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Over-the-Counter Oral Phenylephrine: A Placebo for Nasal Congestion
Editorial
Over-the-Counter Oral Phenylephrine: A Placebo for Nasal Congestion Randy C. Hatton, PharmD, FCCP, BCPSa, and Leslie Hendeles, PharmDb,c Gainesville, Fla
The category of over-the counter (OTC) [nonprescription] drugs was established in the United States in 1951 by the Durham-Humphrey Amendment to the Food, Drug, and Cosmetic Act. The Kefauver-Harris Amendments to the Act required proof of efficacy for all drugs (prescription and nonprescription) approved after 1938. OTC drugs are marketed under regulations that established a monograph approval process, as well as the New Drug Application process. During the 1970s, the US Food and Drug Administration (FDA) convened panels of experts to review the efficacy and safety of OTC products on the market. The panel on Cough, Cold and Allergy Products determined that phenylephrine (PE) and pseudoephedrine were safe and effective for treating nasal congestion. A final OTC Nasal Decongestant Drugs Products monograph was published in 1994.1 Manufacturers can market the drugs listed in the monograph, alone or in combination, as long as the ingredients, dosage, and instructions for use list exactly what is required in the monograph. Even though phenylpropanolamine was effective, it was not included in the final monograph because of safety concerns about hemorrhagic strokes primarily when used as an OTC appetite suppressant.2 Because of the widespread use of pseudoephedrine to illegally make methamphetamine, Congress attached an amendment to the Patriot Act, the Combat Methamphetamine Epidemic Act, placing it “behind the counter” and requiring a photo identification and log of the transaction. This removed pseudoephedrine-containing products (Sudafed and others) from grocery and convenience stores, as well as from “in front of the counter” in pharmacies. The use of PE increased dramatically after 2004, presumably because it was the only “in front of the counter” OTC option. In 2005, we reviewed the existing evidence and questioned whether PE was effective at the FDA-approved dose of 10 mg.3 Subsequently, we undertook a meta-analysis a
Clinical Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Fla b Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Fla c Department of Pediatrics (Pulmonary Division), College of Medicine, University of Florida, Gainesville, Fla Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication June 12, 2015; revised June 12, 2015; accepted for publication June 19, 2015. Corresponding author: Leslie Hendeles, PharmD, 1600 SW Archer Rd, Rm PG-05, PO Box 100486, Gainesville, FL 32610. E-mail: [email protected]fl.edu. J Allergy Clin Immunol Pract 2015;3:709-10. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.06.014
of objective data regarding PE’s effect on nasal airway resistance that the OTC review panel used to designate PE as effective.4 Then, we filed a citizen’s petition asking the FDA to require better proof of efficacy and to reconsider the appropriate dosage.5 As a result of the citizen’s petition, the FDA convened its Nonprescription Drugs Advisory Committee on December 14, 2007. It concluded that available evidence “is suggestive of efficacy,” but 9 of the 12 committee members voted that new studies on response to higher doses were required.6 At the FDA meeting, the Consumer Health Products Association presented a meta-analysis that concluded that PE was effective at a 10-mg dose on the basis of a small but significant effect on nasal airway resistance.7 It included unpublished studies identified using an undescribed method. We question the clinical significance of the magnitude of their finding. Their results were driven by a very small study with little variability in the data and no placebo effect, studies dominated by one laboratory (Elizabeth Biochemical), and studies not reflective of a comprehensive search for unpublished studies (ie, additional unpublished negative results). In contrast, Schering-Plough Pharmaceuticals, contemplating the substitution of PE for pseudoephedrine in Claritin-D, presented studies conducted in allergen challenge chambers demonstrating no significant difference from placebo in relieving nasal congestion and nasal airway resistance.8,9 At the 2007 FDA meeting, the agency expressed a preference for subjective symptom scores over objective measurement of nasal airway resistance to support the use of PE for temporary relief of nasal congestion. Our meta-analysis4 evaluated only nasal airway resistance, because it was an objective measure and because the subjective measurements used in the studies varied and could not be combined. In this issue of the journal, Meltzer et al10 have responded to the FDA request for a dose-response study of the treatment of nasal congestion. The results of this study clearly indicate that PE is no more effective than placebo. There are a few limitations to the study, but the large sample size (n ¼ 539) overcomes them. The study was not quite double-blind, which could have resulted in measurement bias. However, one would expect this to favor PE, which it did not. Subjects were given 5 tablets for each dose consisting of various combinations of Sudafed-PE and a red concave placebo that was not exactly matching. Neither subjects nor investigators knew what treatment was being given. Another limitation was the use of intent-to-treat analysis, which could have minimized the difference between the groups. Reporting a per-protocol analysis would help address this issue. Last, lack of adherence could have minimized the difference between placebo and the PE groups, but tablet counts indicated about 80% adherence. 709
710
HATTON AND HENDELES
Interestingly, even though the 40-mg treatment dose was not effective, some subjects did experience adverse events at this dose. Because oral PE is metabolized by monoamine oxidase and sulfotransferases in the gut, there may be genetic polymorphisms that cause variation in absorption and/or alpha agonist response. The most likely explanation for the lack of efficacy is the very poor oral bioavailability of PE.11 A commonly cited estimate of 38% bioavailability12 is an overestimate because it does not differentiate active parent drug and inactive conjugated metabolites.11 A sensitive assay with a low limit of detection (ie, <0.05 ng/mL) showed that the amount of active PE in the blood is about 100-fold less than the amount of total PE. This suggests a bioavailability of less than 1% of the active parent drug. In contrast, alpha receptor stimulation is observed when PE is administered intravenously13 or topically in the nose14 or eyes.15 The lack of effect on blood pressure and heart rate is a surrogate for the lack of systemic effect of oral PE on nasal airways. We do not know the effective dose of PE, nor do we know what are therapeutic blood levels of unconjugated PE. The OTC monograph process served its usefulness in accomplishing a monumental task of reviewing thousands of OTC drugs for safety and efficacy. However, it should be recognized that the methods used had limitations and the science reviewed would often not meet today’s standards for good evidence. PE data do not meet current standards for efficacy when PE is administered orally. This is true for other OTC drugs as well. A recent Cochrane systematic review of drugs for acute cough (ie, antitussives, expectorants, mucolytics, antihistamines, and other combinations) in children and adults questions the effectiveness of these agents.16 The overall quality of the studies reviewed is poor and results are conflicting. Whether subjective improvement or an objective measure of the number of coughs should be used as an outcome in these types of studies is an ongoing debate. It is time for attention and resources to be put toward validating the findings of the OTC monograph process. At this point, we essentially have a system in which evidence must show that an OTC product is unsafe and/or does not work for it to be removed from the market. The FDA appears to be motivated more by safety concerns than by ineffectiveness. Patients who seek an OTC remedy should get what they pay for: an effective and relatively safe alternative to a prescription drug. There have been multiple changes to FDA’s review process for prescription drugs. It is time for changes to the OTC approval process as well! Accordingly, based on the study by Meltzer et al10 and others,8,9 it is clear that PE is no more effective than a placebo. Therefore, we recommend that the FDA remove PE from the decongestant
J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2015
monograph. Other alternatives can be recommended. For example, oral pseudoephedrine from behind the counter, nasal steroids for allergic rhinitis, and topical decongestants for viral-induced nasal stuffiness are all safe, effective, and available OTC drugs. REFERENCES 1. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use: final monograph for OTC nasal decongestant drug products. Fed Reg 1994;59:43386-412. 2. Phenylpropanolamine (PPA) information page dated 12/23/2005. Available from: https://web.archive.org/web/20090112142816/http://www.fda.gov/cder/ drug/infopage/ppa/. Accessed June 14, 2015. 3. Hendeles L, Hatton RC. Oral phenylephrine: an effective replacement for pseudoephedrine? J Allergy Clin Immunol 2006;118:279-80. 4. Hatton RC, Winterstein AG, McKelvey RP, Shuster J, Hendeles L. Efficacy and safety of oral phenylephrine: systematic review and meta-analysis. Ann Pharmacother 2007;41:381-90. 5. Hendeles L, Hatton R. Citizens petition—phenylephrine, 2007P-0047/CP1. Available from: http://www.fda.gov/ohrms/dockets/dockets/07p0047/07p-0047 -cp00001-01-vol1.pdf. Accessed June 12, 2015. 6. Food and Drug Administration. Summary minutes of the Nonprescription Drugs Advisory Committee meeting, December 14, 2007. Available from: http://www. fda.gov/ohrms/dockets/ac/07/minutes/2007-4335m1-Final.pdf. Accessed June 12, 2015. 7. Kollar C, Schneider H, Waksman J, Krusinska E. Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to common cold. Clin Ther 2007;29:1057-70. 8. Horak F, Zieglmayer P, Zieglmayer R, Lemell P, Yao R, Staudinger H, et al. A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber. Ann Allergy Asthma Immunol 2009;102:116-20. 9. Day JH, Briscoe MP, Ratz JD, Danzig M, Yao R. Efficacy of loratadinemontelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit. Ann Allergy Asthma Immunol 2009;102: 328-38. 10. Meltzer EO, Ratner PH, McGraw T. Oral phenylephrine HCl for nasal congestion in seasonal allergic rhinitis: a randomized, open-label, placebocontrolled study. J Allergy Clin Immunol Pract 2015;3:702-8. 11. O’Mullane J. Understanding phenylephrine metabolism, pharmacokinetics, bioavailability and activity. Available from: http://www.fda.gov/ohrms/dockets/ ac/07/briefing/2007-4335b1-01-Schering-Plough.pdf; 2007. Accessed June 12, 2015. 12. Hengstmann JH, Goronzy J. Pharmacokinetics of 3H-phenylephrine in man. Eur J Clin Pharmacol 1982;21:335-41. 13. Strieper MJ, Campbell RM. Efficacy of alpha-adrenergic agonist therapy for prevention of pediatric neurocardiogenic syncope. J Am Coll Cardiol 1993;22: 594-7. 14. Dressler WE, Myers T, Rankell AS, London SJ, Poetsch CE. A system of rhinomanometry in the clinical evaluation of nasal decongestants. Ann Otol Rhinol Laryngol 1977;86:310-7. 15. Brown MM, Brown GC, Spaeth GL. Lack of side effects from topically administered 10% phenylephrine eyedrops: a controlled study. Arch Ophthalmol 1980;98:487-9. 16. Smith SM, Schroeder K, Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in community settings. Cochrane Database Syst Rev 2014;11:CD001831.
Over-the-Counter Oral Phenylephrine: A Placebo for Nasal Congestion Randy C. Hatton, PharmD, FCCP, BCPSa, and Leslie Hendeles, PharmDb,c Gainesville, Fla
The category of over-the counter (OTC) [nonprescription] drugs was established in the United States in 1951 by the Durham-Humphrey Amendment to the Food, Drug, and Cosmetic Act. The Kefauver-Harris Amendments to the Act required proof of efficacy for all drugs (prescription and nonprescription) approved after 1938. OTC drugs are marketed under regulations that established a monograph approval process, as well as the New Drug Application process. During the 1970s, the US Food and Drug Administration (FDA) convened panels of experts to review the efficacy and safety of OTC products on the market. The panel on Cough, Cold and Allergy Products determined that phenylephrine (PE) and pseudoephedrine were safe and effective for treating nasal congestion. A final OTC Nasal Decongestant Drugs Products monograph was published in 1994.1 Manufacturers can market the drugs listed in the monograph, alone or in combination, as long as the ingredients, dosage, and instructions for use list exactly what is required in the monograph. Even though phenylpropanolamine was effective, it was not included in the final monograph because of safety concerns about hemorrhagic strokes primarily when used as an OTC appetite suppressant.2 Because of the widespread use of pseudoephedrine to illegally make methamphetamine, Congress attached an amendment to the Patriot Act, the Combat Methamphetamine Epidemic Act, placing it “behind the counter” and requiring a photo identification and log of the transaction. This removed pseudoephedrine-containing products (Sudafed and others) from grocery and convenience stores, as well as from “in front of the counter” in pharmacies. The use of PE increased dramatically after 2004, presumably because it was the only “in front of the counter” OTC option. In 2005, we reviewed the existing evidence and questioned whether PE was effective at the FDA-approved dose of 10 mg.3 Subsequently, we undertook a meta-analysis a
Clinical Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Fla b Professor, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Fla c Department of Pediatrics (Pulmonary Division), College of Medicine, University of Florida, Gainesville, Fla Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication June 12, 2015; revised June 12, 2015; accepted for publication June 19, 2015. Corresponding author: Leslie Hendeles, PharmD, 1600 SW Archer Rd, Rm PG-05, PO Box 100486, Gainesville, FL 32610. E-mail: [email protected]fl.edu. J Allergy Clin Immunol Pract 2015;3:709-10. 2213-2198 Ó 2015 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2015.06.014
of objective data regarding PE’s effect on nasal airway resistance that the OTC review panel used to designate PE as effective.4 Then, we filed a citizen’s petition asking the FDA to require better proof of efficacy and to reconsider the appropriate dosage.5 As a result of the citizen’s petition, the FDA convened its Nonprescription Drugs Advisory Committee on December 14, 2007. It concluded that available evidence “is suggestive of efficacy,” but 9 of the 12 committee members voted that new studies on response to higher doses were required.6 At the FDA meeting, the Consumer Health Products Association presented a meta-analysis that concluded that PE was effective at a 10-mg dose on the basis of a small but significant effect on nasal airway resistance.7 It included unpublished studies identified using an undescribed method. We question the clinical significance of the magnitude of their finding. Their results were driven by a very small study with little variability in the data and no placebo effect, studies dominated by one laboratory (Elizabeth Biochemical), and studies not reflective of a comprehensive search for unpublished studies (ie, additional unpublished negative results). In contrast, Schering-Plough Pharmaceuticals, contemplating the substitution of PE for pseudoephedrine in Claritin-D, presented studies conducted in allergen challenge chambers demonstrating no significant difference from placebo in relieving nasal congestion and nasal airway resistance.8,9 At the 2007 FDA meeting, the agency expressed a preference for subjective symptom scores over objective measurement of nasal airway resistance to support the use of PE for temporary relief of nasal congestion. Our meta-analysis4 evaluated only nasal airway resistance, because it was an objective measure and because the subjective measurements used in the studies varied and could not be combined. In this issue of the journal, Meltzer et al10 have responded to the FDA request for a dose-response study of the treatment of nasal congestion. The results of this study clearly indicate that PE is no more effective than placebo. There are a few limitations to the study, but the large sample size (n ¼ 539) overcomes them. The study was not quite double-blind, which could have resulted in measurement bias. However, one would expect this to favor PE, which it did not. Subjects were given 5 tablets for each dose consisting of various combinations of Sudafed-PE and a red concave placebo that was not exactly matching. Neither subjects nor investigators knew what treatment was being given. Another limitation was the use of intent-to-treat analysis, which could have minimized the difference between the groups. Reporting a per-protocol analysis would help address this issue. Last, lack of adherence could have minimized the difference between placebo and the PE groups, but tablet counts indicated about 80% adherence. 709
710
HATTON AND HENDELES
Interestingly, even though the 40-mg treatment dose was not effective, some subjects did experience adverse events at this dose. Because oral PE is metabolized by monoamine oxidase and sulfotransferases in the gut, there may be genetic polymorphisms that cause variation in absorption and/or alpha agonist response. The most likely explanation for the lack of efficacy is the very poor oral bioavailability of PE.11 A commonly cited estimate of 38% bioavailability12 is an overestimate because it does not differentiate active parent drug and inactive conjugated metabolites.11 A sensitive assay with a low limit of detection (ie, <0.05 ng/mL) showed that the amount of active PE in the blood is about 100-fold less than the amount of total PE. This suggests a bioavailability of less than 1% of the active parent drug. In contrast, alpha receptor stimulation is observed when PE is administered intravenously13 or topically in the nose14 or eyes.15 The lack of effect on blood pressure and heart rate is a surrogate for the lack of systemic effect of oral PE on nasal airways. We do not know the effective dose of PE, nor do we know what are therapeutic blood levels of unconjugated PE. The OTC monograph process served its usefulness in accomplishing a monumental task of reviewing thousands of OTC drugs for safety and efficacy. However, it should be recognized that the methods used had limitations and the science reviewed would often not meet today’s standards for good evidence. PE data do not meet current standards for efficacy when PE is administered orally. This is true for other OTC drugs as well. A recent Cochrane systematic review of drugs for acute cough (ie, antitussives, expectorants, mucolytics, antihistamines, and other combinations) in children and adults questions the effectiveness of these agents.16 The overall quality of the studies reviewed is poor and results are conflicting. Whether subjective improvement or an objective measure of the number of coughs should be used as an outcome in these types of studies is an ongoing debate. It is time for attention and resources to be put toward validating the findings of the OTC monograph process. At this point, we essentially have a system in which evidence must show that an OTC product is unsafe and/or does not work for it to be removed from the market. The FDA appears to be motivated more by safety concerns than by ineffectiveness. Patients who seek an OTC remedy should get what they pay for: an effective and relatively safe alternative to a prescription drug. There have been multiple changes to FDA’s review process for prescription drugs. It is time for changes to the OTC approval process as well! Accordingly, based on the study by Meltzer et al10 and others,8,9 it is clear that PE is no more effective than a placebo. Therefore, we recommend that the FDA remove PE from the decongestant
J ALLERGY CLIN IMMUNOL PRACT SEPTEMBER/OCTOBER 2015
monograph. Other alternatives can be recommended. For example, oral pseudoephedrine from behind the counter, nasal steroids for allergic rhinitis, and topical decongestants for viral-induced nasal stuffiness are all safe, effective, and available OTC drugs. REFERENCES 1. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use: final monograph for OTC nasal decongestant drug products. Fed Reg 1994;59:43386-412. 2. Phenylpropanolamine (PPA) information page dated 12/23/2005. Available from: https://web.archive.org/web/20090112142816/http://www.fda.gov/cder/ drug/infopage/ppa/. Accessed June 14, 2015. 3. Hendeles L, Hatton RC. Oral phenylephrine: an effective replacement for pseudoephedrine? J Allergy Clin Immunol 2006;118:279-80. 4. Hatton RC, Winterstein AG, McKelvey RP, Shuster J, Hendeles L. Efficacy and safety of oral phenylephrine: systematic review and meta-analysis. Ann Pharmacother 2007;41:381-90. 5. Hendeles L, Hatton R. Citizens petition—phenylephrine, 2007P-0047/CP1. Available from: http://www.fda.gov/ohrms/dockets/dockets/07p0047/07p-0047 -cp00001-01-vol1.pdf. Accessed June 12, 2015. 6. Food and Drug Administration. Summary minutes of the Nonprescription Drugs Advisory Committee meeting, December 14, 2007. Available from: http://www. fda.gov/ohrms/dockets/ac/07/minutes/2007-4335m1-Final.pdf. Accessed June 12, 2015. 7. Kollar C, Schneider H, Waksman J, Krusinska E. Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to common cold. Clin Ther 2007;29:1057-70. 8. Horak F, Zieglmayer P, Zieglmayer R, Lemell P, Yao R, Staudinger H, et al. A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber. Ann Allergy Asthma Immunol 2009;102:116-20. 9. Day JH, Briscoe MP, Ratz JD, Danzig M, Yao R. Efficacy of loratadinemontelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit. Ann Allergy Asthma Immunol 2009;102: 328-38. 10. Meltzer EO, Ratner PH, McGraw T. Oral phenylephrine HCl for nasal congestion in seasonal allergic rhinitis: a randomized, open-label, placebocontrolled study. J Allergy Clin Immunol Pract 2015;3:702-8. 11. O’Mullane J. Understanding phenylephrine metabolism, pharmacokinetics, bioavailability and activity. Available from: http://www.fda.gov/ohrms/dockets/ ac/07/briefing/2007-4335b1-01-Schering-Plough.pdf; 2007. Accessed June 12, 2015. 12. Hengstmann JH, Goronzy J. Pharmacokinetics of 3H-phenylephrine in man. Eur J Clin Pharmacol 1982;21:335-41. 13. Strieper MJ, Campbell RM. Efficacy of alpha-adrenergic agonist therapy for prevention of pediatric neurocardiogenic syncope. J Am Coll Cardiol 1993;22: 594-7. 14. Dressler WE, Myers T, Rankell AS, London SJ, Poetsch CE. A system of rhinomanometry in the clinical evaluation of nasal decongestants. Ann Otol Rhinol Laryngol 1977;86:310-7. 15. Brown MM, Brown GC, Spaeth GL. Lack of side effects from topically administered 10% phenylephrine eyedrops: a controlled study. Arch Ophthalmol 1980;98:487-9. 16. Smith SM, Schroeder K, Fahey T. Over-the-counter (OTC) medications for acute cough in children and adults in community settings. Cochrane Database Syst Rev 2014;11:CD001831.