FDA Approves First Generic Blood Thinner Enoxaparin Sodium Injection (Lovenox)
Editor's ChoiceMain Category: Blood / Hematology
Also Included In: Regulatory Affairs / Drug Approvals; Vascular; Cardiovascular / Cardiology
Article Date: 24 Jul 2010 - 9:00 PDT
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Lovenox is made from heparin and was approved for use in the USA in 1993. It is a blood-thinning medication whose active ingredient is a naturally-derived complex mixture of sugar molecules.
For the FDA to approve a generic drug, the manufacturer needs to show that it contains the same active ingredient as the brand-name product. In the case of a natural product, such as enoxaparin, the process may be more complex.
Keith Webber, Ph.D., deputy director of the FDA's Office of Pharmaceutical Science said:
Before approving generic enoxaparin sodium injection, we expected, among other things, a series of sophisticated analytical tests and a study in healthy volunteers to assure that the drug would be as safe and effective as the brand name product.
The FDA had received a citizen petition questioning the approval criteria for generic enoxaparin sodium injection prior to approval. After a careful review of the petition, the agency decided that the currently available scientific evidence, precedent, and the FDA's legal authority establish "a sound basis for the approval of generic enoxaparin sodium injection." A response to the petition was released by the FDA yesterday (23rd July).
Enoxaparin therapy can prevent deep vein thrombosis - the formation of a clot in a deep vein, especially the lower thigh, which can result in a sudden pulmonary embolism.
A pulmonary embolism (pulmonary meaning "of the lungs" from the Latin pulmonarius) occurs when an embolus blocks blood flowing through an artery that feeds the lungs. Typically, a blood clot first forms in an arm or leg (deep venous thrombosis or DVT) and then eventually manages to break free. The embolus can travel throughout the circulatory system towards the lungs, but eventually it is too large to pass through the small vessels of the lungs and forms a blockage. This prohibits blood from flowing into an area of the lung, and the part of the lung dies because it does not receive oxygen.
There are over 100,000 cases of pulmonary embolism in the USA annually. Among hospitalized patients it is the third most common cause of American deaths. This medication is also used to prevent blood clots in patients with chest pains, heart attacks, as well as individuals who are confined to bed.
The prescribing information for both Lovenox and its generic version includes a boxed warning that use of the drug in patients undergoing spinal/epidural anesthesia or spinal puncture increases the risk of spinal or epidural bleeding and bruising (hematoma), which may cause long-term or permanent paralysis.
Approval of generic enoxaparin sodium injection has been granted to Sandoz Inc. of Broomfield, Colo. The generic product has been approved in the following strengths: 30 mg/0.3 mL, 40 mg/0.4 mL, 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL, 120 mg/0.8 mL, and 150 mg/mL.
Source: FDA
Written by Christian Nordqvist
Copyright: Medical News Today
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Why does the FDA authorisation of the first generic Lovenox, Enoxaparin Sodium Injection, cause so much interest these days?
posted by Henriette Fraedrich on 13 Aug 2010 at 2:07 amTHE FACTS:
On July 23, 2010 the U.S. Food and Drug Administration FDA approved the first generic version of Lovenox (enoxaparin sodium injection), an anti-coagulant drug used for multiple indications including prevention of deep vein thrombosis. FDA approved an abbreviated new drug application (ANDA) for Sandoz‘ product which is a generic version of Lovenox, approved for Sanofi-Aventis in 1993. Enoxaparin, the active ingredient of Lovenox, is a low molecular weight heparin (LMWH) with approximately 4500 Da manufactured from heparin by alkaline beta-eliminative cleavage of the benzyl ester of heparin. Other LMWHs are authorised which use different methods of heparin depolymerisation. The heparin underlying the manufacture of LMWHs is derived from natural sources, mainly porcine intestine.
The generic was developed by Sandoz and Momenta Pharmaceuticals and applied for FDA approval in 2005 already. Prior to the approval, the FDA also had to review a citizen petition questioning the approval criteria for generic enoxaparin sodium injection and determined in response to it that it had a sound basis for the approval.
All primary information related to the FDA decision including the approval letter and the response to the citizen petition can be found here.
On August 17, 2010, a U.S. federal judge hearing is hold in response to Sanovi-Aventis‘ lawsuit filed against the FDA on July 26, 2010. It says that the FDA has exceeded its authority given by the mechanism of ANDA approval.
THE ISSUE:
Enoxaparin remains a biologically derived product despite the semi-synthetic manufacturing steps used to depolymerize the heparin from which it is produced, the resulting low molecular weight and the structure which is possible to be well-characterised by analytical methods. Products derived from a biological source are by definition complex, difficult to fully characterise by analytical means and the relationship of structure with clinical effect and safety is difficult to determine by non-clinical investigations only. This is common understanding. Accordingly, the basis of approval of a generic version of a biologically-derived product needs to take this into account. In the EU, the legal articles determining the pathways for authorisation of a generic version of a product with chemical/synthetic or biological origin are thus different – see article 10 of the EU-Directive 2001/83 as published here.
Furthermore, there is a difference in terminology: generics are chemical or synthetic drugs whereas the generic version of a biologically-derived product is to be called a biosimilar. The difference is furthermore supported by the requirements for the scientific data to be submitted. The approach to develop a biosimilar requires a comprehensive comparability package which includes - most importantly in the context of this case - also the requirement to conduct clinical studies comparative in nature with the reference product as the control arm. For LMWH, the European Medicines Agency EMA has adopted a specific guideline in March 2009 which illustrates in detail which data are expected for a biosimilar LMWH.
This guideline requires a PK/PD study in healthy volunteers plus a clinical efficacy/safety study in patients being relevant for the clinical use of LMWH such as those undergoing major orthopaedic surgery.
The FDA has acknowledged the fact as well that enoxaparin is a biologically-derived product while commenting on the approval of the first generic enoxaparin since it referred to the fact that the process can be more complex for a natural product. Despite this, FDA considered it justified to base the approval of this biologically-derived product on the ANDA legal pathway which is nothing else than approving it with the criteria applied for a common chemical generic drug for the evidence of sameness. FDA has, however, taken into account the nature of enoxaparin specifically in their review by adapting these criteria by the following five criteria:
1. Equivalence of heparin source material and mode of depolymerization
2. Equivalence of physiochemical properties
3. Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species
4. Equivalence in biological and biochemical assays
5. Equivalence of in vivo pharmacodynamic profile
These five criteria would have been part of a European dossier as well. The first three criteria are used to ensure that the heparin source material, the chemical reaction used in the manufacturing process, and the structure (the distribution of molecular weight, chemical composition and sequence) of the active ingredient, enoxaparin sodium, in the generic drug product is equivalent to that in the brand name counterpart, Lovenox. The difference lays in the interpretation of the fourth and fifth criteria. FDA used them to require the applicant to ensure that the generic enoxaparin sodium has the same degree of anticoagulant activity as Lovenox. And based on all these five criteria FDA considered that the generic enoxaparin sodium has the same active ingredient as Lovenox.
In the EU guideline on biosimilar LMWH, the criterion five is also included, i.e. the requirement to conduct a study in healthy volunteers to investigate the pharmacokinetic/pharmacodynamic properties. FDA did, however, not insist on the conduct of a clinical efficacy/safety study in patients reflecting the clinical use of enoxaparin as it would have been the case in the EU in addition to the five criteria. The study is required in the EU due to the heterogeneity of LMWH and the uncertainty on the relevance of PD markers for the clinical efficacy.
By the way, the EU guideline is intended to be utilised for all LMWH applied for authorisation as biosimilars, independently of an eventually demonstrated high-grade similarity (EMA) or sameness (FDA) of the active ingredient by other means than clinical testing. Thus, it does require the same grade of data as the FDA did in this case but plus the clinical study in patients.
The European Directive defining the legal pathways of a generic and biosimilar product requires differentiation based on whether the product is chemical or biologically derived. To acknowledge the fact that the sameness of biologically-derived products could not fully be proven based on analytical tests or surrogate PK/PD markers – therefore also the term similarity is used instead in the EU. However, reading the EU Directive again and again, there might be room for interpretation, i.e. when a biological fulfils the definition of a generic product given there. This has not yet been proven for an even less complex biosimilar than enoxaparin such as growth hormone but may be the case for the future?
(from our blog at http://www.pharmatching.com )
lungs severely damaged
posted by gary richards on 22 Dec 2010 at 7:19 amI need help for disabled daughter, who is suffering like I am with factor five leiden blooding clotting disease. Since May, 2010, I have suffered massive pulmonary blood clots destroying 50% of my lung capacity, and the issue is the use of lovenox. It costs money, and at times my insurance company has been less than cooperative in getting to me. This in turn has caused me to suffer with repeat episodes of blood clots, and I think that I could die from this disease.
My daughter is suffering to with repeat episodes of pulmonary embolisms and deep vein thrombosis, and she is not well. Her legs are swollen huge, and I fear for her. Her local doctor is hindered by a hillbilly nurse, that wants to play around with my daughter's health, and my daughter is on MEDICAID. I do not want this for her, and the insurance company called PEIA for state workers here in WV is too CHEAP to pay for my daughter's medicine too. THE DHHR of WOOD COUNTY is a cheap affair, and they let allot of people suffer with not getting their MEDICINES and healthcare. It is a disgrace here in WV, where the DRS. pick and chose who will live and die.
I asking over Christmas a hands up, instead of the nasty opinions I received from SANOFI-AVENTIS the makers of LOVENOX. They said they would not help my daughter, and she had to pay for the MEDICINE called LOVENOX.
My repeated calls for help, just passed me over to the customer service people, who then let me talk to the NASTY pharmacists, who wanted me to just call SANDOZ to ask them for the GENERIC brand. The makers of LOVENOX said I might get a FREE LUNCH for my family over at SANDOZ. I told them just because I was from WV
did not mean that we were hilbillies, and they just laughed it off.
We could DIE with this disease. It is not working right for me to be on LOVENOX. The coumadin was not effective therapy for the prior blood clots. Now I HAVE AN OXYGEN CONCENTRATOR to live off of, because I could not GET HELP.
MY DAUGHTER DESERVES BETTER, and the DHHR or PEIA or WHOMEVER needs to HELP MY DAUGHTER STAY ALIVE.
Will you RESPOND INSTEAD OF TELLING ME TO GO SOMEWHERE ELSE FOR HELP?
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