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Pharmacy Clinical Policy Bulletins
Aetna Non-Medicare Prescription Drug Plan
Subject: Nonsedating Antihistamines (Peripherally Selective)

Status Drug PR PR-QL PR-AL ST M EX‡
FE Allegra®  (fexofenadine) X X     X
FE Allegra-D®, Allegra-D® 24 hour  (fexofenadine/pseudoephedrine) X X     X
FE Clarinex®  (desloratadine) X X     X
FE Clarinex-D®, Clarinex-D® 24 hour  (desloratadine / pseudoephedrine) X X     X
FE fexofenadine X X     X
FE Semprex-D®  (acrivastine/pseudoephedrine) X X     X
FE Xyzal®  (levocetirizine dihydrochloride) X X   X X
FE Zyrtec®  (cetirizine) X X     X
FE Zyrtec-D®  (cetirizine/pseudoephedrine) X X     X
Note: Non-prescription (OTC) products available (NOT covered under standard benefit plans) loratadine, Alavert, Claritin (OTC)


Policy:

  1. Precertification Criteria

    2. Under some plans, including plans that use an open or closed formulary, Allegra, Allegra-D, Clarinex, Clarinex-D, fexofenadine, Semprex-D, Xyzal, Zyrtec and Zyrtec-D are subject to precertification.  If precertification requirements apply, Aetna considers Allegra, Allegra-D, Clarinex, Clarinex-D, fexofenadine, Semprex-D, Xyzal, Zyrtec or Zyrtec-D to be medically necessary for those members who meet ALL of the following criteria:

    A AND B AND E - For All NSAs
    A     AND (B OR C OR D) AND E- For fexofenadine, Allegra, Clarinex, Xyzal, Zyrtec

    A. A documented diagnosis of an FDA-approved indication of rhinitis (allergic perennial or seasonal, vasomotor) or chronic idiopathic urticaria (hives) or allergic conjunctivitis OR one of the following accepted unlabeled indications listed in the pharmaceutical compendia (United States Pharmacopeia Drug Information or American Hospital Formulary Service): pruritus can be caused by atopic dermatitis  (eczema, or contact dermatitis )  urticaria (hives), angioedema, dermatographism, transfusion reactions, urticarial anaphylactic/anaphylactoid reactions, allergies, asthma, mastocytosis.

    AND

    B. A documented:

    • Contraindication to loratadine (nonprescription or generic/brand prescription) OR
    • Intolerance to loratadine (nonprescription or generic/brand prescription) OR
    • Allergy to loratadine (nonprescription or generic/brand prescription) OR
    • Failure of an adequate trial of two weeks of loratadine (nonprescription or generic/brand prescription) or desloratadine (Clarinex) -

    OR

    C. Member is a child < 2 years of age - FOR Allegra, Clarinex & Zyrtec ONLY

    OR

    D.  Member is pregnant AND failed loratadine OR Alavert OR Claritin -FOR  Xyzal, Zyrtec ONLY

    Note. loratadine, Alavert, Claritin, Xyzal and Zyrtec are designated as Pregnancy Category B.
    Clarinex and fexofenadine/Allegra are designated as  Pregnancy Category C

    AND

    E.  According to the manufacturer, the nonsedating antihistamines can be dosed up to a maximum daily dose at the interval(s) indicated in the table below.  A quantity of each drug will be considered medically necessary as indicated in the table below, if member fulfills criteria A and (B or C) above.

     

    Drug Maximum Daily Dose/ Dosing Interval Dosage Strength Quantity Limits
    Allegra, fexofenadine 120 mg/Once or Twice Daily 30 mg, 60 mg Up to 60 tablets in 30 days
    Allegra, fexofenadine 180 mg/Once Daily 180 mg Up to 30 tablets in 30 days
    Allegra 180 mg/ Once or Twice daily 30 mg/ 5 ml susp Greater than or equal to 12 yrs ** Up to 900 mls (3 bottles) in 30 days
    Allegra 60 mg/ Once Daily 30 mg/ 5 ml susp Less than 12yrs of age Up to 300 mls (1 bottle) in 30 days (10 mls/day)
    Allegra-D 12 hour Two tablets/Twice Daily 60 mg/120 mg Up to 60 tablets in 30 days
    Allegra-D 12 hour Two tablets/Twice Daily 60 mg/120 mg Up to 60 tablets in 30 days
    Allegra-D 24 hour One tablet/Once Daily 180 mg / 240 mg Up to 30 tablets in 30 days
    Clarinex 5 mg/Once Daily 5 mg Up to 30 tablets in 30 days
    Clarinex 5 mg/Once Daily 5 mg Reditab Up to 30 tablets in 30 days
    Clarinex 5 mg/Once Daily 5 mg/10 ml Up to 300 mls in 30 days (10 mls/day)
    Clarinex-D Two Tablets/Once or Twice Daily 2.5mg/120mg Up to 60 tablets in 30 days
    Clarinex-D One tablet/Once Daily 5 mg/240 mg Up to 30 tablets in 30 days
    Semprex-D Four Capsules/Up to 4 times per day 8 mg/60 mg Up to 120 capsules in 30 days
    Xyzal 5 mg/ Once Daily 5 mg Up to 30 tablets in 30 days
    Zyrtec 10 mg/Once or Twice Daily 5 mg, 10 mg Up to 30 tablets in 30 days
    Zyrtec 10 mg/Once or Twice Daily 5 mg, 10 mg chewable tab Up to 30 chewable tablets in 30 days
    Zyrtec 10 mg/Once or Twice Daily 5 mg/5 ml syrup Up to 300 mls in 30 days (10 mls/day)
    Zyrtec-D Two tablets/Twice Daily 5 mg/120 mg Up to 60 tablets in 30 days


    For coverage of additional quantities, a member's treating physician must request prior authorization through the Pharmacy Management Precertification Unit. Additional quantities of the nonsedating antihistamines will be considered medically necessary for those members who meet ANY of the following criteria:

    •  Member requires a dose including half tablets (Zyrtec) OR
    •  Member's dose is being titrated by physician (Zyrtec or Allegra; 3-month limit) OR
    •  Member has had intolerance to drug administered as a single daily dose (Zyrtec) OR
    •  Member has documented severe chronic urticaria (hives) or angioedema and has failed doses in table above (all products) OR
    • **Member(12 yrs and older) has documented medical reason for requiring the oral suspension instead of the tablets For Allegra suspension- only If dosing required is 120mg/day (600ml = 2 bottles/30 days are allowed); If dosing required is 180mg/ day (900ml =3 bottles/30 days are allowed)
    •  Member's physician provides documentation (controlled clinical trial) from the peer-reviewed medical literature for use of a higher dose (all products).


  2. Step Therapy Criteria

    3. Under some plans, including plans that use an open or closed formulary, Xyzal is subject to step-therapy.  Aetna considers Xyzal  to be medically necessary for those members who meet the following step-therapy criteria:

    A documented trial of two weeks each of BOTH preferred nasal steroid alternatives (fluticasone nasal spray AND Nasonex) OR a documented trial of two weeks of nasal antihistamine Astelin.

    If it is medically necessary for a member to be treated initially with a medication subject to step-therapy, the member's treating physician may contact the Aetna Pharmacy Management Precertification Unit to request coverage as a medical exception. (See criteria under section III below.)

  3. Medical Exception Criteria

    4.            Allegra, Allegra-D, Clarinex, Clarinex-D, fexofenadine, Semprex-D, Zyrtec and Zyrtec-D are currently listed on the Aetna Formulary Exclusions List.* Therefore, they are excluded from coverage for members enrolled in prescription drug benefits plans that use a closed formulary, unless a medical exception is granted. Aetna considers Allegra, Allegra-D, Clarinex, Clarinex-D, fexofenadine, Semprex-D, Zyrtec or Zyrtec-D to be medically necessary for those members who meet ALL of the following criteria:


     

                Xyzal is currently  listed on the Aetna Formulary Exclusions and Step-Therapy lists.* Therefore, Xyzal is excluded from coverage for members enrolled in prescription drug benefit plans that use a closed formulary or that require step-therapy criteria, unless a medical exception is granted.  Aetna considers Xyzal to be medically necessary for those members who meet the criteria specified below


    A AND B- FOR ALL NSAs  
    A AND (B OR C OR D)- For fexofenadine, Allegra, Clarinex, & Zyrtec ONLY
    A AND (B OR D) AND E - For Xyzal


     

                A.  A documented diagnosis of an FDA-approved indication of rhinitis (allergic perennial or seasonal, vasomotor) or chronic idiopathic urticaria(hives) or allergic conjunctivitis OR one of the following accepted unlabeled indications listed in the pharmaceutical compendia (United States Pharmacopeia Drug Information or American Hospital Formulary Service): pruritus can be caused for example by (atopic dermatitis  i.e eczema, or contact dermatitis ) urticaria (hives), angioedema, dermatographism, transfusion reactions, urticarial, anaphylactic/anaphylactoid reactions, atopic dermatitis(eczema), allergies, asthma, mastocytosis.
    AND

                B.   A documented:

     

    • Contraindication to loratadine (nonprescription or generic/brand prescription) OR
    • Intolerance to loratadine (nonprescription or generic/brand prescription) OR 
    • Allergy to loratadine (nonprescription or generic/brand prescription) OR
    • Failure of an adequate trial of two weeks of loratadine (nonprescription or generic/brand prescription) or desloratadine (Clarinex)

                OR

                C. Member is a child < 2 years of age - For Allegra, Clarinex & Zyrtec ONLY

                OR

                D.   Member is pregnant AND failed loratadine OR Alavert OR Claritin - For Xyzal,
            Zyrtec ONLY

     

                Note.   

                 loratadine, Alavert, Claritin, Xyzal and Zyrtec are designated as Pregnancy Category B.
     Clarinex and fexofenadine/Allegra are designated as  Pregnancy Category C.

               

                AND

                 E. A documented: 

    • Contraindication to BOTH  preferred nasal steroid alternatives; (fluticasone nasal spray AND Nasonex) OR nasal antihistamine Astelin OR 
    • Intolerance to BOTH preferred nasal steroid alternatives;(fluticasone nasal spray AND Nasonex) OR nasal antihistamine Astelin OR 
    • Allergy to BOTH preferred nasal steroid alternatives; (fluticasone nasal spray AND Nasonex) OR nasal antihistamine Astelin OR 
    • Failure of an adequate trial of two weeks each of BOTH preferred nasal steroid alternatives; (fluticasone nasal spray AND Nasonex) OR documented trial of two weeks of nasal antihistamine Astelin OR
    • Member has a documented diagnosis of chronic idiopathic urticaria

    NOTE: Aetna does NOT consider concurrent therapy with TWO nonsedating antihistamines to be medically necessary.  However, a member who fulfills criteria for a twice-daily nonsedating antihistamine could choose to receive the antihistamine-decongestant combination in the morning (or for the earlier dose) AND then the antihistamine single entity product for a later or evening dose; total daily quantity limits would apply to the SUM of both products.


Special Notes:

Treatment of urticaria (hives) and angioedema can be difficult, and several authors have discussed drugs and doses used to treat this condition.44-51

The article with guidelines and algorithm for chronic urticaria/angioedema from AAAI50 lists the following agents and combinations that may be useful in suppressing the symptomatology of urticaria:  1) first-generation H1 antihistamines; 2) combinations of first and second generations using nonsedating agents in the morning and first-generation drugs at night; 3) combinations of second-generation antihistamines; 4) combination of an agent with both H1 and H2 antireceptor activity (that is, doxepin) with a first- or second-generation antihistamine; and 5) combination of an H2 antireceptor antihistamine (for example,  cimetidine or ranitidine) with a first- or second-generation antihistamine.  Antihistamines may not be entirely effective in controlling urticaria, and other agents to consider are corticosteroids, mast cell inhibitors, calcium channel blockers, antileukotrienes, and other immunosuppressants or immunomodulator agents.  No specific dose ranges are mentioned here.

Kaplan (46) states that patients with more severe cases of urticaria may not benefit from the usual recommended doses of the antihistamines.  In his discussion he mentions specifically doses of fexofenadine up to 240 mg/day and hydroxyzine up to 100 mg/day.  But he also says "We need to document whether high doses of antihistamines, particularly the nonsedating types, are superior to lower doses."  He suggests maximum doses of Allegra 240 mg per day, Claritin 20 mg per day, and Zyrtec 20 mg per day.

Zuberbier and Henz (45) discuss antihistamine as first choice for symptomatic treatment of chronic urticaria.  They state that in prospective studies, 10 mg of cetirizine has been shown to be superior to the standard dose of terfenadine or astemizole [both removed from the US market at this time.]  In their experience, "up to 40 mg cetirizine per day may be necessary to control symptoms in more severe cases [of chronic urticaria] and should be used since other treatment alternatives have more side effects."  This article also mentions that 20 to 30 mg of cetirizine have reduced severity of symptoms of delayed pressure urticaria; 10 mg twice daily has been used to treat atopic dermatitis.

Muller (44) and Awad and Mehler (51) both also suggest doses of Zyrtec up to 20 mg per day, but they do not mention higher doses [than FDA-labeled doses] for other antihistamines.



Place of Service:

Outpatient

The above policy is based on the following references:

1.                  Drug Facts and Comparisons on-line. (www.drugfacts.com), Wolters Kluwer Health, St. Louis, MO. 2006.

2.                  USP DI® Drug Information For The Health Care Professional - 26th Ed. (online from www.statref.com) Thomson Micromedex, Greenwood Village, CO. 2006.

3.                  AHFS Drug Information® with AHFSfirstReleases®. (online from www.statref.com), American Society Of Health-System Pharmacists®, Bethesda, MD. 2006.

4.                  DRUGDEX® System: Klasco RK (Ed):DRUGDEX® System. Online edition. Thomson Micromedex, Greenwood Village, CO.

5.                  PDR® Electronic Library, Thomson Micromedex, Greenwood Village, Colorado (Edition expires 2006).

6.                  Horak, F, et al., Controlled Comparison of the Efficacy and Safety of Cetirizine 10 mg o.d. and Fexofenadine 120 mg o.d. in Reducing Symptoms of Seasonal Allergic Rhinitis, Int Arch Allergy Immunol, 2001;125:73-79.

7.                  Howarth, P., et al., Double blind, placebo controlled study comparing the efficacy and safety of fexofenadine hydrochloride (120 and 180 mg once daily) and cetirizine in seasonal allergic rhinitis, J Allergy Clin Immunol, 1999;104:927-33.

8.                  Van Cauwenberg, P, et al., Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 gm and placebo administered once daily for the treatment of seasonal allergic rhinitis, Clinical and Experimental Allergy, 2000;30:891-899.

9.                  Prenner, BM, et al., Efficacy and Tolerability of Loratidine Versus Fexofenadine in the Treatment of Seasonal Allergic Rhinitis: A Double-Blind Comparison with Crossover Treatment of Nonresponders, Clinical Therapeutics, 2000;22:760-69.

10.              Grant, JA, et al., A double blind single dose, crossover comparison of cetirizine, ebastine, epinastine, fexofenadine, terfenadine, and loratadine versus placebo: suppression of histamine induced wheal and flare response for 24 h in, Allergy, 1999;54:700-707.

11.              Lee, J, et al, A Descriptive Analysis of the Use and Cost of New-Generation Antihistamines in the Treatment of Allergic Rhinitis: A Retrospective Database Analysis, Amer. J Managed Care, May 2001; 7(4 suppl):S103-S112.

12.              Mann, RD, et al., Sedation with “non-sedating” antihistamines: four prescription-event monitoring studies in general practice, BMJ, 2000; 320:1184-7.

13.              DuBuske, LM, Second-Generation Antihistamines: The Risk of Ventricular Arrhythmias, Clinical Therapeutics, 1999 Feb; 21(2):281-95.

14.              Greaves, MW, Systemic Dermatologic Therapy, Dermatologic Clinics, 2001 Jan; 19(1).

15.              Greaves, M, Current Reviews of Allergy and Clinical Immunology, Chronic Urticaria, Journal of Allergy and Clinical Immunology, 2000 April; 105(4).

16.              Meuther, PS, and Gwaltney, JM, Variant Effect of First and Second Generation Antihistamines as Clues to Their Mechanism of Action on the Sneeze Reflex in the Common Cold, Clinical Infectious Diseases, 2001; 33:1483-1488.

17.              Walsh, GM, et al., New Insights into the Second Generation Antihistamines, Drugs, 2001; 61(2):217-236.

18.              Wilson AM, Orr LC, Coutie WJR et al.  A comparison of once daily fexofenadine versus the combination of montelukast plus loratadine on domiciliary nasal peak flow and symptoms in seasonal allergic rhinitis.  Clin Exp All.  2002;32:126-32.

19.              Bayramgurler D, Bilen N, Apaydyn R et al: Effects of acrivastine, loratadine and cetirizine on histamine-induced wheal and flare responses. Clin Exper Dermatol 1999; 24:407-411.

20.              Tarchalsak-Krynska B, Zawisza E.  A 6-week, cross—over study comparing cetirizine and loratadine in seasonal allergic rhinitis.  Pneumonol Alergol Pol.  1994;62:573-7.

21.              Simons FER.  H1-receptor antagonists: safety issues.  Ann Allergy Asthma Immunol.  1999;83:481-88.

22.              Simons FER.  Comparative pharmacology of H1 antihistamines: clinical relevance.  Am J Med.  2002;113(8 suppl):38S.

23.              Simons FER, Johnston L, Simons KJ.  Clinical pharmacology of the H1-receptor antagonists cetirizine and loratadine in children.  Pediatr Allergy Immunol. 2000;11:116-9.

24.              Day JH, Briscoe MP, Clark RH, et al.  Onset of action and efficacy of terfenadine, astemizole, cetirizine, and loratadine for the relief of symptoms of allergic rhinitis.  Ann Allergy Asthma Immunol. 1997;79:163-72.

25.              Day JH, Briscoe M, Widitz MD. Cetirizine, loratadine, or placebo in subjects with seasonal allergic rhinitis: effects after controlled ragweed pollen challenge in an environmental exposure unit.  J Allergy Clin Immunol. 1998;101:638-45.

26.              Day JH, Briscoe M, Rafeiro E, et al.  Comparative onset of action and symptom relief with cetirizine, loratadine, or placebo in an environmental exposure unit in subjects with seasonal allergic rhinitis: confirmation of a test system.  Ann Allergy Asthma Immunol. 2001;87:474-81.

27.              Gispert J, Antonijoan R, Barbanoj M, et al.  Efficacy of ebastine, cetirizine, and loratadine in histamine cutaneous challenges.  Ann Allergy Asthma Immunnol.  2002;89:259-64.

28.              Grant JA, Riethuisen JM, Moulaert B, DeVos C.  A double-blind, randomize, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects. Ann Allergy Asthma Immunol. 2002;88:190-7

29.              Simons FER, Simons KJ.  Peripheral H1-blockade effect of fexofenadine.  Ann Allergy Asthma Immunol. 1997;79:530-2.

30.              Purohit A, Duvernelle C, Melac M, et al.  Twenty-four hours of activity of cetirizine and fexofenadine in the skin.  Ann Allergy Asthma Immunol. 2001;86:387-92.

31.              Simons FER, Silver NA, Gu X, Simons KJ.  Clinical pharmacology of H1-antihistamines in the skin.  J Allergy Clin Immunol. 2002;110:777-83.

32.              Simons FER, Silver NA, Gu X, Simons KJ.  Skin concentrations of H1-receptor antagonists.  J Allergy Clin Immunol.  2001;107:526-30.

33.              Lai DS, Lue KH, Hsieh JC, et al.  The comparison of the efficacy and safety of cetirizine, oxatomide, ketotifen, and a placebo for the treatment of childhood perennial allergic rhinitis.  Ann Allergy Asthma Immunol. 2002;89:589-98.

34.              Persi L, Demoly P, Harris AG, et al.  Comparison between nasal provocation tests and skin tests in patients treated with loratadine and cetirizine.  J Allergy Clin Immunol.  1999;103:591-4.

35.              TenEick AP, Blumer JL, Reed MD.  Safety of antihistamines in children.  Drug Safety. 2001;24:119-47.

36.              Galant SP, Wilkinson R.  Clinical prescribing of allergic rhinitis medication in the preschool and young school-age child.  BioDrugs.  2001;15:453-63.

37.              Yang YH, Lin YT, Lu MY, et al.  A double-blind, placebo-controlled, and randomized study of loratadine (Clarityne) syrup for the treatment of allergic rhinitis in children aged 3 to 12 years.  Asian Pac J Allergy Immunol. 2001;19:171-75.

38.              Bender BG, McCormick DR, Milgrom H.  Children’s school performance is not impaired by short-term administration of diphenhydramine or loratadine.  J Pediatr. 2001;138:656-60.

39.              Finn AF, Kaplan AP, Fretwell R, et al.  A double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria.  J Allergy Clin Immunol. 1999;103:1071-8.

40.              Simons FER, for ETAC Study Group.  Prospective, long-term safety evaluation of the H1-receptor antagonist cetirizine in very young children with atopic dermatitis.  J Allergy Clin Immunol. 1999;104:433-40.

41.              Simons FER, for ETAC Study Group.  Prevention of acute urticaria in young children with atopic dermatitis.  J Allergy Clin Immunol. 2001;107:703-6.

42.              Warner JO for ETAC Study Group.  A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months’ treatment and 18 months’ posttreatment follow-up.  J Allergy Clin Immunol.  2001;108:929-37.

43.              Frossard N, Walsh GM.  Comparing the H1 profile of second-generation antihistamines.  Allergy.  2000;55 suppl 60:40-5.

44.              Muller BA.  Urticaria and angioedema: a practical approach.  Am Fam Physician.  2004;69:1123-8.

45.              Zuberbier T, Henz BM.  Use of cetirizine in dermatologic disorders.  Ann Allergy Asthma Immunol.  1999;83:476-80.

46.              Kaplan AP.  Chronic urticaria and angioedema.  N Engl J Med.  2002;346:175-9.

47.              Greaves MW.  Chronic urticaria.  N Engl J Med.  1995;332:1767-72.

48.              Awad R, Mehler P.  Managing chronic urticaria and angioedema effectively.  Women’s Health in Primary Care.  2003;6:99-106.

49.              Charlesworth EN.  Urticarea and angioedema: a clinical spectrum.  Ann Allergy Asthma Immunol.  1996;76:484-96.

50.              Joint Task Force on Practice Parameters.  The diagnosis and management of urticaria: a practice parameter. Part I: acute urticaria/angioedema; part II: chronic urticaria/angioedema. Ann Allergy Asthma Immunol. 2000;85:521-44.

51.              Awad R, Mehler P.  Managing chronic urticaria and angioedema effectively.  Women’s Health in Primary Care.  2003;6:99-106.

52.              Morgan MM, Khan DA, Nathan RA. Treatment for allergic rhinitis and chronic idiopathic urticaria: focus on oral antihistamines. Ann Pharmacother. 2005;39(12):2056-64. 

53.       Xyzal Product Information accessed 8-21-07 at http://xyzal.com/pdf/XYZAL.pdf

 

 

 

 

Copyright Aetna Inc. All rights reserved. Pharmacy Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.

October 7, 2007
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