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.

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The main point of the trial was to show that a dosage higher than Oracea’s 40mg a day, won’t result in a better decrease in papules and pustules, but may show side effects commonly associated with higher doses of antibiotics.

If Oracea is too costly to be a part of your rosacea regime, you should consider 50mg a day of generic doxycycline. This is likely to be a much cheaper alternative but also offer the same benefits as oracea.

A paper related to this press release was titled Anti-Inflammatory Dose Doxycycline (40 mg Controlled-Release) Confers Maximum Anti-Inflammatory Efficacy in Rosacea and had the following conclusion ;

Higher mg/kg doses led to higher plasma concentrations but did not lead to increased clinical efficacy. Anti-inflammatory dose doxycycline (40-mg controlled-release formulation) conferred peak anti-inflammatory efficacy in the treatment of rosacea.

From today’s Press Release:

Oracea is a patented, delayed release formulation of doxycycline, 40 mg, that is the only FDA-approved treatment for the papules and pustules associated with rosacea. Doxycycline at much higher doses is often prescribed off-label by dermatologists for the treatment of rosacea. The study demonstrated that the higher, antimicrobial dose does not provide a greater clinical benefit than the anti-inflammatory dose of 40 mg, controlled release. However, the higher dose was associated with a significantly higher incidence of adverse events.
…
In contrast, a clear difference was observed between the two treatment groups (Oracea vs. 100mg doxycycline) in the incidence of adverse events, primarily gastrointestinal reactions. Gastrointestinal adverse events, including nausea, vomiting, diarrhea and stomach discomfort, were observed in 26% of patients administered 100 mg of doxycycline versus only 5% in the Oracea group.
…
This study has demonstrated that, in patients with rosacea, increasing the daily dose of doxycycline to 100 mg does not lead to greater efficacy than Oracea, but has a much greater incidence of gastrointestinal side effects. In addition, Oracea’s onset of action was not different from the 100 mg doxycycline dose.”

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This phase 2 trial’s purpose is to determine the safety and efficacy of sub-antimicrobial dose doxycycline in the treatment of patients who have both blepharitis and facial rosacea.

The trial is due to complete in July 2008. The conditions treated include Blepharitis, Meibomianitis & Dry Eye. Interestingly the trial participants will take either oracea or a placebo for a period of 84 days. This suggests that 3 months is a reasonable treatment period for Oracea.

We know that Collagenex holds up to 6 patents relating to Oracea. One of these patents, which was highlighted by Rosacea News in May 2006, covers treating ocular and facial rosacea at the same time with one treatment.

A survey from the NRS suggested that eye symptoms are often undiagnosed in rosacea sufferers. Additionally some sufferers of facial rosacea are only diagnosed when their opthamologist finds one of the related conditions such as blepharitis or meibomianitis.

Extending the marketing reach of Oracea to be a FDA approved treatment for ocular rosacea is another sign that Collagenex are serious about growing the market for their products. Even though doxycycline is not new science, it is still a good thing if the revenues generated by Oracea can be re-invested in developing promising new-styled treatments like Sansrosa/COL-118.

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This recently published paper shows that a daily dose of 40mg of doxycycline is as effective in reducing the lesions of rosacea as a higher dose of 100mg or 200mg a day.

Note that this is a statistical study using existing clinical trial data, and that the authors work for Collagenex who make Oracea.

Anti-Inflammatory Dose Doxycycline (40 mg Controlled-Release) Confers Maximum Anti-Inflammatory Efficacy in Rosacea.

Skinmed. 2007 Sep-Oct;6(5):221-6., Theobald K, Bradshaw M, Leyden J., CollaGenex Pharmaceuticals Inc, Newtown, PA.

Background. Two large clinical trials have recently demonstrated the efficacy of a 40-mg controlled-release formulation of doxycycline in the treatment of rosacea, a dose well below the conventional level of 100 to 200 mg/d. Since no formal dose-response studies have been conducted, the authors analyzed phase 3 data to determine whether a dose-efficacy relationship exists.

Methods. Standard parametric regression analyses were used to estimate the correlations between dose (mg/kg body weight) and overall drug exposure (area under the curve [AUC]) in a phase 1 pharmacokinetic study and between dose and efficacy (mean change from baseline in total inflammatory lesion count at week 16) in 2 pooled phase 3 clinical efficacy studies. Additional regressions were run at each visit for the clinical efficacy studies to determine whether results differed across visits. A regression analysis was also performed in a subset of patients who showed a greater efficacy response.

Results. We found overall drug exposure (AUC) to have a highly significant correlation with dose (mg/kg) (r=0.49; P=.006). In contrast, clinical efficacy did not correlate with dose at any of the visits at week 3 (r=0.01; P=.85), week 6 (r=0.04; P=.53), week 12 (r<0.01; P=.98), and week 16 (r=0.03; P=.64) or among the subset of patients who showed greater clinical benefit.

Conclusions. Higher mg/kg doses led to higher plasma concentrations but did not lead to increased clinical efficacy. Anti-inflammatory dose doxycycline (40-mg controlled-release formulation) conferred peak anti-inflammatory efficacy in the treatment of rosacea.

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We can see from a Collagenex annual report that COL-101 was the name for Periostat MR, which then became Oracea.

Safety and Efficacy Study to Compare Two Rosacea Treatment Regimens

Purpose: To compare the safety and efficacy of two treatment regimens: 1) COL-101 and metronidazole gel 1%; 2) Doxycycline hyclate 100 mg and metronidazole gel 1%

Official Title: A Clinical Trial to Determine the Effects of COL-101 Administered Once Daily With Metronidazole Topical Gel, 1% Versus Doxycycline Hyclate 100 mg Administered Once Daily With Metronidazole Topical Gel, 1% in Patients With Moderate to Severe Rosacea

This trial follows on from a 2005 paper that studied the combination of periostat and metrogel. That study concluded that combining sub antibiotic dose doxycycline with metrogel 0.75% was better than metrogel on its own.

Combining a systemic antibiotic with metronidazole has been the mainstay of rosacea treatment for several years. What we are seeing here is updates to studies since the introduction of oracea and metrogel 1%.

Tear fluid levels of MMP-8 are elevated in ocular rosacea-treatment effect of oral doxycycline, Graefe’s Archive for Clinical and Experimental Ophthalmology, 2006 Jan 13;:1-6, Authors: Maatta M, Kari O, Tervahartiala T, Peltonen S, Kari M, Saari M, Sorsa T

BACKGROUND: Ocular rosacea (OcR) is a chronic inflammatory disease especially affecting lid margins. Previous studies have shown that it is accompanied by increased levels and activation of tear fluid gelatinases. Matrix metalloproteinase 8 (MMP-8; collagenase 2) levels and activation are commonly elevated in many inflammatory conditions. Therefore we studied here whether MMP-8 concentration and activation in tear fluid are increased also in OcR, and if an oral doxycycline regimen could rectify the situation.

METHODS: Tear fluid samples were collected from 22 OcR patients and 22 healthy controls. The OcR patients were then treated with an oral doxycycline regimen for 8 weeks and tear fluid samples collected again after 4 and 8 weeks. Conjunctival brush cytology and patients’ subjective symptoms were scored. MMP-8 concentrations in the tear fluid were assessed by immunofluorometric assay and the molecular forms and isoenzyme expression of MMP-8 were studied by Western immunoblotting.

RESULTS: The mean MMP-8 concentration was statistically significantly higher in OcR (156.8+/-207.4 mug/ml) than in the normal subjects (53.5+/-66.7 mug/ml) (P=0.036), but decreased to 79.2+/-141.6 mug/l and 53.6+/-75.2 mug/l after 4 and 8 weeks doxycycline treatment, respectively. There was a statistically significant difference between the untreated OcR and the MMP-8 results after 4 or 8 weeks of oral doxycycline (P=0.041 and 0.069, respectively) and the OcR patients experienced statistically significant relief of their subjective symptoms (P=0.0001) after the doxycycline regimen. Both the normal and OcR tear fluid contained the larger, 60-80 kDa highly- glycosylated polymorphonuclear leukocyte-type MMP-8 isoform in Western immunoblotting, but not the 45-55 kDa less glycosylated mesenchymal-type isoform. MMP-8 activation was in practice present only in the OcR samples, and was inhibited by oral doxycycline.

CONCLUSIONS: MMP-8 concentration and activation degree in tear fluid are increased in OcR, probably reflecting increased inflammatory activity. Doxycycline effectively reduces these pathologically excessive levels and activation of MMP-8, and relieves patients’ subjective symptoms

• PubMed Extract
• Abstract Online

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From BJO At A GlanceDOXYCYCLINE, DOES IT REPAIR OCULAR SURFACE?

Background/aims: Doxycycline is a broad spectrum antibiotic that chelates metal ions and is frequently used as part of the treatment of ocular surface diseases. Its therapeutic value has been ascribed to an ability to inhibit matrix metalloproteinase (MMP) activity and both MMP and IL-1 synthesis. The aim of this study was to evaluate the role of doxycycline as an inhibitor of corneal MMPs and assess its contribution to ocular surface repair mechanisms.

Methods: Corneal epithelial cell and keratocyte cultures were grown to confluence and incubated with IL-1, LPS, doxycycline, or doxycycline and LPS in serum free medium for 4 days. The cells were either harvested and assayed for caspase-3 activity or stained with either AE5 or antivimentin antibodies. Media samples were concentrated and assayed for MMP activity by zymography or using a fluorigenic substrate. ELISA was used to quantify IL-1, MMPs -1,-2,-3,-9, and TIMPs -1 and -2.

Results: IL-1 and LPS had no effect on MMP/TIMP production by cultured corneal epithelial cells and keratocytes. Corneal MMP-2 inhibition by doxycycline was partially [Ca2+] dependent but irreversible. At the minimum inhibitory concentration, 100 µm, doxycycline had no apparent effect on MMP and TIMP production, but ultimately caused the death of keratocytes and some of the epithelial cells that detached from their basement membrane. Caspase-3 activity was not detected in dead or dying keratocytes. The mechanism of cell death in cultured corneal epithelial cells was not caspase-3 related apoptosis as the activity of this enzyme, normally detectable, was lost. The epithelial cells that survived doxycycline treatment did not bind antivimentin antibody and compared with controls, reacted less with the AE5 antibody. They were probably transient amplifying cells.

Conclusions: Doxycycline irreversibly inhibits corneal MMP-2 activity by chelating the metal ions that are catalytically and structurally essential. Corneal MMP/TIMP production in vitro is not modulated by IL-1, LPS, or doxycycline. The therapeutic value of doxycycline may depend upon its effective concentration at the ocular surface and probably relates to its chelating properties.

• Abstract Online
• Full Article Online
• Full Article as a PDF

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Some more background about subantimicrobial (sometimes referred to as SD – Subantimicrobial Dosage) doxycycline and rosacea. A dosage of around 50mg per day is enough to see a benefit in rosacea symptoms but also low enough to not affect gut flora or cause other antibiotic related side effects. SD doxycycline can also be take safely for longer periods of time compared to higher doses of doxycycline.

Subantimicrobial Dose Doxycycline for Acne and Rosacea, From SKINmed, 2(4):234-245, 2003

Conclusions: The tetracyclines have been used effectively for decades for the treatment of acne and rosacea at doses of 50-200 mg daily for doxycycline and minocycline and 250 mg twice or four times daily for tetracycline HCl. Reports of serious adverse events and the increasing rates of bacterial resistance to tetracyclines at standard doses in patients undergoing long-term therapy have prompted interest in new therapeutic approaches for their use in acne and rosacea therapy.

Lesions of periodontitis and acne are mediated by a somewhat similar inflammatory response. The efficacy of clinical trials and subsequent approval of SD doxycycline in adult periodontitis was the impetus for the study of its effect in acne. Results from the study of SD doxycycline in acne are promising and should encourage further research into this new strategy for treating acne. A 50-patient, open-label experience trial with SD doxycycline in the treatment of rosacea also provided evidence of the utility of the drug. The use of SD doxycycline can potentially avoid the adverse events of standard-dose, long-term therapy with tetracyclines for acne and thereby enhance patient compliance. In addition, widespread adoption of this dosage as part of a maintenance therapy for acne and rosacea will limit exposure of patients and their microflora to doxycycline and may slow the steadily increasing rate of resistance of P. acnes and other organisms to the tetracyclines.

Full Article Online

SKINmed is a peer reviewed outreach journal specifically written to be of interest to Dermatologists and serve as a teaching, didactic resource of clinical content for non-Dermatologists.

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From US Pharmacist, Vol. No: 29:04 Posted: 4/15/04.

New Applications of Doxycycline Hyclate in Medicine and Dentistry

Golub and his colleagues were able to show that tetracycline exerted a unique property that was independent of its antimicrobial effects. The chemically modified tetracyclines (CMTs) showed no antimicrobial effect but rather inhibited an enzyme called collagenase, which is produced by host neutrophils (white blood cells) and structural cells (eg, fibroblasts and osteoclasts).

…

Certain skin diseases appear to have etiologies similar to those seen with periodontitis. Inflammatory, collagenolytic skin diseases that are involved with collagen destruction via the production and release of collagenase include acne vulgaris, rosacea, and other pathological collagen breakdown, such as arthritis.

…

In another recent study, 50 rosacea patients (manifesting all stages of disease) received monotherapy with doxycycline hyclate 20 mg tablets twice daily for eight weeks. Most patients had no previous history of treatment for their rosacea symptoms. Patients were evaluated at the initial visit and again between two and eight weeks for erythema, inflammatory lesions, and telangiectasias (spider veins). After an average of four weeks of treatment with doxycycline hyclate 20 mg, patients experienced an 80% to 100% clearing of inflammatory lesions and a 50% reduction in erythema. A decrease in the size and diameter of telangiectasias was also observed, although complete clearing was not achieved. There were no reports of GI side effects, headaches, vaginitis, or photosensitivity (including for patients who had experienced such adverse effects on antimicrobial dosages of doxycycline).

…

In an ongoing study, 150 patients with moderate to severe rosacea are randomized to receive doxycycline hyclate 20-mg tablets twice daily or placebo for four months.39 The primary efficacy parameters include change in total papule and pustule lesion counts and change in clinician’s erythema scores from baseline.Although doxycycline hyclate 20 mg tablets are not currently indicated for the treatment of rosacea or acne vulgaris, similarities between these diseases and periodontitis, as well as the encouraging results from studies of its use in acne and rosacea patients, have prompted FDA phase III studies involving orally administered SDD in rosacea patients. Ongoing and planned SDD studies include patients with blepharitis, postmenopausal osteopenia, periodontal implantitis, perioral dermatitis, and additional rosacea studies.

See also

• Full Article Online
• Periostat (doxycycline hyclate) 20mg Prescribing Information (PDF)

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Periostat (20 mgs doxycycline hyclate) has been helpful to some rosacea sufferers. Originally developed to combat periodontal disease (gum disease), periostat was approved by the FDA in 1998. Recently the FDA approved the introduction of generic periostat equivalents. Ivax Pharmaceuticals and CorePharma are now free to sell their generic equivalents of Periostat.

Oracea is a new form of doxycycline, the same active ingredient as CollaGenex’s gum disease treatment Periostat. CollaGenex is shifting its focus to the dermatology market following the approval of generic competition for Periostat.

Colin Stewart, CollaGenex’s president and chief executive officer of CollaGenex, said he believes the product could “significantly expand” the current $500 million market for prescription drugs to treat rosacea.

The lead investigator for the trial, says

“Oracea provides therapeutic efficacy in rosacea through anti-inflammatory and anti-collagenolytic effects and is devoid of antibiotic activity. Therefore, even with long-term use, development of antibiotic resistance is not an issue. Many rosacea patients will benefit from a once-daily formulation of doxycycline that has been optimized to treat rosacea effectively and safely.”

Oracea is a new sustained release, once a day 40 mg tablet. 10mg of this 40mg is coated to delay the release of the doxycycline.

As part of the latest Phase III study for Oracea, when compared to the placebo, erythema showed a trend towards improvement. In a second study, the reduction in erythema achieved statistical significance as erythema scores improved (again against placebo).

CollaGenex is also developing a new once-daily version of Periostat, called Periostat MR, to protect it position in the dental market. Collagenex has restructured their sales team around the fact that Periostat is about to become a generic label.

The company is also seeking to expand the label for the drug’s main ingredient to include its use in treating a variety of skin disorders including acne and rosacea. Additionally Oracea may also be targeted towards treating ocular rosacea as well.

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.

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).

Collagenex reports that Oracea is equally effective as 100mg of doxycycline. That particular press release is a culmination of a trial that we have reported previously – oracea plus metrogel, better than 100mg doxycycline plus metrogel ? and also a 2007 SkinMed paper; maximum effective dose of doxycycline is 40mg a day.

See more about how Collagenex are promoting Oracea.

Oracea Plasma Concentration

The following graph, sourced from Collagenex, shows the blood plasma concentration of doxycycline for 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 anti-microbial threshold is listed here as a concentration of 1000 nano grams/mL (i.e. 1.0µg/mL).

(click for a larger view)

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.

Method of Action

As part of Collagenex’ push to promote Oracea and Incyclinide, a new web site developing the idea that rosacea is a chronic inflammatory disease has been created. Be sure to check out the video of the the suggested Doxycycline Method of Action.

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, it is likely to be very close. 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.

Your Thoughts

Have you tried Oracea or another low-dose doxycycline ? How long did it take to see some benefit ? Did you experience any side effects ? Please leave a comment below.

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