Terra Sigillata

The safety and effectiveness of medicines and other health products is dependent upon their proper use, particularly the proper route of administration. There are reasons why products are labeled as “for topical use only” or “do not swallow” – two recent warnings from the US FDA illustrate these issues.

Allergic Reactions with Use/Misuse of Denture Cleansers

The FDA recently announced reports of one death and 72 other adverse reactions in individuals who ingested denture cleansers meant to be used in a container with one’s dentures removed. A crucial oxidizing agent, salts of persulfate, can cause allergic reactions in susceptible individuals when swallowed, when swished in the mouth or, more alarmingly, even when residual cleanser solution remains on the dentures when reinserted.

[All sorts of biologists will recognize persulfate (ammonium salt) as the oxidizing agent used to catalyze the crosslinking of acrylamide monomers to make gels for the resolution of proteins and nucleic acids - that is, if you don't have the luxury of purchasing per-poured gels]

An allergic reaction to persulfates may not occur after the first use or even until after many years of use. Symptoms of an allergic reaction may not appear for several minutes or even hours after actual use. Symptoms may include irritation, tissue damage, rash, hives, gum tenderness, breathing problems, and low blood pressure.

As a result of these cases, FDA is recommending that denture cleanser manufacturers clarify product instructions and offer a consumer education campaign (FDA’s PDF here). Moreover, FDA is recommending that manufacturers begin to investigate the potential for replacing persulfate with other oxidizing/bleaching agents that do not cause these hypersensitivity reactions:

To reduce misuse of denture cleansers, FDA is also recommending that manufacturers improve the directions on the label. Labeling revisions are needed to make it clear that these products are meant to clean dentures in a container, not while still in the mouth. Some patients have gargled or swallowed denture cleansers, resulting in abdominal pain, vomiting, seizures, breathing problems, and low blood pressure. Dentures should be thoroughly rinsed with water before they are placed in the mouth.

Inhale, Do Not Swallow Spiriva or Foradil Capsules

This FDA public health advisory may come as a surprise to many who don’t use bronchial inhalers. Spiriva® brand of tiotropium bromide and Foradil® brand of formeterol fumarate are inhalation powders used to treat asthma and chronic obstructive pulmonary disease (COPD) as “maintenance” medications, as opposed to fast-acting inhaled drugs like albuterol that are used during acute asthma attacks.

Supplied as capsules, they are meant to be used in inhalation devices HandiHaler® (Spiriva) and Aerolizer® (Foradil) – each of these drugs and devices require that the patient insert a capsule into an inhaler device, then press a button or buttons that pierces the capsule and allows the micronized drug powder to be inhaled.

For pharmacology background: tiotropium is of the anticholinergic drug class, meaning that it has a potent inhibitory effect against acetylcholine nerve-induced contraction of airways; formeterol is a β2 adrenergic receptor antagonist, or blocker, meaning that it mimics the effect of your own norepinephrine- or epinephrine-induced dilation of airways but in a much more sustained manner.

Back to these inhalable capsules: I look at these instructions and dosage forms and I’m even a bit confused at first – the capsules come in a blister pack that most of us associate with popping open and then swallowing the capsule. It’s a pretty new idea to use a capsule-piercing inhaler because most asthmatics are accustomed to using an inhaled spray where the little aerosol canister is attached to the inhalation device.

I look at the older gentleman in the masthead of this instructional page with the little kid playing doctor and he seems to be saying, “You have got to be kidding me. Where the hell is my old medicine?” A doc I know (not a pulmonologist) took one look at the instructions and said that she doubted if more than 10% of her patients would be able to use the product correctly.

There seems to be little danger directly in swallowing either of these capsules since the drugs are designed to be active when inhaled into the lung then broken down quickly when in the bloodstream and metabolized by the liver (although some minor side effects have been reported). The real danger is that patients with live-threatening bronchial diseases can essentially go unmedicated if the product is used improperly.

I understand the purpose of these inhaled powders: the particles containing the drug are much smaller than even the finest mist that could be produced by a spray inhaler, allowing the medicine to penetrate much more deeply into the lungs to smaller and smaller bronchioles.

i-8fcdaac95922e0c3ac582ba34c0182e7-diskus.gifIn fact, this method first came on the scene in the form of a patented dosage form called a Diskus®. This micronized particle inhaler is self-contained: the medicine is encased inside the device on what looks like a tape with individual blisters. Each time the Diskus is opened and clicked, the mechanism opens one blister and you simply inhale. Much easier to use than fumbling with capsules and putting them into a device that you then activate and to inhale the powder.

Of course, the simpler Diskus device is patented by a company different from the one that makes Spiriva or Foradil. I claim no inside information whatsoever but I suspect that no financial agreement could be reached that would allow these two drugs to be sold in the Diskus dosage form. As a result, we’ve got patients with life-threatening illnesses, many of older age, fumbling around with blister-pack capsules not understanding they are to be inserted into a poker-piercer-inhaler thingie and not just swallowed straightaway.

I use a drug that comes in a Diskus format and it’s very easy and very effective. However, the pharmacy benefits management (PBM) company used by my health insurer recently informed me that they were raising the co-payment on my Diskus to a “higher-tier” and encouraged me to have my doc prescribe two other inhaled medication forms that are still less expensive even when combined.

Ease-of-use and minimization of the number of drugs needed (by formulating two or more drugs together into one product) is well-known to increase patient compliance, the percentage of doses taken as directed. Increasing patient compliance is the single most-cost effective approach in pharmacy to result in the most optimal management of disease. A ridiculous and cumbersome dosage form is not consistent with improving patient compliance, nor is asking a patient to use two separate drugs when a reasonable combination agent exists and has been used successfully by the patient.

Yes, yes, I know that cost issues influence these decisions and choices. And, yes, pharmacists can play a crucial role in educating patients on how to use these new inhalers, when they have the time to step away from the sweatshop.

Shouldn’t it be easier?

Comments

  1. #1 acmegirl
    March 20, 2008

    A ridiculous and cumbersome dosage form is not consistent with improving patient compliance, nor is asking a patient to use two separate drugs when a reasonable combination agent exists and has been used successfully by the patient.

    This is especially true for children, who often have to use a spacer with the traditional style inhaler, which is not portable, tricky to use, and very slow. It could take five minutes or more to take two separate medicines in this way. Not very good for compliance. I was glad that my doctor switched my daughter to the Diskus instead of adding a second inhaler, even though my copay for it was a little more than it would have been for the two separate drugs.

  2. #2 DuWayne
    March 20, 2008

    Should be easier, but I’ll settle for attainable. While I sympathize with people having trouble managing their meds, it’s tempered by the fact that they can actually get the meds in the first place.

    Something that could help a lot, is more doctors doing what the one I grew up with does, make sure before they leave, that they understand the medications that have been prescribed. Make sure they know how to take it, why exactly they are supposed to take it, how it works and why they need to follow the directions so closely. This needn’t be done specifically by the doctor, if Dr. Troyer was too busy, his nurses would go over it with patients. But his patients never left his office, without knowing exactly how to deal with their medications. He even had a pamphlet full of suggestions for helping people remember to take drug regimen.

  3. #3 N.B.
    March 20, 2008

    Nice post. The Spiriva thing is one of those little dosage form stories that pharmacy students chuckle at, but it’s easy to see why it would be confusing if you’ve ever actually played with a HandiHaler device. I think they’re just a few steps away from being as ridiculous as the cumbersome Exubera inhaler. At least they fit in your pocket, whereas the Exubera inhaler would require a larger holding compartment than most concealable handguns.

    As a somewhat random aside, I actually have an Exubera inhaler that was intended for demo purposes; I swiped it from work when the product was discontinued. It sits on my desk, a memoir of a failed product. I think it would make a great lightsaber hilt, should science leap forward substantially.

  4. #4 Abel Pharmboy
    March 21, 2008

    N.B., save the Exubera inhaler – you may be able to sell it to the Smithsonian (or at least the USP) for historic purposes and pay off your student loans after you’re done.

    btw, I posted when Exubera was canned about WSJ Health Blog citing how the inhaler looked like a bong.

  5. #5 PalMD
    March 21, 2008

    I resisted prescribing Spirva for a very long time. Even regular inhalers are hard to use…take an elderly patient with poor eyesight and give them a 4 step process to follow…

    The medication is useful. I keep hoping for an easier delivery device one of these days.

    Hey, crack-heads and meth addicts seem to invent new ways to deliver a drug every day. Maybe the drug companies have a vast, untapped resource.

  6. #6 N.B.
    March 21, 2008

    PalMD: That reminds me of a lecture I attended given by a researcher on MDMA abuse. He had been studying the topic for at least ten years, and he was particularly surprised (and amused) by the development of “Ecstasy suppositories.”

  7. #7 DuWayne
    March 21, 2008

    PalMD –

    Hey, crack-heads and meth addicts seem to invent new ways to deliver a drug every day. Maybe the drug companies have a vast, untapped resource.

    I know more than one “end the drug war” advocate, who has said repeatedly that it could only be good for big pharma, citing exactly that as one of the reasons. I know that in my younger days, I was remarkably adept at improvising pot smoking devices in a pinch.

    I also managed to design the circuitry for and make a digital vaporizer that held temp within 1/10 of a degree. My machinist buddy made the body for it out of scrap stainless. We took a Dewalt battery charger apart and made it so the vaporizer would run on a Dewalt, 18v battery or could be plugged in to run and charge the battery. Never really worked out as commercially viable, it cost too much to make them, even compared to the insane amounts of money some tokers will spend on paraphernalia.

    On the reverse, I could totally see the Diskus being the perfect delivery device for cocaine or meth.

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