Rosacea Support Group » tetracyclines

Oracea should be tested against Generic Doxycycline

David Pascoe — Wed, 24 Mar 2010 10:45:37 +0000

This just published abstract is looking at recent advances in the use of the tetracycline family in treating rosacea. Of course a lot of the interest in subantimicrobial dose doxycyline has been motivated by the introduction of the Oracea to the market.

A previous published study instigated by Collagenex (now owned by Galderma) showed that 100mg doxycycline was no better than oracea in treating the papules and pustules of rosacea.

What would be really interesting, though, would be to see a double blind study comparing 50mg a day of generic doxycyline with Oracea. I doubt that Galderma would be at interested in the this sort of comparison, but perhaps one of the manufacturers of generic doxycycline should undertake such a trial.

Galderma holds up to 6 patents related to Oracea, so we can expect that it will be may years before generic oracea becomes available. Pharmaceutical companies that want to make generic oracea will have to wait until all of the patents lapse.

This paper additionally calls for further trials of metronidazole vs. oral tetracyclines. Now that is something for which I think we already have enough published, light weight papers.

The role of tetracyclines in rosacea, Am J Clin Dermatol. 2010;11(2):79-87

There is a great deal of evidence to support the use of tetracycline and doxycycline in the treatment of papulopustular rosacea. Nevertheless, these agents have shared and unique adverse effects and relative contraindications.

Recently, subantimicrobial-dose doxycycline was demonstrated to be an effective treatment for rosacea, due to its inherent anti-inflammatory properties.

Furthermore, subantimicrobial-dose doxycycline has a more preferable tolerability profile and a lower occurrence of bacterial resistance than traditional-dose doxycycline.

To further elucidate the role of tetracycline agents in rosacea, clinical trials that compare these agents with each other as well as with other effective rosacea treatments are called for. Adherence studies comparing oral tetracycline treatment with topical metronidazole treatment may also enhance clinical decision making.

Tetracyclines and Rosacea: what we already knew

David Pascoe — Thu, 01 Oct 2009 08:40:40 +0000

Reading this just published abstract highlights for me just how slowly indeed research moves along. These recently proposed methods of action of tetracyclines seem to embody far from ground breaking research.

We learnt in 2007 that tetracyclines have anti-inflammatory actions: “Tetracyclines are known to exhibit multiple significant anti-inflammatory actions … the mechanisms of this anti-inflammatory activity, such as inhibition of chemotaxis, granuloma formation, and protease.”

Further, back in in 2006 we learnt that tetracyclines help rosacea via their anti-inflammatory effects – “More recently, biologic actions affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism have been researched.”.

More related research from 2006: how do tetracyclines help rosacea ?

“Thus the therapeutic effect of tetracyclines in acne may at least in part be due to reduction in neutrophilic chemotaxis as well as their inhibitory effect on proinflammatory cytokines and MMP-9.

…

The anti-inflammatory effects of tetracyclines already mentioned may explain, at least in part, their beneficial effects in rosacea. Inhibition of angiogenes may be a contributory factor in the therapeutic effect of tetracyclines in this group of disorders. Features that favor angiogenesis may contribute to the telangiectasia of rosacea. These include protease-triggered release of angiogenetic factors stored in the extracellular matrix, release of inhibition of endothelial factors, and release of angiogenic factors from activated macrophages.”

So the following abstract hardly seems to be moving us forward in rosacea research ;

Tetracycline Actions Relevant to Rosacea Treatment, Skin Pharmacol Physiol. 2009 Sep 25;22(6):287-294

Until today, the pathogenesis of rosacea is not known in detail. Yet in recent years evidence has been accumulating that rosacea with its common symptoms such as inflammatory lesions, erythema, telangiectasia, phymatous changes, and ocular symptoms is of inflammatory nature. Tetracycline derivatives like doxycycline successfully used in the treatment of skin diseases like acne and rosacea seem to inhibit different inflammatory pathways involved in the pathogenesis by various modes of action. Although data for skin diseases are relatively scanty, the following modes of action of tetracyclines seem to be most relevant for an effective treatment of acne and rosacea: inhibition of matrix metalloproteinases, downmodulation of cytokines, inhibition of cell movement and proliferation, inhibition of granuloma formation, inhibition of reactive oxygen species, nitric oxide, and angiogenesis, whereas inhibition of phospholipase A2 seems to be of lower importance. The role of the saprophytic mite Demodex folliculorum remains to be clarified. Additional studies are necessary to further elucidate how tetracyclines work in rosacea treatment.

Oh well, all rosacea specific research is welcomed and seeing rosacea researchers from around the world get papers published is a good thing for all rosacea sufferers.

doryx + applesauce, for those who can’t swallow tablets

David Pascoe — Mon, 29 Jun 2009 15:28:47 +0000

If you have trouble swallowing tablets, here is an official FDA sanctioned tip. Open the tablet and sprinkle the delayed release pellets on to a spoonful of applesauce. This is a good option for anyone who finds swallowing the capsule difficult.

This advice is only given for the 100mg and 75mg delayed release formulations of doryx which contain specially coated pellets of doxycycline hyclate. A clinical trial confirmed that the absorption of doxycycline is comparable when the table is taken whole or sprinkled on applesauce, both with and without water.

From Daily Med, Current Medical Information, Doryx (doxycycline hyclate) Tablet, Delayed Release

DORYX Tablets contain specially coated pellets of doxycycline hyclate, a broad-spectrum antibiotic synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration.

Sprinkling the Tablet on Applesauce

Doryx Tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed release pellets) on a spoonful of applesauce. The delayed release pellets must not be crushed or damaged when breaking up the tablet. Any loss of pellets in the transfer would prevent using the dose. The applesauce/Doryx mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/Doryx tablet cannot be taken immediately, the mixture should be discarded and not stored for later use.

The FDA has also issued instructions on how to prepare 100mg tablets of doxycycline (in an emergency), for children and adults who cannot swallow pills. See Mixing Doxycycline Hyclate 100mg Tables with Food. This method crushes a tablet into 4 teaspoons of water and then combines this with 3 teaspoons of milk, or chocolate milk or chocolate pudding or apple juice + sugar.

Is Oracea different to 50mg doxycycline ?

David Pascoe — Wed, 10 Jun 2009 03:36:08 +0000

I came across the following graph in a recent presentation at the recent AAD meeting and figured it was interesting enough to highlight it here.

The following graph, sourced from Collagenex (who sell Oracea), shows the blood plasma concentration of doxycycline after taking Oracea compared to 50mg once a day of generic doxycycline. The horizontal axis stretches out to 24 hours post dosage. The vertical axis is in nano-grams per milli-litre (ng/mL).

The horizontal grey line is labelled anti-microbial threshold is listed here as a concentration of 1000 nano grams/mL (i.e. 1.0µg/mL). This value of 1 microgram per millilitre is considered to be the concentration at which doxycycline is able to affect bacteria i.e. have an anti-bacterial effect.

The two inverted curves show the amount of doxycycline that is present in the blood over a 24 hour period. The top grey curve is for 50mg of generic doxycycline and the bottom green curve is for Oracea.

I read this graph to suggest that Oracea is able to maintain a sustained release of the active ingredient doxycycline without venturing into anti-microbial territory. The advantage of a delayed release product is that Oracea can offer the `area under the concentration-by-time curve’ delivery, but at sub-antimicrobial dosage over 24 hours.

That is, Oracea can deliver a dosage of doxycycline that can give measurable results, but keep the concentration of doxycycline in your blood low enough to reduce potential problems associated with antibiotics.

(click image for larger view)

*16 healthy adult subjects, per arm; mean weight 75 kg

† Measured at 7 days

Data on file, CollaGenex Pharmaceuticals, Inc.

What is happening here ?

We do know that antibiotics have non-antibiotic properties. Recent research has found biologic actions affecting inflammation, proteolysis, angiogenesis, apoptosis, metal chelation, ionophoresis, and bone metabolism. Thus a whole new range of clinical applications are being investigated. So it does appear that taking a low dose, or even a sub-antibiotic dose of antibiotics can have real clinical benefits.

A Cheaper Alternative ?

As Oracea is a new prescription product it can be quite expensive, especially if you don’t have comprehensive insurance coverage. One possible alternative you could discuss with your doctor is 50mg a day of generic doxycycline. Whilst this dosage won’t have exactly the same profile in your blood, the benefits and side effects are likely to be close. See your doctor for a better opinion.

I doubt whether we will ever see a trial to prove that the benefits and side effects of Oracea and 50mg of doxycycline are comparable. Therefore it seems unlikely that one can say either way whether the above graph shows an important distinction between the two treatments.

Does it really matter that 50mg a day of doxycycline ventures above the anti-microbial threshold for a couple of hours a day, or that the overall dosage delivered is around twice for the generic ? These are questions that can’t be answered at this stage.

As with all systemic treatments, both Oracea and a low dose of doxycycline can cause unwanted side effects so the supervision of your doctor is important.

Oracea too expensive ?

David Pascoe — Tue, 19 May 2009 02:30:45 +0000

Some interesting comments from KUNC commentator Dr. Marc Ringel via a NPR segment. He raises two points that are worth discussing. Firstly is Oracea really any better than generic doxycycline and secondly what does it say about the pharmaceutical industry (and insurance companies – ed) that a repackaged old product can be so expensive ?

Galderma would say that Oracea is sub-antimicrobial and 50mg doxycycline is a low-dose antibiotic. The distinction is that Oracea will maintain a blood serum level less than 1000 nano grams/mL (i.e. 1.0µg/mL) for the 24 hours post ingestion. 50mg of doxycycline will result in a blood serum level above the `antimicrobial threshold’ of 1.0µg/mL. This can potentially lead to side effects such as antibiotic resistance, abdominal upsets etc., although the amount by which this threshold is exceeded is still relatively small.

At best I would say that the pharmacological benefits of Oracea over 50mg generic doxycycline are are still up for debate.

As to the cost of Oracea, Galderma of course has shareholders like every large pharmaceutical company. Marketing to both health providers and directly to consumers make sense to gain the largest market share possible. Given that they are so few treatments directly targeted at rosacea sufferers it is clear why Galderma wants patients to ask for Oracea by name and for Oracea to be strongly associated as a front line rosacea treatment.

By way of comparison, in Australia pharmaceutical companies are prohibited from marketing prescription brand names directly to the public. Advertisements usually end with a request to ask your doctor for more information. This reduces the pressure doctors feel to prescribe a particular product but may also result in less consumer choice and involvement in their treatment.

In the end, for those with good insurance cover this whole topic is pretty moot as Oracea will be affordable. Additionally those who cannot afford Oracea have a cheap viable alternative in 50 mg of generic doxycycline once a day. See your doctor for more information.

KUNC: The Big Zit Rip-off, Marc Ringel

GREELEY, CO (2009-05-18) Most agree that something needs to be done to overhaul America’s healthcare system. But leave it to KUNC commentator Dr. Marc Ringel to illustrate the problem – through something as small and innocuous as a pimple.

Or you can buy Oracea, a brand-name doxycycline marketed by Galderma Laboratories. Oracea will set you back over $200 a month if you purchase it in this country or about $150 if you shop online and make your buy from a Canadian outfit. To be sure, the dosage of Oracea is 40mg, making it, like the baby bear’s porridge, just right.
…

I cannot imagine, though, how the extra 10 mg in a 50 mg generic doxycycline capsule could cause close to the distress that too-hot or too-cold porridge did to Goldilocks. Nor do I see how Oracea would work better than the plain vanilla generic except, perhaps, for an enhanced placebo effect generated by spending so much money on a product marketed especially to this affliction. A person might figure that such an exorbitantly expensive brand name would just have to work better.

novel tetracycline from Warner Chilcott and Paratek

David Pascoe — Fri, 08 May 2009 07:41:37 +0000

Some very preliminary internet crumbs about a new possible rosacea treatment under development. The treatment under development is listed as a “novel tetracycline”.

Warner Chilcott Limited calls itself a “specialty pharmaceutical company, that engages in the development, manufacture, marketing, and sale of branded prescription pharmaceutical products in women’s healthcare and dermatology segments primarily in the United States”.

In the WCRX 2007 Annual Report we find ;

WC3035. In July 2007, we entered into an agreement with Paratek under which we acquired certain rights to novel tetracyclines under development for the treatment of acne and rosacea. Currently, we are working with Paratek to select a lead compound for development.

The 2009 annual report notes that a lead compound is currently in preclinical development.

Warner Chilcott own patents for and manufactures Doryx delayed release tablets for 75mg, 100mg and 150mg. WCRX claim that “DORYX Delayed-Release Tablets contain unique enteric-coated pellets of doxycycline hyclate. DORYX is the only enteric-coated pelletized doxycycline.”

We’ve seen novel antibiotics under development for rosacea in recent years. Collagenex, now owned by Galderma, was developing a “tetracycline which has no antibacterial activities but is a pure play anti-inflammatory, and it’s being targeted for the treatment of acne.” The product was called Incyclinide. This formulation of tetracycline was shelved as a rosacea treatment when it was discovered that a 40mg dose causes photo-toxicity and also trial participants who were give the Incyclinide did not demonstrate a greater reduction in papules and pustules compared to patients on the placebo.

How Collagenex (Galderma) are Promoting Oracea

David Pascoe — Thu, 06 Dec 2007 07:44:14 +0000

A recent investor presentation from Collagenex shows some interesting insights into how Collagenex are promoting Oracea.

Oracea is promoted as safe and effective for long term use. It was reported that the average duration of Oracea therapy is 4 months, compared to an average of 2.5 months for other rosacea prescriptions.

52% of Oracea prescriptions are refills – the presentation suggests that this is a high refill rate thus implying high patient satisfaction.

Of the 14 million adults in the US who have rosacea, only 1.4 million currently seek treatment. The current value of rosacea prescriptions is greater than $500m a year – leading to the implication that the rosacea treatment market has plenty of room for growth. The dermatology market as a whole is presented as a $8.9 billion opportunity.

Collagenex are holding up to 6 patents relating to Oracea. These patents cover Oracea’s method of use, mechanism of action and pharmacokinetic profile (i.e. how it is absorbed and acts over time).

Their aim is to generate 85% of rosacea prescriptions by targeting 5,600 dermatologists. Collagenex need to market Oracea effectively as they have a some good competition from generic doxycycline (50mg a day). As I’ve mentioned before we should thank Collagenex for proving that low dose doxycycline is an effective and safe treatment for the papules and pustules of rosacea.

From my reading of their graphs, Oracea is now selling over 1.2 millions units a month.

Your turn to write something: How much are you paying for a month of Oracea ? Were you convinced to try it by your doctor and has it worked ? Have you been able to try generic doxycycline as an alternative ? Please let us know in the comments below.

incyclinide fails for rosacea, acne still possible

David Pascoe — Thu, 27 Sep 2007 00:44:28 +0000

Despite promising looking Phase 1 and initial Phase 2 dose finding studies, Incyclinide will no longer be developed as a treatment for rosacea. Incyclinide is a chemically modified tetracycline that its developers – Collagenex, was hoping would become another systemic treatment for rosacea. We did get a warning in May that clinical trials for Incyclinide weren’t all going smoothly – when the dose finding trials for acne found that 40mg a day causes photo-toxicity.

From the press release: CollaGenex Pharmaceuticals Announces Results of Phase 2 Dose-Finding Study of Incyclinide for the Treatment of Rosacea

The study demonstrated that incyclinide was well-tolerated, with most adverse events being mild or moderate. However, the patients who were administered incyclinide did not demonstrate a greater reduction in inflammatory lesions than the patients on placebo at any time point during the study.

…

Klaus Theobald, M.D., Ph.D., chief medical officer of CollaGenex, said, “We are surprised and disappointed that the results of this large, well-controlled Phase 2 study did not support the findings of an earlier, much smaller pilot study in rosacea patients. On the basis of these results, we will not be pursuing further clinical development of incyclinide in rosacea patients.

This is disappointing for rosacea sufferers, and again proves the high risk of developing new treatments for rosacea. Collagenex will continue to develop Incyclinide as an acne treatment (and indeed as a treatment for diseases other than rosacea) and also continue to develop COL-118/Sansrosa for facial redness. Collagenex is of course also responsible for the low dose doxycycline treatment it called Oracea.

Related Articles:

Tetracyclines: their non-antibiotic properties
Incyclinide phase 2 for acne
incyclinide targets conditions other than rosacea
Rosacea Support Resource Pages: Antibiotics & Anti-Inflammatories
how do tetracyclines help rosacea ?

incyclinide dosage trials: 40mg too much

David Pascoe — Tue, 22 May 2007 07:06:00 +0000

Collagenex has announced that their ongoing trials to find the best dosage for Incyclinide have discovered that 40mg can cause photo-toxicity.

Collagenex is conducting parallel Phase II trials for Incyclinide for both acne and rosacea.

As detailed in a recent news item, incyclinide targets conditions other than rosacea, Incyclinide differs from a non-antibiotic tetracycline in that it is also chemically modified. Thus we might expect that Incyclinide will offer different benefits compared to oracea.

It will be interesting to see how Collagenex decides to market Incyclinide, especially given that it has invested heavily in the development of another tetracycline based systemic treatment targetted at rosacea – namely Oracea.

From: CollaGenex Pharmaceuticals Discontinues 40 mg Cohort of Phase II Dose-Finding Study of Incyclinide for the Treatment of Acne

Klaus Theobald, M.D., Ph.D., said, “One of the objectives of our Phase II dose-finding study of incyclinide for the treatment of acne was to determine a maximum effective or maximum tolerated dose. We have already identified a minimum effective dose at 10 mg and greater efficacy at 20 mg, with side effects similar to placebo at these doses. Because we have determined there to be unacceptable drug-related adverse events in the 40 mg cohort, we are discontinuing this cohort. Since we observed no adverse events at lower doses, we are evaluating our options for the continuing development of incyclinide in acne at lower doses, and we are continuing the Phase II dose-finding trial of incyclinide for the treatment of rosacea.”

…

Research has shown that compounds can be created by chemically modifying certain tetracyclines and that these new compounds have properties that may make them effective in treating diseases involving inflammation and/or destruction of the body’s connective tissues. CollaGenex is evaluating various chemically modified tetracyclines (so called “IMPACS”(TM) compounds because they are Inhibitors of Multiple Proteases And CytokineS) to assess whether they are safe and effective in these applications.

Further Reading ;

oxytetracycline (Terramycin) joins low dose antibiotics

David Pascoe — Tue, 24 Apr 2007 03:37:00 +0000

There has been a lot of publicity lately about Oracea, which is a low dosage, sustained release 40mg form of doxycyline. Oracea was born out of the expiration of the patent on periostat – a twice a day 20mg dose of doxycycline originally targetted at gum disease.

Another new low dose antiobiotic is Solodyn (45mg, 90mg and 135mg of extended release minocycline HCL, dose is based on your weight).

This paper (sadly only available in Polish) highlights the fact that one more tetracycline – oxytetracycline is joining the ranks of proven low dose antibiotics. A normal dose of oxytetracycline is 250-500mg four times a day.

Oxytetracycline–mechanism of action and application in skin diseases, Wiad Lek. 2006;59(11-12):829-33, Olszewska M.

Oxytetracycline is a bacteriostatic antibiotic. Newly discovered, additional mechanisms of action include antioxidant, antiinflammatory and immynosupresive activity of oxytetracycline and other tetracyclines. These activities were the basis for developing therapy regimens with oxytetracycline in subantimicrobial doses. Due to its significant efficacy, limited adverse effects and low therapy costs, oxytetracycline at the dose of 500 mg per day is presently considered as therapy of choice in papulopustulous acne. Rosacea and perioral dermatitis are other indications. Topical oxytetracycline shows significant efficacy in primary and secondary skin infections with inflammatory reaction.

Further Reading ;