal range of human plasma.

Pharmaceutical standard: ATC-Code: B05AX03

Product Characteristics:

OCTAPLASMA is solvent detergent (S/D) treated human plasma (45-70 mg/mL human plasma proteins). During the manufacturing process, OCTAPLASMA is treated with a combination of 1 % Tri(nbutyl)- phosphate (TNBP) and 1 % Octoxynol. These S/D reagents are removed by castor oil extraction (TNBP) and subsequent solid phase extraction (Octoxynol) before sterile filtration. After sterile filtration, 200 mL OCTAPLASMA is filled into sterile, pyrogen-free, plasticised polyvinyl chloride (PVC) blood bags that are over-wrapped with a polyamide/polyethylene film.

The coagulation activity values are close to the corresponding values for normal human single-donor fresh-frozen plasma (FFP) and a minimum of 0.5 IU/mL is obtained for all clotting factors. However, as a result of the S/D treatment and purification, the content of lipids and lipoproteins is reduced. This is of no relevance for the indications for OCTAPLASMA. OCTAPLASMA has similar pharmacokinetic properties as normal FFP.

Viral Inactivation

Precautions against viral transmission include: selection of plasma donors, screening of donations and plasma pool, as well as quality control measurements of the final product. As with any blood product, a potential problem is the transmission of blood borne pathogens including those of hitherto unknown origin. When medicinal products prepared from human blood or plasma are given to a patient, the transmission of infectious agents cannot be totally excluded. This applies also to hitherto unknown pathogens. This product is prepared from large pools of human plasma, which may contain the causative agents of hepatitis and other viral diseases (see Warnings and Precautions section).

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. To improve the viral safety of OCTAPLASMA compared to FFP, virus inactivation using the S/D method has been included in the OCTAPLASMA manufacturing process. The S/D method has been shown to inactivate the enveloped viruses (such as HIV, HBV and HCV) in a rapid and complete manner.

From its mode of action it is clear that the S/D method has no effect on non-enveloped viruses such as HAV and parvovirus B19. Thus, there is an increased risk of transmitting these viruses by pooling of plasma. However, the presence of justified limits for neutralising antibodies towards HAV and parvovirus B19 in the starting plasma and the final product, result in immune neutralisation and passive immunisation which both serve to limit or prevent virus replication in vivo and thereby infection in patients.

Five cases of possible transmission of vCJD, or the causative agent of this disease, by non-leukocyte-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. 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 B-lymphocytes and follicular dendritic cells, in particular, acting as a 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. 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. 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. No animal material is used in the production of OCTAPLASMA.

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 neutralizing antibodies towards HAV (anti-HAV IgG with a minimum level of 0.6 IU/mL).

Transmission of parvovirus B19 may occur following transfusion of OCTAPLASMA. However plasma pools are tested for the presence of neutralizing antibodies towards parvovirus B19 (antiparvovirus B19 IgG with a minimum level of 11 IU/mL is acceptable) and the parvovirus B 19– NAT (an upper limit of 10.0 IU/μl is acceptable). 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.

14 Clinical Trials

14.1 Clinical Trials by Indication

Clinical trials in coagulation factor deficiencies

Table 9 - Summary of Patient Demographics for Clinical Trials in Coagulation Factor Deficiency

Efficacy and safety of OCTAPLASMA in coagulation factor deficiency were assessed in four prospective clinical studies (Studies Nos. 1 to 4) and 1 post-authorisation study (Study No. 5).

In total 91 adult patients with coagulation factor deficiency (Studies Nos. 1 to 4) were enrolled. The post-authorisation study (Studies No. 5) has been conducted in 50 pediatric patients (age range 0-20 years). All these studies used an open design, which is an acceptable approach for a compound of this class.

Efficacy

An open-label non-interventional single centre study (LAS-Study 1-D) was conducted in 30 patients with disseminated intravascular coagulation (DIC) or coagulopathy due to dilution or blood loss requiring coagulation-active plasma therapy. The objectives were to assess the effects of OCTAPLASMA on manifest bleeding, coagulation parameters and vital signs. Patients received a single infusion of OCTAPLASMA at an average dose of 377±90 mL (range 200 to 600 mL), at least 6 hours after the last administration of another blood product. In 16 out of 22 patients with a manifest bleeding before the start of the OCTAPLASMA infusion, an appropriate haemostatic effect was obtained, as evidenced by cessation or reduction of bleeding. A significant increase in PT, fibrinogen and antithrombin III activity was observed after the infusion compared to baseline.

One open-labelled prospective clinical study (PLAS_IV_90) aimed to investigate the pharmacokinetics and pharmacodynamics of OCTAPLASMA. Five male and six female patients, included for hereditary, acquired, isolated or combined coagulation deficiency, received OCTAPLASMA as a single, i.v. injection. Thereof, 2 patients each had a factor VII or factor X, and 4 patients a factor XI deficiency. Two patients received OCTAPLASMA for ongoing bleeding, one for plasmapheresis and eight for prevention of bleeding before an invasive procedure. Bleeding was stopped in the two patients with ongoing bleeding. In the nine other patients, plasmapheresis and surgical procedures were uneventful, with no abnormal bleeding. The overall effectiveness of OCTAPLASMA as rated by the investigator was good in all patients.

19/PLAS/IV/91 an open-label, parallel group study was performed in severely ill surgical patients who were allocated to receive either a single infusion of OCTAPLASMA (n=20) or no plasma treatment (n=26) during open-heart surgery. A historical control group of patients having received standard FFP (n=20) was used to compare the efficacy and safety of OCTAPLASMA. Despite the fact that patients in need of plasma had more pronounced bleeds before transfusion, haematological and coagulation parameters were not significantly different in the OCTAPLASMA and the ‘no plasma’ treatment groups. Plasma colloid osmotic pressure and complement activation data were also comparable.

The prospective, single-blind, randomized study (LAS-1-03-UK) was designed to investigate the safety and efficacy of OCTAPLASMA compared with standard FFP in adult patients with coagulopathies due to liver disease (LD) or liver transplantation (LTX), or for the management of newly diagnosed thrombotic thrombocytopenic purpura (TTP). In total, 55 patients were included. Thereof, 3 patients were suffering from TTP and all received OCTAPLASMA. Of the 24 patients with LD, 11 were treated with OCTAPLASMA, and out of the 28 LTX patients, 13 received OCTAPLASMA. There were 3 patients who had to be excluded from the efficacy evaluation because of major protocol violations. Within the LD and the LTX groups, patients were comparable in all clinical aspects and in the dose of plasma given. There were no relevant changes in any of the coagulation factors, but protein C and fibrinogen improved considerably in both groups, accompanied by a corresponding improvement in partial thromboplastin time (PTT) levels 24 hours after infusion. Similar degrees of correction of prolonged international normalized ratio (INR) and PTT values were achieved with both OCTAPLASMA and FFP. All 3 patients with TTP attained platelet counts of >50x109/L by Day 10, and remained in stable remission 1 year later. Concerning the LD group and the LTX group, the results were almost identical, and no difference was seen between FFP and OCTAPLASMA.

LAS-212 a prospective, open-label, multicenter, single arm, postmarketing study was conducted to investigate the safety, tolerability and efficacy of OCTAPLASMA in the management of pediatric patients requiring replacement of multiple coagulation factors. A total of 50 patients [37 neonates/infants (0 to 2 years old) and 13 children and adolescents (> 2 to 16 years old)] requiring cardiac surgery (N=40), liver transplantation and/or with liver dysfunction (N=5), sepsis-related coagulopathy (N=4) and hypoxic encephalopathy (N=1) were included in the study. Hemostatic parameters as measured by INR, PT, aPTT, thromboelastography (TEG) or thromboelastometry (TEM) were within expected ranges following use of OCTAPLASMA.

Clinical trials in therapeutic plasma exchange (TPE)

Table 10 - Summary of Patient Demographics for Clinical Trials in Therapeutic Plasma Exchange (TPE)

Efficacy and tolerability of OCTAPLASMA in TPE were assessed in a post-authorisation study (Study No. 6 in 41 pediatrics.

Efficacy

LAS-213 a prospective, open-label, multicenter, single-arm, postmarketing study assessed the safety and tolerability of OCTAPLASMA in the management of subjects who underwent TPE. A total of 102 TPE procedures were performed in 41 subjects aged 2 to 20 years [young children: Group 1 (age 2 to <12): N=15; adolescents: Group 2 (12 to <17): N=13; and young adults: Group 3 (≥17): N=13]. Overall, a total of 135,137 mL of OCTAPLASMA was administered. The underlying disease category for these subjects included immune system disorders (N=14), nervous system disorders (N=12), renal and urinary disorders (N=8), infections and infestations (N=4), and other disorders (N=3). Each subject underwent between 1 and 6 TPEs (mean: 2.5 TPEs). The actual dose administered per TPE ranged from 4 mL/kg to 72 mL/kg (mean: 28.6 mL/kg), with a mean total volume administered per TPE of 1325 mL (range: 113 mL to 4000 mL). Infusion rates (mean) were similar across age groups (0.32 mL/kg/min to 0.41 mL/kg/min).

Based on the experience gathered during the clinical development phase and the post-marketing period, it can be concluded that OCTAPLASMA is efficacious.

16 Non-Clinical Toxicology

OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) is a virus inactivated frozen human plasma and is assumed to be active on a species-specific basis. Human plasma may cause severe toxic reactions in animals and is not tolerated at dosages approaching those generally used in humans. Routine toxicology testing in laboratory animals is not considered to add any relevant information for the safety and efficacy of OCTAPLASMA in the clinical use. Therefore, no toxicological studies have been carried out in animals.

Studies were conducted to evaluate the effects of the materials used for viral inactivation by the S/D method. After purification, the maximum amounts of TNBP and Octoxynol in the finished product are 2.0 µg/mL and 5.0 µg/mL, respectively. Pharmacological and toxicological studies in animals indicate that these residual levels should present no clinical problem for the indications and dosages specified.

Based on preclinical data it is not possible to give information on the total quantity of OCTAPLASMA that can be administrated before any adverse effects of the S/D components are likely to become apparent.

However, “therapeutic windows” might be calculated for humans: according to acute intravenous toxicity tests in rats the lowest toxic sum dose of TNBP and Octoxynol (1:5) was 10,000 µg/kg. For a single dose of 20 mL/kg OCTAPLASMA containing < 140 µg/kg TNBP and Octoxynol at the ratio 2+5 this window is ≥ 71.4.

• For a transfusion period of 5x20 mL/kg per day the window is ≥ 14.3.
• For a 3-day treatment with 5x20 mL/kg per day the window is ≥ 4.8.

These calculations, however, neglect the rapid metabolism of these compounds. As a consequence, greater safety margins might be assumed for repeated administration of OCTAPLASMA.