cover letter to fda commissioner margaret hamburg, m.d., and janet woodcock, m.d., director of the center for drug evaluation and research

Director, Center for Drug Evaluation and Research Dear Commissioner Hamburg and Director Woodcock: The American Dental Association (ADA) respectfully requests that your agency consider requiring medications that are commonly associated with moderate-to-severe dry mouth (xerostomia) to carry warning-label information about the oral complications associated with reduced salivary flow. In recent years, many prescribed and over-the-counter medications have been recognized as a primary cause of chronic dry mouth. The condition is particularly common among individuals taking multiple drugs, including many antihistamines, decongestants, painkillers, high blood pressure medications, antidepressants and other medications. Without the cleansing effects of saliva, chronic dry mouth can lead to tooth decay, inflammation or infection of the mouth, throat or tongue, impaired chewing or swallowing, and other maladies. These potential effects should be listed on the warning labels of drugs commonly associated with dry mouth. Enclosed you will find more detailed comments in support of this request. If you have any questions or require additional information, please contact Mr. Robert J. Burns at 202-789-5176 or [email protected]. Thank you for considering this request. Sincerely, Kathleen T. O’Loughlin, D.M.D., M.P.H. Warning Label Information on
Medications Associated with Xerostomia (Dry Mouth)
The American Dental Association encourages the U.S. Food and Drug Administration to consider requiring medications that are commonly associated with moderate-to-severe dry mouth (xerostomia) to carry warning-label information about the oral complications associated with reduced salivary flow, including dental caries, oral candidiasis, glossitis, mucosal sores or infections, and impaired mastication or swallowing function. Including an oral health warning on medications associated with xerostomia, such as anticholinergics, would raise public awareness about the risks associated with regular use of xerogenic medications and their potential impact on oral health and quality of life, particularly for the elderly. Commonly known as "dry mouth," xerostomia is the subjective complaint of oral dryness that typically, but not always, is associated with salivary gland hypofunction (i.e., objective evidence of reduced saliva secretion). Dry mouth occurs from alterations to the quantity or quality of saliva due to systemic disease (e.g., Sjogren’s syndrome, diabetes mellitus), radiation therapy for head and neck cancer, medication use, dehydration and other contributing factors. In the past, radiation treatment for head and neck cancer was considered the most common cause of xerostomia, particularly in its severest form following radiotherapy–induced damage to the salivary glands. However, in recent years, prescribed and over-the-counter medications have become increasingly recognized as a primary cause of chronic dry mouth, particularly for older individuals taking multiple medications.1,2,3 As noted in the U.S. Surgeon General’s Report on Oral Health in America, over 400 prescribed and over-the-counter drugs can reduce salivary output or quality as a peripheral side effect.4 Chronic dry mouth is a common adverse effect for each of the following medication groups:1 [ -blockers, ß-blockers, diuretics, calcium channel blockers]; (antimuscarinic) agents for treatment of urinary incontinence (e.g., Anti-psychotic agents (e.g., chlorpromazine); Central Anti-allergy medications (e.g., antihistamines). Dry mouth is an under-recognized but common side effect associated with the above medication groups, particularly with anticholinergics, tricyclic antidepressants, antipsychotics, beta-blockers and antihistamines.4 Many medications associated with xerostomia or salivary gland hypofunction generally have anticholinergic or sympathomimetic activity. As an example, oxybutynin is an anticholinergic medication that is often associated with moderate-to-severe dry mouth, affecting an estimated 14 to 46 percent of users of immediate- or extended-release oxybutynin.5 Dry mouth rates of over 80 percent have been reported for individuals taking oxybutynin, and dry-mouth incidence increases as duration of use extends from four to eight weeks.5,6,7 According to a systematic review, one in three individuals taking oxybutynin or other April 25, 2011 Page 2 anticholinergics for overactive bladder reported having dry mouth.8 Another study found that over 20 percent of patients discontinued oxybutynin use due to severe oral dryness.9 Using oxybutynin for over four weeks can place individuals, particularly older adults, at elevated risk for chronic dry mouth, a common precursor for caries activity or other oral complications due to reduced buffer capacity of saliva and lower plaque pH. This promotes growth of cariogenic bacteria, and the lower rate of salivary secretion leads to the development of oral flora such as Lactobacilli, Candida species and Streptococcus mutans, which are associated with the development of dental caries.10,11 Oxybutynin and other anticholinergics (e.g., tolterodine, darefinacin) are muscarinic receptor antagonists that inhibit salivary secretion by blocking the action of acetylcholine. Antidepressants are another medication group with anticholinergic side effects such as chronic dry mouth. Older adults on antidepressant therapy have been found to have a higher index of root caries,12 and children receiving antidepressants also have increased levels of caries activity.13 As with anticholinergic medications for urinary incontinence, long-term use of antidepressants with significant anticholinergic effects (e.g., amitriptyline) can place individuals at increased risks for xerostomia, mucosal injury, pain, difficulty swallowing or other oral complications. Adverse oral health effects associated with the use of xerogenic medications include: higher incidence of root and coronal caries, particularly in adult/geriatric populations14,15 oral thrush (candidiasis); oral mucosal inflammation and/or dessication16; burning mouth syndrome17,18; cracked lips; impaired taste, mastication or speech; and compromised nutritional intake, especially for older denture-wearers with dry mouth. Denture wearers taking anticholinergics are a particularly high-risk population for drug-related oral complications, such as mucosal sores or infections from poor denture retention. Xerostomia associated with medications and other causes (e.g., Sjogren’s syndrome, radiotherapy, chemotherapy) has also been cited as a potential risk factor for the development of aspiration pneumonia among elderly institutionalized patients, stroke victims, and individuals with oropharyngeal dysphagia.19 Dentists routinely witness the oral complications of drug-induced dry mouth, especially in older individuals and frail, elderly patients with diminished physical function and impaired ability to maintain adequate oral hygiene. Given the growing number of older Americans using multiple medications for various conditions, more individuals than ever may be at elevated risk of sustaining oral complications associated with the use of medications that induce oral dryness. Further, medication-associated dry mouth is also a concern in younger adults and children.20 The addition of dry-mouth-associated oral complication warnings on xerogenic medications could be strongly promoted by the dental profession to support optimal oral health and reduce oral health complications for individuals who use such medication. Additionally, focus on the potential for oral complications by dispensing pharmacists could significantly impact patient awareness and behavior and improve oral health outcomes. The ADA supports warning-label information on xerogenic medications to promote awareness of the potential oral complications associated with drug-induced dry mouth. This ADA recommendation is presented for consideration in accordance with current OTC labeling requirements for product warnings, as set forth in 21 Code of Federal Regulations (CFR) 201.66 and the FDA’s strategic goal to “advance human drug safety and effectiveness.”21 Our recommendation is also aligned with the HealthyPeople 2020 Medical Product Safety goal to “reduce the number of adverse events from medical products.”22 April 25, 2011 Page 3 It should also be noted that scientific research on drug-induced dry mouth has been limited due to numerous methodological factors, including heterogenous study populations, comorbidities, limitations in study design/validity and in obtaining accurate salivary measurements. Evaluating relative incidence rates of dry mouth for specific medications has been hampered by multiple confounders involved in assessing medication effects in population samples, including behavioral factors (e.g., oral hygiene practice), use of multiple medications (i.e., polypharmacy), and other factors (e.g., drugs that impede saliva secretion and/or neuronal transmission to salivary glands).2,16,23 Nevertheless, it remains well established in the research literature that the risks of chronic dry mouth induced by medications become increasingly elevated based on the number of drugs taken at any given time.24 All too often, chronic dry mouth is overlooked or tolerated by medication users as a “negligible” side effect or nuisance. But it is precisely those individuals, especially the elderly, who are prone to extensive caries activity, oral candidiasis or other complications. Fortunately, the impact of drug-induced xerostomia can be mitigated by simple steps dentists can take in collaboration with patients and their primary care provider: considering a less xerogenic medication and/or lower dosage to reduce dry-mouth severity; promoting good oral hygiene, chewing sugarless gum, avoiding acidic/caffeinated beverages, and/or the use of salivary substitutes and/or fluoride-containing products (e.g., gels); referral to physician for adequate hydration treatment. Since Americans are using more medications and retaining their natural dentition across the lifespan, they should be made more aware of the potentially harmful oral side effects of chronic dry mouth, especially with regard to highly xerogenic medications. The ADA thus supports including oral complication risk warnings for xerogenic medications with moderate-to-strong anticholinergic properties (e.g., oxybutynin, tricyclic antidepressants), particularly when taken over extended periods of time. 1 ADA Council on Scientific Affairs. Xerostomia. J Am Dent Assoc 2003;134:619-20. 2 Guggenheimer J, Moore PA. Xerostomia: etiology, recognition and treatment. J Am Dent Assoc. 2003 Jan;134(1):61-9. 3 Scully C. Drug effects on salivary glands: dry mouth. Oral Diseases (2003) 9, 165–176. 4 U.S. Department of Health and Human Services. Oral Health in America: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health, 2000. 5 Novara G et al. A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Antimuscarinic Drugs for Overactive Bladder. European Urology 54 (2008 ) 740–764. 6 Herschorn S, Stothers L, Carlson K, Egerdie B, Gajewski JB, Pommerville P, Schulz J, Radomski S, Drutz H, Barkin J, Paradiso-Hardy F. Tolerability of 5 mg solifenacin once daily versus 5 mg oxybutynin immediate release 3 times daily: results of the VECTOR trial. J Urol. 2010 May;183(5):1892-8. 7 Burgio KL, Locher JL, Goode PS, Hardin JM, McDowell BJ, Dombrowski M, Candib D. Behavioral vs drug treatment for urge urinary incontinence in older women: a randomized controlled trial. JAMA. 1998 Dec 16;280(23):1995-2000. 8 Nabi G, Cody JD, EllisG, Hay-Smith J, Herbison GP. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD003781. 9 Yarker YE, Goa KL, Fitton A. Oxybutynin: a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging. 1995;6:243–262. 10 Almståhl A, Wikström M. Oral microflora in subjects with reduced salivary secretion. J Dent Res 1999 Aug;78(8):1410-6. 11 Anttila SS, Knuuttila MLE, Sakki TK. Depressive symptoms favor abundant growth of salivary lactobacilli. Psychosom Med 1999; 61: 508–512. 12 Thomson WM, Slade GD, Spencer AJ. Dental caries experience and use of prescription medications among people aged 60+ in South Australia. Gerodontology 1995;12:104–10. 13 von Knorring AL, Wahlin YB. Tricyclic antidepressants and dental caries in children. Neuropsychobiology 1986;15(3–4):143–5. 14 Guggenheimer J, Moore PA. Xerostomia: etiology, recognition and treatment. J Am Dent Assoc. 2003;134(1):61–69. 15 Papas AS, Joshi A, MacDonald SL, Maravelis-Splagounias L, Pretara-Spanedda P, Curro FA. Caries prevalence in xerostomic individuals. Journal of the Canadian Dental Association, 1993 Feb;59(2):171-4, 177-9. 16 Janket SJ, Jones J, Rich S, Miller D, Wehler CJ, Van Dyke TE, Garcia R, Meurman JH. The effects of xerogenic medications on oral mucosa among the Veterans Dental Study participants. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Feb;103(2):223-30. 17 Bergdahl M, Bergdahl J (1999). Burning mouth syndrome: prevalence and associated factors. J Oral Pathol Med 28:350-354. 18 Klasser GD et al. Burning mouth syndrome: recognition, understanding, and management. Oral Maxillofacial Surg Clin N Am 20 (2008), 255-271. 19 Rofes L, Arreola V, Almirall J, Cabré M, Campins L, García-Peris P, Speyer R, Clavé P. Diagnosis and Management of oropharyngeal dysphagia and its nutritional and respiratory complications in the elderly. Gastroenterol Res Pract. 2011;2011. pii: 818979. Epub 2010 Aug 3. 20 Walsh LJ. Dry mouth: a clinical problem for children and young adults. International Dentistry SA 9(5):48-58. 21 U.S. Food and Drug Administration. Strategic Priorities, 2011-2015. Available at: . Accessed February 28, 2011. 22 HealthyPeople 2020. U.S. Department of Health and Human Services. Available at: Product+Safety&Objective=MPS+HP2020-3&TopicAreaId=33. 23 Götrick B, Giglio D, Tobin G. Effects of amphetamine on salivary secretion. Eur J Oral Sci 2009; 117: 218–223. 24 Nederfors T. Xerostomia: prevalence and pharmacotherapy. With special reference to beta-andrenoceptor antagonists. Swed Dent J Suppl 1996;116:1-70.


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