Octapharma AG Update: Product Withdrawal/Product Recall - Octagam(R)
Summary As communicated earlier, in the framework of routine pharmacovigilance activities, Octapharma noted an increased reporting frequency of thromboembolic events (TEEs) following administration of octagam®(5%). There has not been any reported TEE with respect to the use of octagam®10% (100 mg/ml).
In the interest of patient safety and conducted with the full knowledge and cooperation of national regulatory authorities a voluntary market withdrawal of certain batches of octagam®(5%) (octagam®50mg/ml) was performed in August of 2010. Since the voluntary withdrawal of these selected batches of octagam®(5%) no new reports of TEEs in connection with the products have been filed. Also, as a precautionary measure, Octapharma has voluntarily introduced testing methodologies for the release of every single batch of octagam®(5%) and octagam®10% with the aim of ensuring that only batches are released to the market for which an increased risk of thromboembolic events can be excluded with a high probability. Results from this test also served as basis for selecting the batches for withdrawal mentioned above.
Octapharma has been working proactively with national regulatory authorities to arrive at a mutually agreeable solution. In this context Octapharma announces the following additional measures:
USA
On August 20, 2010, in the interest of patient safety, Octapharma USA Inc. initiated a voluntary market withdrawal of selected lots of octagam® [Immune Globulin Intravenous (human)] 5% Liquid Preparation]. This was performed as a result of an increased number of reported thromboembolic events, some of which were serious. A total of 31 lots were voluntarily withdrawn at that time.
Effective immediately, at the request of the Food and Drug Administration (FDA), Octapharma USA Inc. is initiating a voluntary market withdrawal of all lots of octagam® [Immune Globulin Intravenous (human)] 5% Liquid Preparation] currently in the US market. While Octapharma has not received any reports of thromboembolic events after advanced testing and the above voluntary market withdrawal was performed, the FDA and Octapharma agree that until a root cause of the previously reported thromboembolic events can be determined, the most prudent course of action is to suspend further administration of octagam®.
EU
On 15 September 2010, as the first regulatory authority in the EU, the Paul-Ehrlich-Institut in Germany has issued a temporary suspension of the marketing authorization of octagam®(5%). This was followed by similar actions regarding octagam®(5%) and, in some cases, octagam®10% in additional six EU countries and Switzerland.
On 24 September 2010, EMA has recommended to suspend the marketing authorization for octagam®(5%) and octagam®10% throughout the EU and to initiate a recall of all octagam®(5%) and octagam®10% batches from the EU market place. The suspension will remain in place until the problem has been rectified. This recommendation has yet to be adopted by the European Commission.
Octapharma would like to point out that it has filed its disagreement with the EMA recommendation to the European Commission. Due to the following reasons Octapharma considers the suspension of the marketing authorization affecting all four Octapharma manufacturing sites and both products, octagam®(5%) and octagam®10% as disproportionate:
• Over the past three years 8.5 tonnes (200,000 standard treatment doses) of octagam®(5%) manufactured in two out of Octapharma's four production plants haven been distributed. Only seven TEEs occurred related to this quantity, leading to an incidence of only 1 TEE in approx. 28,600 standard doses or 1 in 1.21 million grams used, which represents a rate that is clearly not increased over the expected TEE rate.
• For the totality of octagam®10% manufactured to date (approx. 2.8 tons), not a single TEE was reported.
• The combined fact that (a) octagam®10% is supplied almost universally to highly regulated western markets with a very strong reporting discipline on adverse events, and (b) the absence of reported TEEs for octagam®10% despite years of administration in thousands of patients strongly supports Octapharma's belief that both products from these production sites are safe.
Australia
On 24 September 2010, agreed with the Australian Therapeutic Goods Administration (TGA) to voluntarily quarantine octagam®(5%) for 10 days, to allow the TGA sufficient time to consider Octapharma's request to continue supplying octagam®(5%) for Australia sourced solely from intermediate paste II fraction emanating from the two Octapharma production plants that have not experienced increased rates of TEEs in the products manufactured there. It is Octapharma's opinion that these products are suitable for continued use by patients.
Octapharma deeply regrets the unexpected increase in the rate of TEEs.
As Octapharma believes that it has identified the root cause of the increased incidence of TEEs, the corrective measures can be implemented without delay with the aim of minimizing the time period in which Octapharma's two intravenous immunoglobulin products will not be available to the market place. We are presently assuming that the issue has been resolved by end of 2010. Octapharma believes that an unexpected increase in Factor XIa in the final products played a role in the increase of the rate of TEEs.
Octapharma believes that, since its market introduction in Europe in 1995, octagam®(5%) has gained a track record of proven tolerability, as is published in Debes et al. 20071. The same applies to octagam®10%, launched in 2008, even at high doses and at high infusion rates, as published in Cherin et al. 20102.
Further information Thromboembolic events, including stroke, myocardial infarction, pulmonary embolism and deep vein thrombosis have been observed with all intravenous immune globulin products through published literature and post-marketing surveillance. The potential for these adverse events are listed in all manufacturer package inserts.
About octagam®(5%) octagam® is a 5% (50 mg/mL) immune globulin (human) solution for intravenous administration (IVIG) which is currently registered in about 60 countries, including the USA and the EU. In the USA it is indicated for treatment of primary humoral immunodeficiency (PI).
In the EU and other countries it is indicated for the use in: primary humoral immunodeficiency (PI); myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections; in children with congenital AIDS who have repeated bacterial infections; immune thrombocytopenic purpura (ITP) in children or adults at high risk of bleeding or prior to surgery to correct the platelet count; Guillain Barré syndrome; Kawasaki disease.
About octagam®10%: octagam®10% is a liquid, 10% (100 mg/mL) immune globulin (human) solution for intravenous administration (IVIG) which is currently registered in European countries, where it is indicated for the use in: primary humoral immunodeficiency (PI); myeloma or chronic lymphatic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections; in children with congenital AIDS who have repeated bacterial infections; immune thrombocytopenic purpura (ITP) in children or adults at high risk of bleeding or prior to surgery to correct the platelet count; Guillain Barré syndrome; Kawasaki disease. octagam®10% is the 10% version of octagam® (50 mg/mL) which was first launched in 1995.
About octagam® and octagam®10%: Both products are contraindicated in patients with known anaphylactic or severe hypersensitivity responses to immune globulin (human). Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Immune globulin intravenous (human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IVIG products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIG products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Neither octagam® nor octagam®10% contain sucrose. Some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose contained in octagam® as glucose. This has resulted in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. The same may apply to octagam®10%. Accordingly, when administering octagam®, octagam®10% or other parenteral maltose- containing products, the measurement of blood glucose must be done with a glucose-specific method. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products. Both products are made from human plasma. They may carry a risk of transmitting infectious agents, viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Components used in the packaging of the products are latex-free. IVIG products can contain blood group antibodies that may cause a positive direct antiglobulin reaction and, rarely, hemolysis. Thrombotic events have been reported in association with IVIG. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity, hypercoagulable disorders, and prolonged periods of immobilization. Various mild and moderate reactions, such as headache, fever, fatigue, chills, flushing, dizziness, urticaria, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, muscle cramps, and changes in blood pressure may occur with infusions of Immune Globulin Intravenous (Human). For full country specific prescribing information, please visit www.octapharma.com.
About Octapharma
Octapharma is a biopharmaceutical company. It is dedicated to the safe and optimal usage of human proteins. Octapharma products are state-of-the-art within treatment of haemophilia, immune diseases, volume expansion and plasma transfusions. The company was founded in 1983 and since then has grown to over 4,000 employees. Nowadays it has 37 subsidiaries and representative offices and is making sales in over 80 countries. Turnover in 2009 was Euro 1,008 million.
Forward-looking statements This news release contains forward-looking statements, which include known and unknown risks, uncertainties and other factors not under the company’s control. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. These factors include results of current or pending research and development activities and actions by regulatory authorities.
1. Debes A et al.: Tolerability and safety of the intravenous immunoglobulin octagam®: a 10 year prospective observational study. Pharmacoepidemiology and Drug Safety 2007; 16; 1038-1047
2. Cherin P, Cabane J: Relevant criteria for selecting an intravenous immunoglobulin preparation for clinical use. Biodrugs 2010:24(4) 211-223
Contacts Octapharma Group Kim Björnstrup Vice Chairman Tel. +41 796054735 Kim.bjoernstrup@octapharma.ch