Many popular oral over-the-counter (OTC) drugs were originally available only by prescription, but not at the low doses contained in their OTC counterparts. Yet, if OTC doses are effective for treating mild symptoms, why weren't these low, often safer doses made available at least by prescription when the drugs were first approved?
OBJECTIVE
To examine issues surrounding the delayed approval of OTC doses by the Food and Drug Administration (FDA).
METHODS
Information reviewed included package inserts, data obtained from manufacturers, and articles published in MEDLINE (1966 to December 2001). Medications examined included presently available and potentially approved OTC antiinflammatory, gastrointestinal, and antihistamine drugs.
RESULTS
Considerable data demonstrate the effectiveness of ibuprofen, naproxen, ranitidine, famotidine, nizatidine, diphenhydramine, and clemastine at OTC doses. Published studies also show the effectiveness of celecoxib, omeprazole, and fexofenadine at doses 33–50% lower than currently recommended for prescription use.
CONCLUSIONS
OTC doses are effective for many patients with mild symptoms and for some with serious symptoms. However, OTC-like doses are usually not offered when drugs are approved for prescription use because new drugs are usually studied in patients with serious conditions requiring higher doses; manufacturers and the FDA seem to prefer a middle-dose approach; >75% of subjects in premarketing dose studies are male; and averaging the responses of study subjects may obscure a wide range of interindividual variation in drug response. Simplistic dosage guidelines make therapeutic decisions easier. Because dose-related adverse effects frequently diminish quality-of-life and reduce adherence, the early availability of OTC-like doses, at least by prescription, would allow healthcare professionals greater flexibility in matching medication doses to patients’ widely differing needs.
. ParnhamMJ. Meeting report: Joint International Meeting of the 3rd Meeting on Side Effects of Anti-Inflammatory Drugs and 13th European Workshop on Inflammation. Agents Actions1992; 35: 37–9.
2.
. WolfeMM, LichtensteinDR, SinghG.Gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. N Engl J Med1999; 340: 1888–99.
3.
. Physicians' desk reference for nonprescription drugs and dietary supplements. 20th ed.Montvale, NJ: Medical Economics, 1999.
4.
. JacobsLR. Prescription to over-the-counter drug reclassification. Am Fam Physician1998; 57: 2209–14.
5.
. WesterlundLT, MarklundBR, HandlWH, ThunbergME, AllebeckP.Nonprescription drug-related problems and pharmacy interventions. Ann Pharmacother2001; 35: 1343–9.
6.
. Physicians' desk reference. 54th ed.Montvale, NJ: Medical Economics, 2000.
7.
. LazarouJ, PomeranzBH, CoreyPN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA1998; 279: 1200–5.
8.
. ThompsonM, BellD.Further experience with ibuprofen in the treatment of arthritis. Rheumatol Phys Med1970; 10 (suppl): 100–3.
9.
. ChalmersTM. Clinical experience with ibuprofen in the treatment of rheumatoid arthritis. Ann Rheum Dis1969; 28: 513–7.
10.
. BrooksCD, SchmidFR, BiundoJ, BlauS, Gonzalez-AlcoverR, GowansJD, et al. Ibuprofen and aspirin in the treatment of rheumatoid arthritis: A cooperative double-blind trial. Rheumatol Phys Med, 1970; 10 (suppl 10): 48–63.
11.
. ShapiroSS, DiemK.The effects of ibuprofen in the treatment of dysmenorrhea. Curr Ther Res1981; 30: 327–34.
. HelznerEC, FrickeJ, CunninghamBG. An evaluation of ibuprofen 200 mg, ibuprofen 400 mg and naproxen 200 mg and 400 mg in postoperative oral surgery pain (abstract). Clin Pharmacol Ther1992; 51: 122.
14.
. CooperSA. The relative efficacy of ibuprofen in dental pain. Compend Contin Educ Dent1986; 7: 578, 580–1, 584–8 passim.
15.
. CooperSA. Five studies on ibuprofen for postsurgical dental pain. Am J Med1984; 77: 70–7.
16.
. BensenWG, FiechtnerJJ, McMillenJI, ZhaoWW, YuSS, WoodsEM, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc1999; 74: 1095–105.
17.
. HubbardR, GeisGS, WoodsE, YuS, ZhaoW. Efficacy, tolerability, and safety of celecoxib, a specific cox-2 inhibitor, in osteoarthritis (abstract). Arthritis Rheum1998; 41 (9 suppl): S196.
18.
. DobrillaG, de PretisG, FelderM, ChiloviF.Endoscopic double-blind controlled trial of ranitidine vs. placebo in the short-term treatment of duodenal ulcer. Hepato-Gastroenterol1981; 28: 49–52.
19.
. LangmanJS, HenryDA, OgilvieA.Ranitidine and cimetidine for duodenal ulcer. Scand J Gastroenterol1981; 69 (suppl): 115–7.
20.
. BerstadA, KettK, AadlandE, CarlsenE, FrislidK, SaxhaugK, et al. Treatment of duodenal ulcer with ranitidine, a new histamine H2-receptor antagonist. Scand J Gastroenterol1980; 15: 637–9.
21.
. DobrillaG, BarbaraL, Bianchi-PorroG, FelderM, MazzaccaG, MiglioliA, et al. Placebo controlled studies with ranitidine in duodenal ulcer. Scand J Gastroenterol1981; 69 (suppl): 103–4.
22.
. DyckWP, CloudML, OffenWW, MatsumotoC, ChernishSM. Treatment of duodenal ulcers in the United States. Scand J Gastroenterol1987; 136 (suppl): 47–55.
23.
. SamantaA, NahassD, HabbaS.Efficacy of nizatidine: a new H2 receptor antagonist in the treatment of duodenal ulcer; a dose response study (abstract). Am J Gastroenterol1986; 81: 852.
24.
. CloudML, OffenWW, MatsumotoC.Healing and subsequent recurrence of duodenal ulcer in a clinical trial comparing nizatidine 300-mg and 100-mg evening doses and placebo in the treatment of active duodenal ulcer. Curr Ther Res1989; 45: 359–67.
. FiorucciS, ClausiGG, CascettaR, FarinelliMF, PelliMA, MorelliA.Effects of low and high doses of famotidine and ranitidine on nocturnal gastric pH (abstract). Dig Dis Sci1986; 31 (suppl 10): 393S.
27.
. SavarinoV, MelaGS, ZentilinP, BonifacinoG, MorettiM, ValleF, et al. Low bedtime doses of H2-receptor antagonists for acute treatment of duodenal ulcers. Dig Dis Sci1989; 34: 1043–6.
28.
. YoungMD, FrankWO, DicksonBD, PeaceKP, BravermanA, MounceW.Determining the optimal dosage regimen for H2-receptor antagonist therapy — a dose validation approach. Aliment Pharmacol Ther1989; 3: 47–57.
29.
. LindT, CederbergC, AxelsonM, OlbeL.Long-term acid inhibitory effect of different daily doses of omeprazole 24 hours after dosing. Scand J Gastroenterol1986; 21 (suppl 118): 137–8.
30.
. RobinsonM, MatonPN, AllenML, HumphriesTJ, McIntoshD, CagliolaAJ, et al. Effect of different doses of omeprazole on 24-hour oesophageal acid exposure in patients with gastro-oesophageal reflux. Aliment Pharmacol Ther1991; 5: 645–51.
31.
. LauritsenK, AndersenBN, LaursenLS, HansenJ, HavelundT, EriksenJ, et al. Omeprazole 20 mg three days a week and 10 mg daily in prevention of duodenal ulcer relapse; double-blind comparative trial. Gastroenterology1991; 100: 663–9.
32.
. WeilerJM, BloomfieldJR, WoodworthGG, GrantAR, LaytonTA, BrownTL, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator. Ann Intern Med2000; 132: 354–63.
33.
. Associated Press. Tests urged of pills' role in vehicular fatalities. San Diego Union-Tribune, Wed., Jan. 19, 2000:A-6.
34.
. TinkelmanD, FalliersM, BronskyE, KaiserH, MasonJ.Efficacy and safety of fexofenadine in fall seasonal allergic rhinitis (abstract). J Allergy Clin Immunol1996; 97 (pt 3): 1009.
35.
. WoosleyRL, ChenY, FreimanJP, GillisRA. Mechanism of the cardiotoxic actions of terfenadine. JAMA1993; 269: 1532–6.
36.
. BrandonML, WeinerM.Clinical investigation of terfenadine, a non-sedating antihistamine. Ann Allergy1980; 44: 71–5.
37.
. DickinsonJG. FDA OKs new drugs that over-dose millions, physician says; FDA replies. Dickinson's FDA Rev2002; 9 (1): 3, 10–5.
38.
. Women sufficiently represented in new drug testing, but FDA oversight needs improvement. Report to Congressional Requesters. US General Accounting Office, GAO-01-754, July 6, 2001. Available from:URL: www.fda.gov/womens/informat.html.
39.
. JorgensenT, JohanssonS, KennerfalkA, WallanderMA, SvardsuddK.Prescription drug use, diagnoses, and healthcare utilization among the elderly. Ann Pharmacother2001; 35: 1004–9.
40.
. GebhartF.Is standard dosing to blame for adverse drug reactions?Drug Topics2000; 2: 34.
41.
. PeckCC. Drug development: improving the process. Food Drug Law J1997; 52: 163–7.
42.
. PeckCC, BarrWH, BenetLZ, CollinsJ, DesjardinsRE, FurstDE, et al. Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development. J Clin Pharmacol1994; 34: 111–9.
43.
. CohenJS, InselPA. The Physicians' desk reference: problems and possible improvements. Arch Intern Med1996; 156: 1375–80.
44.
. CohenJS. Dose discrepancies between the Physicians' desk reference and the medical literature, and their possible role in the high incidence of dose-related adverse drug events. Arch Intern Med2001:161: 957–64.
45.
. CohenJS. Adverse drug effects, compliance, and the initial doses of antihypertensive drugs recommended by the Joint National Community vs. the Physicians' desk reference. Arch Intern Med2001; 161: 880–5.
46.
. MonaneM, BohnRL, GurwitzJH, GlynnRJ, LevinR, AvornJ.Compliance with antihypertensive therapy among elderly Medicaid enrollees: the roles of age, gender, and race. Am J Public Health1996; 86: 1805–8.
47.
. Sanson-FisherRW, CloverK.Compliance in the treatment of hypertension. A need for action. Am J Hypertens1995; 8 (10 pt 2): 82S–8S.
48.
. AvornJ, MonetteJ, LacourA, BohnRL, MonaneM, MogunH, et al. Persistence of use of lipid-lowering medications: a cross-national study. JAMA1998; 279: 1458–62.
49.
. BrettKM, MadansJH. Use of postmenopausal hormone replacement therapy: estimates from a nationally representative cohort study. Am J Epidemiol1997; 145: 536–45.
50.
. FergusonRP, WetleT, DubitzkyD, WinsemiusD.Relative importance to elderly patients of effectiveness, adverse effects, convenience and cost of antihypertensive medications. A pilot study. Drugs Aging1994; 4: 56–62.
51.
. American Medical Association Council on Ethical and Judicial Affairs. Code of medical ethics, 1998–1999 ed.Chicago: American Medical Association.
