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

Animal Pharmacology

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.

The level of impurities putatively present in the end product is controlled by the manufacturing process itself, specifications for the raw materials and in process controls, as well as by the final product specification. Two contaminants derived from the manufacturing process, namely TNBP and Octoxynol, may be present in the final product at levels not exceeding 2.0 mcg/mL for TNBP and 5.0 mcg/mL for Octoxynol. A program of studies has been carried out to assess the pharmacokinetic profile of TNBP and Octoxynol. It should be borne in mind that the exposure to TNBP and Octoxynol may be large in patients undergoing therapeutic plasmapheresis. 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 ²⁴.

Animal Pharmacokinetics and Metabolism

A pharmacokinetic study was carried out by the applicant in rats, which were given 300 mcg of TNBP/kg + 1,500 mcg of Octoxynol/kg BM i.v. The plasma half-life for TNBP was approximately 20 minutes, Octoxynol was not detected.

According to published data ²⁵ the plasma half-life for TNBP in rats after intravenous administration of 5 mg/kg is 1.3 hours. The main excretion route is via the urine, small amounts are excreted via faeces and the breathing air (CO₂).

There are no pharmacokinetic studies for Octoxynol in the literature. However, the very similar nonoxynol-9 is excreted (within 7 days) via the faeces 52-78%, the urine 20-39% and the breathing air (CO₂) 0-1.2% in rats after oral and intraperitoneal administration ²⁶.

Human Pharmacokinetics

During one clinical study pharmacokinetic data of coagulation factors after treatment with OCTAPLASMA reconstituted as lyophylisate have been collected from eight patients suffering from hereditary coagulation factor deficiencies ¹². 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 the Table 7.

Table 7. Pharmacokinetic parameters after administration of OCTAPLASMA:

Vd=volume of distribution; Cl=clearance; MRT=mean residence time; t½=half-life

These pharmacokinetics parameters after OCTAPLASMA administration were within the kinetic profile of coagulation factors after administration of FFP [21-23]. No pharmacokinetic results are available for the remaining coagulation factors.

Human 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 8 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 ≤0.3 IU/ml and ≤2.0 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 8).

Table 8. Plasma Protein Levels in OCTAPLASMA Compared to Single-Donor Fresh-Frozen Plasma ²⁰:

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

One clinical study aimed to investigate the pharmacodynamics of OCTAPLASMA (Solvent Detergent (S/D) Treated Human Plasma) has been performed. ¹².

Five male and six female patients, included for hereditary, acquired, isolated or combined coagulation deficiency, received lyophilised 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 lyophylisate 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.

Two patients experienced a total of three adverse events (AEs), consisting of an anaphylactoid reaction and urticaria with pruritus. These AEs resolved with an antihistaminic and both patients recovered. No patient dropped out of the study for safety reasons. No serious and/or unexpected AEs occurred. No adverse laboratory findings were observed for haematology, blood biochemistry and viral safety parameters.

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.

Studies were conducted to evaluate the effects of the materials used for viral inactivation by the S/D method [1% Tri(N-Butyl) Phosphate (TNBP) and 1% Octoxynol]. After purification, the maximum amounts of TNBP and Octoxynol in the finished product are 2.0 mcg/mL and 5.0 mcg/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 mcg/kg For a single dose of 20 mL/kg OCTAPLASMA containing <140 mcg/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.

Mutagenic Potential

The mutagenicity investigations of TNBP and Octoxynol performed by the applicant and available in the literature [27-29] likewise give no indication of mutagenic properties.

Reproductive Toxicity

A study of the embryotoxic and teratogenic properties of TNBP and Octoxynol was carried out in rats and rabbits at dose levels.

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.

Genotoxicity

In an in vitro test in Aspergillus nidulans on the genotoxic activity at a concentration of 0.01% (corresponding to 100 mg/L) Octoxynol proved to be genotoxically inactive. Higher concentrations were in the cytotoxic range.

Carcinogenicity

No evidence of carcinogenic properties of TNBP + Octoxynol was produced in the subacute toxicity and mutagenesis studies already described. No special carcinogenic studies were carried out.

Additional Toxicology Information

No evidence of sensitising properties of TNBP + Octoxynol (ratio 1:5) was observed. No immunotoxicological reactions were observed after administration of Octoxynol.

Comparison of the doses used during the toxicological studies in animals mentioned to the human therapeutic dose may provide indications of the therapeutic ratio.

Pharmacological and toxicological studies in animals indicate that these residual levels of TNBP and Octoxynol do not represent a clinical problem for the indications and dosages specified for OCTAPLASMA [30, 31].