European Medicines Agency Updates Advice for Spraying Fibrin Sealants During Surgery

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued new instructions to promote safe use of the fibrin sealants Tisseel, Tissucol, Artiss, and Beriplast P during surgery. This advice follows that issued for two other fibrin sealants, Evicel and Quixil, in November 2012. Employed to help reduce local bleeding, these sealants are typically dripped or sprayed onto bleeding tissue to form a fibrin clot.

Reports of gas embolism with Evicel and Quixil in association with the use of spray devices that use a pressure regulator prompted a review of fibrin sealants. These events appear to be related to the use of the spray device at higher-than-recommended pressures and/or in closer-than-recommended proximity to the tissue surface, EMA stated in a press release.

Although EMA reports that risk of gas embolism with Tisseel, Tissucol, and Artiss when applied as spray during surgery was considered to be very low, the Committee concluded that the risk cannot be excluded. It urges that product information for these medicines be updated with new instructions to optimise their safe use. EMA stated the following: 

• The product information should be updated with clear and consistent advice for healthcare professionals regarding recommended pressure and distance to use during spraying application.
• The marketing-authorisation holders for these medicines should ensure that they are used with pressure regulators that do not exceed the maximum pressure required to deliver the fibrin sealant, and that they contain labels stating the recommended pressure and distance.
• The product information should include a warning that the risk of gas embolism appears to be higher when fibrin sealants are sprayed using air, as compared to CO2, and patients should be closely monitored for signs of gas embolism.
• Healthcare professionals in the European Union (EU) will receive a letter outlining the updated information on the safe use of these medicines.

For the fibrin sealant Beriplast P (and associated names), however, the CHMP concluded that "there is no risk associated with this product because it does not require a gas-assisted spray device during application, therefore there is no risk of gas embolism with this product when used in accordance with prescribing advice and with the recommended device."

Dural repair with four spinal sealants: focused review of the manufacturers' inserts and the current literature.

Abstract

BACKGROUND CONTEXT:

Deliberate or traumatic dural fistulas are typically augmented by a "sealant" or "fibrin glue" to enhance the strength of dural closure.

PURPOSE:

Little is known about the risks and complications associated with two specific "sealants" and two specific "fibrin glues" used for dural closure.

STUDY DESIGN/SETTING:

Review of the manufacturers' inserts and a focused review of the literature concerning the pros and cons for two "sealants" (DuraSeal [Confluent Surgical Inc., Waltham, MA, USA] and BioGlue [Cryolife, Kennesaw, GA, USA]) and two "fibrin glues" (EVICEL [Johnson and Johnson Wound Management, Ethicon Inc., Somerville, NJ, USA] and Tisseel [fibrin sealant; Baxter International Inc., Westlake Village, CA, USA]) were assessed.

PATIENT SAMPLE:

A focused review of the literature using four different "sealants" or "fibrin glues" was performed.

OUTCOME MEASURES:

Documentation of persistent/recurrent postoperative cerebrospinal fluid fistulas was an end point for failure for the four different "sealants" and "fibrin glues."

METHODS:

Manufacturers' inserts and a focused review of the literature concerning the relative safety and efficacy of two "sealants" (DuraSeal and BioGlue) and two "fibrin glues" (EVICEL and Tisseel) used to augment dural closure were assessed.

RESULTS:

Although DuraSeal is approved by the Federal Drug Administration (FDA) for intracranial and spinal application, two instances of paralysis are described in the literature. BioGlue is classified by the manufacturer as neurotoxic. EVICEL, one of the "fibrin glues," appeared in just two animal studies, whereas Tisseel, the other "fibrin glue," has been used in many large clinical series without adverse events.

CONCLUSION:

Despite the lack of FDA approval, Tisseel (fibrin glue) has seen wide adoption in "off-label" use. DuraSeal, which is FDA approved, was associated with two instances of paralysis. Alternatively, BioGlue was described as neurotoxic even by the manufacturer.

FDA approves Evicel Fibrin surgical sealant

TheU.S. Food and Drug Administration (FDA) has approved Evicel Fibrin Sealant, a liquid product that when applied topically helps control oozing from small blood vessels during surgical procedures.

"Evicel provides an effective means to stop oozing from small vessels during vascular surgery when suturing, compression or other standard techniques are not effective or practical," said Jesse Goodman, M.D., M.P.H., director of FDA's Center for Biologics Evaluation and Research.

This product is derived from pooled human plasma and consists of a fibrinogen concentrate and thrombin, two substances used to promote clotting. Both substances go through a two-stage process to reduce the risk of viral transmission in manufacturing, however, the potential risk for the transmission of blood-borne viruses cannot be totally eliminated.

In a pivotal study of 147 patients, the effectiveness of Evicel was compared with the standard bleeding control technique of applying pressure to a plastic covering (graft) placed over the open blood vessel. Eighty-three percent of those who received Evicel stopped bleeding within four minutes, compared with 39.7 percent in the control group.

Adverse events, such as anemia and graft site infection, were generally mild and occurred at about the same frequencies in the Evicel-treated group and the control group.

FDA originally licensed the predecessor of Evicel (Crosseal) in 2003 for use during liver surgery. Evicel is manufactured by OMRIX biopharmaceuticals LTD, Kiryat Ono, Israel.

Omrix Q3

Robert Taub
Thank you, Asaf. As Asaf mentioned, this quarter was another record quarter for biosurgery product sales – $9.5 million. Evicel is continuing to be a strong performer. The number of total accounts continues to increase steadily, and in quarter three, end user sales by our partner, Ethicon, once again included a very significant amount of repeat business. By year-end, we believe that total sales of Evicel will be approximately the same as our competitor.
Additionally, as mentioned in a recent press release, we announced that the EMEA approved Evicel in Europe. Evicel is now licensed for marketing in 27 plus three countries – the 27 countries of the European Union plus another three in Europe, and Ethicon will begin to sell Evicel on a country-by-country basis as Quixil is gradually phased out.
Next, Evithrom, our human-based thrombin standalone product continues to experience moderate dollar sales growth in this market. In quarter three, the total number of accounts purchasing Evithrom, however, increased by 50%, with new customers comprising 52%. As you're probably aware, however, there is currently fierce price competition in the thrombin standalone market, and as we have predicted, the market is moving toward thrombin enhanced hemostats, and we are currently developing two such products.
I would now like to update you on our Fibrin Pad. As you may recall, we have two trials, one in the U.S. in mild-to-moderate bleeding and a second one in Israel in severe bleeding.
With respect to the U.S. trial, we completed enrollment of the 90 patients needed to conduct interim analysis. We were pleased to report that the analysis showed superiority of the Fibrin Pad over Surgicel. Having demonstrated superiority, we are now able to continue with open-label enrollment. The trial will continue to enroll patients only to the Fibrin Pad arm, and according to the study design, we are required to treat at least 100 total patients for safety, which means another additional 40 patients with the Fibrin Pad.
Shortly after we announced that we had achieved superiority we were informed that the U.S. Phase II study had been suspended after a patient had experienced postoperative bleeding. This patient was not among the first 90 enrolled, but part of the subsequent 40 already. Many of you have asked why the trial was suspended if rebleeding is an expected event in surgery and in this protocol. The reason is simple. The protocol is written so that if there is a case of postoperative bleeding the trial must be suspended and an investigation must be conducted. Therefore, the decision to suspend the trial was an administrative one.
A Data Safety Monitoring Board, or DSMB, conducts the investigation and then provides a recommendation on how the trial is to proceed or if it is to be modified or even discontinued. We have now reported that the DSMB concluded their investigation and recommended that the clinical trial resume without any modifications, which it did.
I want to clarify that the DSMB's role is not to determine the relationship between the adverse event and the product. We, however, conducted a thorough product investigation and concluded that there is no issue with the clinical material.
I would still like to emphasize that a trial continuation with no modification is the absolute best case outcome. Therefore, we remain on target to complete enrollment of the 130 patients by the end of '08 or early '09. Although we still expect to be within the window of prior timeline guidance, due to the two-week investigation we are now more comfortable with an early '09 time frame. Once we complete the two-month follow-up and finish analyzing the data, we expect to file the BLA with the FDA in the first half of '09 and then assuming a standard 10-month review, we expect the approval in the first half of 2010.
Now, regarding the severe bleeding indication, I am pleased to inform you that we now have the approval from the British MHRA on behalf of the European Union to conduct a study in soft tissue severe bleeding.
I draw your attention to the fact that the indication and protocol are quite similar to the mild-to-moderate study which is ongoing in the United States. This EU severe bleeding study will be a pivotal study leading to an indication for the use of the Fibrin Pad in severe bleeding in soft tissue surgery. This kind of bleeding is different from the target bleeding in the exploratory Phase II study which we started some time ago in Israel.
Indeed, the Israeli study was purposefully designed to be the most challenging as it addresses the control of severe bleeding when the product is applied directly onto the resected solid organ, such as a kidney, a prostate, a liver or highly vascularized organs, and these organs are not soft tissues.
As you know, we reported a postoperative bleeding event in the Israeli trial. We are conducting an investigation, and pending the conclusion of the investigation of the rebleeding case we have decided to discontinue enrollment of additional patients in that Israeli trial and are focusing on initiating the European trial. But you should understand that the clinical development plan of the Fibrin Pad is proceeding well with a mild-to-moderate study in the United States and a severe bleeding study which will be initiated in Europe in the first half of '09.
Let me give you some details on the European study design. As I mentioned, it is a pivotal clinical study evaluating the safety and efficacy of our Fibrin Pad in soft tissue severe bleeding in abdominal, pelvic, retroperitoneal and noncardiac thoracic surgery. The study is a randomized multicenter clinical study evaluating the superiority of Fibrin Pad versus the standard treatment in controlling challenging severe bleeding in soft tissue for which standard methods of achieving hemostasis are ineffective or impractical.
Alright. Now, moving on to our passive immunotherapy business. Immunotherapy product and byproduct sales amounted to $10.1 million in the third quarter of 2008. And regarding our Phase III clinical trial in the United States for IVIG, the trial is proceeding according to expectations, and we are on track to file the BLA in the third quarter of 2009.
Erik Schneider – UBS
Okay. Great. Evithrom in the U.S., you previously said that it was – had higher sales than Zymo's Recothrom. Both are now in IMS. What is it – what's different about that channel that the IMS data show Evithrom with smaller dollars, but you're confident that they're actually larger?
Robert Taub
No, we don't know what ZymoGenetics sales are other than what we read in a press release from analysts or from their own public statement, so all I can say is that we definitely are way ahead of ZymoGenetics in terms of sales.
Erik Schneider – UBS
Okay. And what we've heard from them is that they're having trouble selling the product and in fact they're seeing pricing pressure in that market, particularly, with hospitals focused on saving money where they can. Have you seen anything like that with either Evithrom or that could be affecting Evicel going forward?
Robert Taub
No, I think that I mentioned in my script that there is a fierce price competition in the thrombin area, and I think ZymoGenetics itself is triggering that. So yes, there's tremendous competition in pricing currently ongoing, but we haven't seen anything in Evicel or in the (inaudible) area. So I don't think it's an overall statement here that has to be made about the Zymo stats in the United States, but rather a very specific thrombin related situation with Kings, ZymoGenetics, Ethicon and Omrix.
Source - seekingalpha

Omrix shares whipsaw on Evicel nod

Omrix Biopharmaceuticals Ltd. probably wants to forget last week, when its share fell 35% after the clinical trial of its fibrin pad was suspended because of safety problems. Subsequently, however, and without any new announcement about the trial, the share recovered half the loss. Omrix closed at $15 yesterday, giving a market cap of $256 million, up from its low point of $11.60 five days after the trial suspension was announced.
Yesterday's 3.4% rise in Omrix's share can be attributed to the company obtaining European Medicines Agency (EMEA) marketing approval for Evicel liquid fibrin sealant, the company's surgical sealant and the product of its kind in the US. Johnson & Johnson (NYSE: JNJ) Ethicon Inc., which markets Evicel in the US, will also market it in Europe.

Omrix Biopharmaceuticals Receives Approval from European Medicines Agency for Evicel Liquid Fibrin Sealant (Human)

NEW YORK - (Business Wire) OMRIX Biopharmaceuticals, Inc. (“Omrix” or the “Company”) (NASDAQ: OMRI), a fully-integrated biopharmaceutical company that develops and markets biosurgical and immunotherapy products, announced today that it has received approval from the European Medicines Agency (EMEA) for Evicel, the Company’s liquid fibrin sealant.
The EMEA’s approval permits EVICEL to be marketed in Europe under the following indication, “As a supportive treatment in surgery where standard surgical techniques are insufficient for improvement of hemostasis. Evicel is also indicated as suture support for hemostasis in vascular surgery.”
EVICEL is currently marketed in the US by Johnson & Johnson Wound Management, a division of ETHICON, INC., a Johnson & Johnson company, with a general hemostasis in surgery indication.
With an EMEA approval, EVICEL is licensed for marketing in the 27 countries of the European Union, or EU. Per the terms of Omrix’ and ETHICON’s supply and distribution agreement, ETHICON has the marketing rights for the EU.

About EVICEL

EVICEL™ is an all-human, plasma-derived fibrin sealant currently indicated in the US as an adjunct to hemostasis for use in patients undergoing surgery, when control of bleeding by standard surgical techniques is ineffective or impractical. It does not contain aprotinin, which has been associated with adverse health effects. EVICEL™ is easy to use and readily available for time-sensitive needs in the operating room. The product is sold as a frozen liquid and requires less than one minute preparation time after thawing.

Omrix Ethicon - We're number 2 in Thrombin

During Omrix Q2 discussion was made on Evicel, Quixil, Evithrom, the Fibrin pad and a mystery bonus product that was just icing on the earnings cake. Revenue was up 72% year over year, led by Johnson & Johnson's Ethicon's 155% jump in sales of Omrix's biosurgical products. Most of that likely came from improved sales of Evicel -- its fibrin sealant used to stop surgical bleeding. The product was approved for use in all surgeries earlier. CEO Taub stated the obvious for the thrombin market "I'll rank the three competitors, King one, Ethicon/Omrix two and ZymoGenetics three."
On Ethicon intiatives with Evicel:
“a focus on burns and orthopedics and plastic surgery”
“an updated evicel website”

On Quixil:
“growing nicely” in Europe especially in Orthopedics.

On Evithrom:
continued “moderate growth” approx. 40% of purchasers were first time buyers.

On Fibrin Pad trials in Israel and USA:
ongoing but on target
anticipating approval first half 2010

On major costs:
Plasma costs expected to rise

On the “mystery” $ 1.9 million contributing by-product of Omrix plasma preparation:
It is an imuno-therapy product not a biosurgical
A 3 year contract is in place to continue selling these previously discarded by-products
The product is used on humans
Contractually unable to release name or country of partner

Omrix recieve positive news on Evicel

Omrix announced today that it has received a positive opinion for EVICEL(TM) Fibrin Sealant (Human) from the Committee for Medicinal Products for Human Use (CHMP). Omrix is seeking approval to market Evicel in Europe for the improvement of hemostasis in surgery.
CHMP is the scientific committee of the European Medicines Agency (EMEA) and is responsible for reviewing medicinal product applications for quality, safety and efficacy. The CHMP's positive opinion for Evicel will now be forwarded to the European Commission for marketing authorization, which is expected by the end of the third quarter of 2008 (3Q08). The CHMP's opinion also stated that the approved indication for EVICEL would read as follows, "Evicel is used as supportive treatment in surgery where standard surgical techniques are insufficient, for improvement of hemostasis. Evicel is also indicated as suture support for hemostasis in vascular surgery."
EVICEL is currently marketed in the US by Johnson & Johnson Wound Management, a division of ETHICON, INC., a Johnson & Johnson company, with a general hemostasis in surgery indication.
Upon its anticipated approval, EVICEL will be licensed for marketing in the 27 countries of the European Union, or EU. Per the terms of Omrix and ETHICON's supply and distribution agreement, ETHICON has the marketing rights for the EU.

About EVICEL:

Omrix say "We have been developing our next generation fibrin sealant, Evicel™, in collaboration with Ethicon. Evicel™ differs from Quixil® in that it does not contain an antifibrinolytic stabilizing agent in the Biologically Active Component. The presence of this agent resulted in Quixil® being contraindicated for surgical procedures involving direct contact with Cerebro Spinal Fluid and/or Dura Mater. "
EVICEL(TM) is an all-human, plasma-derived fibrin sealant currently indicated in the US as an adjunct to hemostasis for use in patients undergoing surgery, when control of bleeding by standard surgical techniques is ineffective or impractical. It does not contain aprotinin, which has been associated with adverse health effects. EVICEL(TM) is easy to use and readily available for time-sensitive needs in the operating room. The product is sold as a frozen liquid and requires less than one minute preparation time after thawing. On Jan. 2, the U.S. Food and Drug Administration (FDA) expanded the indication for a liquid fibrin sealant to help control bleeding during general surgery. Fibrin is a protein that helps blood clot.
The sealant, called Evicel, is sprayed or dripped on small, oozing blood vessels. Once applied, it forms a covering that helps stop bleeding. Evicel was previously approved for use during liver and vascular surgery. This approval expands Evicel’s indication to include general surgery applications.
“This approval provides a new option to help control bleeding during general surgery, when other approaches and techniques are ineffective or impractical,” said Jesse L. Goodman, M.D., M.P.H., director of FDA’s Center for Biologics Evaluation and Research.
Evicel contains fibrinogen and thrombin, two proteins involved in the production of fibrin. Fibrinogen and thrombin are found in human plasma, the liquid portion of blood. The plasma used to manufacture the product is collected from donors who have been screened and tested for blood-transmitted infections. The fibrinogen and thrombin also undergo a two-step process to further reduce the risk for the transmission of potentially contaminating bloodborne viruses. While the potential risk for infectious disease transmission is remote, it cannot be eliminated.
A study of 135 patients undergoing abdominal surgery showed Evicel to be safe and effective in controlling bleeding. Adverse events reported during the clinical trial included anemia, abdominal abscess, blockage of the small intestine, and loss of urinary bladder tone, when the urinary bladder does not empty effectively, which can cause discomfort and infection.
FDA approved Evicel’s predecessor (Crosseal) in 2003 for use during liver surgery. It became Evicel in May 2007 when FDA expanded the indication to include use during vascular surgery.

Evicel Prep video HERE

Johnson & Johnson Video Library

Access J&J video for Evicel and Surgiflo HERE