PharmExec Blog

Preemption Watch: You've Been Warned

The Supreme Court on Wednesday issued its decision in the much-watched case of Wyeth v. Levine—which many in pharma hoped would firmly establish FDA decisions as a bulwark against common-law liability suits in state courts. The decision, as you’ve no doubt heard already, went against Wyeth. Pharm Exec‘s coverage is here. The opinion is here. The estimable Drug and Device Law Blog has provided links to today’s coverage here as well as a quick-and-dirty analysis of the opinion

The case as heard by the Supreme Court deals in a great deal of legal complexity, but the underlying lawsuit that inspired it is based on a fairly simple idea: Diana Levine was severely injured when she was given Wyeth’s Phenergan by a physician’s assistant who was attempting to inject the drug directly into the vein but instead either got it into the artery or injected it in such a way that it leaked out of the vein (“perivascular extravasation”) and mixed with arterial blood. The labeling for the drug warns what can happen, but Levine and her lawyers argued that Wyeth should have acted independently of FDA and contraindicated injection directly into the vein (or “IV push).

Well there are warnings, and there are warnings, so we took a look at the Phenergan PI to see what it had to say. It’ll no doubt make you feel even more sympathy for Diana Levine, but if you’re like me, it will make you wonder whether it makes sense to prevent problems with warnings when a warning like this didn’t suffice:

From the “Contraindications” section of the label:

Under no circumstances should PHENERGAN Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene (see WARNINGS—Injection Site Reactions).</b>

PHENERGAN Injection should not be given by the subcutaneous route; evidence of chemical irritation has been noted, and necrotic lesions have resulted following subcutaneous injection. The preferred parenteral route of administration is by deep intramuscular injection.

Under “Injection Site Reactions”:

PHENERGAN Injection can cause severe chemical irritation and damage to tissues, regardless of the route of administration. Irritation and damage can also result from perivascular extravasation, unintended intra-arterial injection, and intraneuronal or perineuronal infiltration.

Signs, Symptoms, and manifestations of severe tissue irritation include burning, pain, erythema, swelling, severe spasm of distal vessels, thrombophlebitis, venous thrombosis, phlebitis, abscesses, tissue necrosis, and gangrene. Administration of PHENERGAN Injection has resulted in nerve damage ranging from temporary sensory loss to palsies and paralysis. Injection into or near a nerve may result in permanent tissue damage. In some cases, surgical intervention (including fasciotomy, skin graft, and/or amputation) may be required (see ADVERSE REACTIONS).

Inadvertent Intra-Arterial Injection
Due to the close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or unintentional intra-arterial injection. Reports compatible with unintentional intra-arterial injection of PHENERGAN Injection, usually in conjunction with other drugs intended for intravenous use suggest that pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances. Intravenous injection was intended in all the cases reported but perivascular extravasation or arterial placement of the needle is now suspect. There is no proven successful management of unintentional intra-arterial injection or perivascular extravasation after it occurs. Sympathetic block and heparanization have been employed during the acute management of unintentional intra-arterial injection, because of the results of animal experiments with other known arteriolar irritants. Aspiration of dark blood does not preclude intra-arterial needle placement, because blood is discolored upon contact with PHENERGAN Injection. Use of syringes with rigid plungers or of small-bore needles might obscure typical arterial backflow if this is relied upon alone.

When used intravenously, PHENERGAN Injection should be given in a concentration of no greater than 25 mg per mL, and at a rate not to exceed 25 mg per minute. When administering any irritant drug intravenously, it is usually preferable to inject it through the tubing of an intravenous infusion set that is known to be functioning satisfactorily. In the event that a patient complains of pain during intended intravenous injection of PHENERGAN Injection, the injection should be stopped immediately to provide for evaluation of possible arterial placement or perivascular extravasation.

Under “Adverse Reactions”:

INTRA-ARTERIAL INJECTION MAY RESULT IN GANGRENE OF THE AFFECTED EXTREMITY.

Under “Dosage and Administration”:

The preferred parenteral route of administration for PHENERGAN Injection is by deep intramuscular injection. The proper intravenous administration of this product is well tolerated, but use of this route is not without some hazard. Not for subcutaneous administration.

UNINTENTIONAL INTRA-ARTERIAL INJECTION CAN RESULT IN GANGRENE OF THE AFFECTED EXTREMITY (see CONTRAINDICATIONS, WARNINGS—Injection Site Reactions). SUBCUTANEOUS INJECTION IS CONTRAINDICATED, AS IT MAY RESULT IN TISSUE NECROSIS (see CONTRAINDICATIONS, WARNINGS—Injection Site Reactions, and ADVERSE REACTIONS).

 

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6 Comments

  1. Steve in Houston
    Posted March 5, 2009 at 1:51 pm | Permalink

    Ok, Mr. PharmExecBlog, why in the hell after over 20 cases like Ms. Levine’s catastrophic injury from “IV push” did you not send a simple, clear letter to FDA and attach the 20 cases and say, “Wyeth, as the manufacturer of this drug, is obligated under federal law to inform FDA of these catastrophic injuries resulting from this specific method of administration. Wyeth is obligated under federal law to propose to FDA a stronger warning for this specific method of administration. The proposed warning is attached. Wyeth requests a meeting with FDA officials at the earliest possible time to discuss this matter. Until this matter is resolved and a revised label is pubslihed, Wyeth will inform doctors and patients through various methods of communication that (1) Wyeth proposes a stronger warning for the IV push method and (2) Wyeth recommends that the IV push method not ever be used because the catastrophic risks that can result from this specific method of administration far outweigh any potential benefit derived from the drug.”?

    I think I know why: you’re not afraid of the FDA, you had the drug on the market for many years and just let it ride and didn’t want to spend another dime unless it resulted in more sales. Profits over people, sales over safety.

  2. Patrick Clinton
    Posted March 5, 2009 at 2:30 pm | Permalink

    Steve –
    I guess the point of my post was that the language of the warnings shows that FDA was clearly aware of the issues and chose to specifically require Wyeth to leave the warnings as is. Again, I for anyone who reads the warnings, there’s no real difference between what’s there and a recommendation never to use IV push — they even point out that a standard nursing method of determining correct needle placement will fail.

    To me, the real question is who gets to decide. I don’t want companies to decide what the warnings should be. They’ll get it wrong. And I don’t particularly want local courts to decide: They will predictably err on the side of demanding excessive warnings. FDA has a chance of getting it right. In this case, a lot of reasonable people would say they did get it right.

  3. Steve in Houston
    Posted March 5, 2009 at 3:23 pm | Permalink

    Dear Mr. Clinton, thank you for your response.

    You don’t want companies to decide what the warnings should be? Well, Sir, that is the way it has been from the beginning because the manufacturer drafts and submits the label language. FDA approves the label, not the drug.

    Can you show your audience any evidence that you (or Pharma) have ever been critical of FDA and called for FDA to write the label and not the company? Any letters, editorials, or blog entries? I submit to you the answer is “No” because the drug company cherishes the ability to draft the label in the most favorable way possible. While there is a give and take process, a negotiation, the drug company will always want the greatest control over label language.

    As far as FDA goes, did you miss the entire section of the opinion that reveals FDA is grossly underfunded and understaffed and that the GAO and FDA itself have reported the FDA cannot adequately monitor drugs or protect consumer safety? Did FDA get it right with Fen-Phen, Vioxx, Baycol, Prempro, Provera, Premarin, Baycol, and on and on?

    Did you also miss that part of the opinion that stated before 2007, FDA did not have legal authority to require drug companies to modify the label once it was approved? How in the world could FDA get it right when it was powerless to do so, even if new information on risks emerged or if review of prior adverse information revealed the warning was insufficient? Do seriously believe drug companies desire the FDA have authority to call up the company after seeing some adverse event report and say, “fix this insufficient warning, or else?”

    Then, there is the whole issue of drug companies over promoting benefits, even promoting non-FDA approved benefits, ghost writing, and downplaying the risks. Do you seriously believe drug companies desire the FDA have authority to do anything more than what it can do today, which is to send a scolding letter? C’mon!

    Finally, a lot of reasonable people said Wyeth got it wrong. In particular, the jury picked by plaintiff and defense counsel that heard ALL of the evidence. It’s strange that we believe juries are capable and reasonable in deciding whether a person is guilty of murder and in recommening a death sentence or in deciding a complex securities fraud case, but not so when comparing the plain language of a drug label to the facts of what the drug company knew about the risks and deciding whether the label did or did not adequately inform the reader.

  4. Posted March 5, 2009 at 5:51 pm | Permalink

    As an expert in warnings and safety communications with over 30 years designing and evaluating/testing warnings, it is my opinion that the Supreme Court ruling in Levine v. Wyeth will have major implications for not just pharmaceuticals hoping to use preemption as a defense in products liability litigation, but for ANY company hoping to use such a defense. Without a Federal Statute, such as was the case with regards to warnings for cigarettes and automobile airbags, most companies, including pharmaceuticals should now address the significant question raised by the Supreme Court’s ruling: Does my product have known or likely risks and dangers associated with its use that are unknown (i.e., hidden) from the product user AND, according to “best practices”, is my warning adequate to communicate those risks and dangers, as well as how to avoid them in the first place? Responsible companies should immediately be addressing this question, not just to avoid or minimize costly litigation, but because it is the right thing to do in order to help prevent injury and possibly save lives.

  5. p-daddy
    Posted March 9, 2009 at 11:53 am | Permalink

    your argument

    ["but if you’re like me, it will make you wonder whether it makes sense to prevent problems with warnings when a warning like this didn’t suffice:...Under no circumstances should PHENERGAN Injection be given by intra-arterial injection due to the likelihood of severe arteriospasm and the possibility of resultant gangrene (see WARNINGS—Injection Site Reactions). The preferred parenteral route of administration is by deep intramuscular injection."]

    is high sophistry. There are plenty of warnings against intra-arterial injection, yet **no** explicit contra-indication against “IV push”. Wyeth dropped the ball here and (I think) rightfully they have to pay.

    By the way, you can see phenergan/grangrenous adverse event reports here: http://www.fdable.com/aers/advanced_query/4d724e1fe33d

  6. Nicole
    Posted March 26, 2009 at 7:31 am | Permalink

    Is anyone considering the doctors who still think it’s morally acceptable to continue giving out this medication like it’s candy?
    I have a condition that requires me to have some kind of anti-nausea medication, phenergan is what is prescribed to me on a regular basis. Zofran is simply too expensive.
    I, however, do not take the phenergan. I’m aware of the terrifying side effects. I also know what I need for my case. Levine, I’m sure, didn’t. Levine should in no way be expected to know what medication she needs for a problem she’s unaware what caused.
    My story:
    Not too long ago, I was seen in the Emergency Room at Franklin Medical Center in Greenfield, Massachusetts. The emergency hospital visits are normal fare, although I’m generally NOT treated in the ER. I was seen by a doctor who was familiar with my case, and quickly figured out a game plan. I wasn’t told what medications I would be given. Before I had a second to ask, he was out of the room. A few moments later, the RNA returned with two IM injections. I’ve almost received medication that I’m allergic to (which the hospital had been made aware of numerous times, as well as about 20 minutes before the nurse had injections in hand) on several occasions because I haven’t asked what I was being given;
    Me – “Uh… before you inject me with that, what is it?”
    RNA – “It’s Phenergan for the nausea, Dilaudid for the pain.”
    “Okay, well, a woman lost her arm because of gangrene from a phenergan injection.”
    “Yeah, sometimes that happens to people.”
    Then I was injected with the needle before I had any time to protest.
    Clearly I don’t have gengrene. But, my arm is pretty friggen sore.
    The moral: the health care, medical system and FDA in this country are sick and diluted with no concern for the people they should be caring for.
    We’ve gotta do everything we can to change it.

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