Dine Formulary Monograph

Creighton University Medical Center Center for Drug Information & Evidence-Based Practice Drug Evaluation Monograph (September, 2009) GENERIC NAME: Desloratadine BRAND NAME: Clarinex MANUFACTURER: Schering Corporation Monograph prepared by: [Andrew Cohen] INDICATIONS\USE: Desloratadine, the major metabolite of loratadine, is indicated for the relief of nasal and nonnasal symptoms associated with allergic rhinitis, perennial allergic rhinitis, and symptoms related to chronic idiopathic urticaria.1 See Table 1 for a comparison of the FDA approved indications for other second generation antihistamines. Table 1: Comparison of FDA approved indications for various 2nd generation antihistamines1,2,3,4 Indication Desloratadi Loratadine Cetirizine Fexofenadine ne (Clarinex) (Claritin) (Zyrtec) (Allegra) Relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR) Relief of nasal and non-nasal symptoms associated with perennial allergic rhinitis Relief of symptoms related to chronic idiopathic urticaria

X

X

X

X

X

X

X

X

X

X

CLINICAL PHARMACOLOGY: Desloratadine is a peripherally acting and selective histamine-1(H1)-receptor antagonist which results in clinically significant reductions of allergy symptoms and symptoms related to idiopathic urticaria. It does not cross the blood brain barrier and therefore considered non-sedative. The selectivity of 2nd generation antihistamines is related to their negligible or absent anti-cholinergic side effects commonly seen in 1st generation antihistamines. The other 2nd generation antihistamines compared above exhibit the same or similar selectivity in their mechanisms.1,5 PHARMACOKINETICS: Table 2. Pharmacokinetics antihistamines1,2,3,4,5,6,7,8 Parameters Desloratadine

of

desloratadine

and

other

2nd

generation

Loratadine

Cetirizine

Fexofenadine

Onset

~ 3 hours

1.25-3 hours

15-30 minutes

1-3 hours

Tmax

3 hours

1.3 hours

30-60 minutes

24 hours

Peak

Not published

8-12 hours

1 hour

2 hours

Duration Action

24 hours

24-48 hours

24 hours

>12 hours

Absorption

Not published, not affected by food

Rapid, Food delays Tmax by 2.4 hours

Rapid, 70%, absorption affected but Tmax delayed by 1.7 hours and decrease in Cmax by 23%

Metabolism

Extensive Liver metabolism via hydroxylation, Possible CYP3A4, 20% African Americans are slow metabolizers Kidney: 41% Feces: 47% 27 hours

Extensive Liver metabolism via CYP3A4 and 2D6 enzymes

Minimal Liver, minor metabolite O-dealkylation product found in feces

Rapid, delayed AUC and Cmax when administered with food, Coadministration with grapefruit or orangejuice has shown 60-70% reduction in AUC/Cmax Minimal liver, ~5%

Kidney: 40% Feces: 40% 12-15 hours

Kidney 70% Feces: 10% 7.4-9 hours

Excretion T1/2

of

Kidney: 11% Feces: 80% 11-15 hours

THERAPEUTIC/COMPARATIVE EFFICACY (clinical trials) and summary: A review of three randomized, double-blinded, placebo controlled studies, which included just over 1000 subjects who either experienced signs and symptoms of seasonal allergic rhinitis or allergic reaction after histamine challenge, showed consistent improvement of primary and secondary outcomes related to desloratadine in comparison to placebo.9,10,11 In subjects who experienced allergic reaction after being challenged with histamine, desloratadine was inferior to cetirizine in treatment response and duration of action endpoints.11 This suggests that desloratadine has a slower onset of action and higher activity was achieved more quickly with cetirizine than with desloratadine.11 Ref

9

Table 3. Summary of Efficacy Studies Drug N, ages Duratio Desig Regimens n n * Desloratadi ne 5 mg Placebo

N=346 (spring) N=328 (fall) Ages ≥12 Patients with 2-year documente d history of seasonal allergic

14 days

MC RCT DB PC

Primary End Points

Results/Commen ts

Level of Evidenc e**

NNT/NNH

Mean change from baseline in the average assessme nt of am/pm total symptom score (TSS)

Primary endpoint was shown to be significantly than placebo in the spring season for those treated with desloratadine 5 mg (p<0.01) vs placebo (28% and 12.5 % reduction respectively).

Grade 1

Reduction of mean am/pm TSS Fall: NNT=7 Spring: NNT=13

rhinitis (SAR) and who showed a positive skin test to seasonal allergens 12 months prior to enrollment. Patients were randomly assigned to spring treatment with desloratadin e 5 mg daily (n=172) and placebo (n=174) or to fall treatment with desloratadin e 5 mg daily (n=164) and placebo (n=164) 10

Desloratadi ne 5 mg Placebo

N=331 Ages ≥15 Patients with 2 –year minimum history SAR and increased asthma signs or symptoms in conjunction with the fall/winter allergy season. Patients were randomly assigned to treatment with

4 weeks

MC RCT DB PC

Primary: Mean am/pm total symptom score (TSS) expressed as the changes from baseline of days 115 with additional analysis for days 1-29. Secondar y: Change from

Primary endpoint was shown to be greater than placebo in the fall season with those treated with desloratadine 5 mg (p=0.02) vs placebo (30% and 22 % reduction respectively). Adverse effects reported in for both seasons were mild to moderate in severity with most reported being a headache, however similar results occurred in the placebo group as well (16-24% in patients treated with desloratadine vs 14-27% treated with placebo). Primary endpoint was shown to be statistically significant over placebo over days 1-15 (p<0.001) with changes in TTS scores of 4.90 and 2.98 respectively (31.6 % and 19.3% reduction respectively). Desloratadine significantly reduced the mean am/pm reflective nasal congestion score over days 1-15 in

Grade 1

Reduction of mean am/pm TSS 15 days: NNT= 8

baseline in mean am/pm nasal congestio n score, am instantan eous TSS, and am/pm total nasal and non-nasal symptom scores

desloratadine 5 mg daily (n=168) and placebo (n=163).

comparison to placebo (0.56 vs 0.38 reduction, p<0.006), and sustained through days 129 (0.47 vs 0.64 respectively, p=0.014). Secondary endpoint evaluation showed significant reduction in mean am instantaneous TSS at first study timepoint vs placebo (2.57 vs 0.85, respectively, p<0.001). For days 1-15 desloratadine was significantly better than placebo (p=0.001) providing significant reduction in mean am/pm reflective total nasal and non nasal symptoms.

11

Desloratadi ne 5 mg Cetirizine 10 mg Placebo

N=18 Ages 18-50 Patients

24 hours

DB RCT PC XO

Primary: Wheel and flare inhibition measured

Adverse effects reported in this clinical trial were similar to placebo with most frequently reported headache (3.0% vs 2.5%) and dry mouth (1.2% vs 2.5%) Primary endpoints were shown to be statistically significant for

Grade 1

Time to reach 70% wheel inhibition

absent of any clinical disease, passed clinical examination, normal body mass index, no personal history of allergy, and a negative test result for specific IgEs against common aeroallergen. Patients were assigned 3 treatment periods separated by at least 14 days in which they took either desloratadine 5 mg, cetirizine 10 mg, or placebo after challenge to histamine prick test.

as time to reach 70% inhibition, inhibition of flare response, and duration of effect.

cetirizine in outcomes.

all

Time to reach 70% wheel inhibition occurred 0% of the time for placebo, in 17% of the subjects treated with desloratadine 5 mg. Cetirizine performed better at 100% of the subjects achieving wheel inhibition of 70% (p<0.001). Inhibition of wheel response revealed that the activity of cetirizine and desloratadine were greater than placebo alone with cetirizine providing the largest response (p<0.001). The inhibition of flare response of both desloratadine and cetirizine were both significantly greater than placebo with cetirizine exhibiting the largest inhibition response (p<0.001). The median time for which wheal inhibition was 70% for cetirizine and was zero for

Cetirizine: NNT= 1 Desloratadi ne NNT=6

placebo and desloratadine and 21.9 hours with cetirizine (p<0.001).

*Study design abbreviations: DB=double blind; RCT=randomized trial; PC=placebocontrolled; PG=parallel group; XO=crossover ; MC=multi-center **Level of evidence: Grade 1=RCT; Grade 2=nonrandomized concurrent studies; Grade 3=historical cohort & case-control studies; Grade 4=case series; Grade 5=expert opinion. ADVERSE EFFECTS: The most common adverse effects reported in multiple placebo controlled studies were headaches, nausea, and dry mouth with the incidences of these slightly higher in younger populations. Post marketing analysis has shown rare cases of hypersensitivity reactions and elevated liver enzymes. Adverse effects reported here were generally consistent among the other 2nd generation antihistamines besides the incidence of somnolence being highest in cetirizine versus others (13.7% versus 2.1%).1,2,3,4,5

Table 4: Adverse effects associated with desloratadine1 Adverse Effect Incidence Pharyngitis

4.1%

Dry Mouth

3.0%

Somnolence

2.1%

Fatigue

2.1%

Dizziness

2.0%

Flu-like symptoms

2.0%

Dysmenorrhea

2.0%

DRUG INTERACTIONS: Desloratadine has been shown to minimally interact with common drugs and no clinically significant changes in its safety profile have been noted.1 However, it has been noted in the literature that desloratadine Cmax can be altered when given with drugs such as ketoconazole, fluoxetine, cimetidine, azithromycin, and erythromycin. Loratadine can cause an increased risk of QT prolongation in patients taking amiodarone.5 Fexofenadine is a weak inhibitor of CYP2D6 and is a minor substrate of CYP3A4 which contributes to some of its drug interactons.4 Its interaction with droperidol leads to an increased risk of cardiotoxicity through QT prolongation.5 Desloratadine has not been shown to increase the risk of QT prolongation in amiodarone or droperidol and does not interact with antacids, grapefruit juice, or st. johns wort.1,5

As common to all 2nd generation antihistamines, increased effects can be theoretically observed when co-administration with sedatives/CNS depressants and acetylcholinesterase inhibitors.8 Table 5: Drug-Drug/Drug-Nutrient interactions reported antihistamines1,2,3,4,5,8 Drug Interaction Desloratadi Loratadine Cetirizine ne (Clarinex) (Claritin) (Zyrtec) Acetylcholinesteras e Inhibitors

in

(Allegra)

x

x

X

X

x

x

X

CNS Depressants Ketoconazole

X

x

X

Erythromycin

X

x

X

Fluoxetine

X

Cimetidine

X

Azithromycin

X

* x

Theophylline

x

Antacids

*

Grapefruit Juice

*

St. Johns Wort

x

Ritonavir Amiodarone Droperidol

generation

Fexofenadine

X

PEG-Ifa 2b

2nd

X x

* * x= minor interaction *= clinically relevant interaction

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS: Desloratadine is contraindicated in persons with a known hypersensitivity reaction to any of its ingredients or to loratadine.1 Renal impairment warrants a dose reduction in patients receiving desloratadine, loratadine and cetirizine.1,2,5 Liver dysfunction warrants a dose reduction in patients receiving loratadine and cetirizine5. It is unclear if desloratadine needs dosage adjustment due to liver dysfunction.1,5 Cetirizine is cautioned in activities requiring mental alertness and in the elderly. Desloratadine does not have these precautions.1,3 Desloratadine and fexofenadine are both listed as pregnancy category C as there are no controlled clinical trials in pregnant women determining safety. Both manufacturers recommend only to use if the benefits outweigh the risks in pregnancy.1,4 Cetirizine and

loratadine are both listed as pregnancy category B and have been shown to be safe in animal controlled studies but none have been shown in human populations. Both manufacturers recommend similar benefit to risk evaluations as stated above for desloratadine.2,3 Desloratadine does pass into the milk of a nursing mother and the manufacturer suggests risk vs benefit evaluation of therapy to determine appropriateness of use.1 However, due to its low levels found in the breast milk and lack of sedative properties, it is unlikely that it would have an impact on breast fed infants.12 MONITORING: No specific monitoring is needed for desloratadine besides signs/symptoms of any adverse effects to be reported to the primary physician.5 AVAILABILITY AND DOSING: Desloratadine is available as 5 mg tablets (30), 2.5 mg and 5 mg orallydisintegrating tablets (30), and as a 0.5 mg/mL syrup (473 mL).1,8 Adults and children ages 12 and greater – one 5 mg tablet daily, one 5 mg orallydisintegrating tablet daily, or two teaspoonfuls (5 mg) of syrup daily.1 Children ages 6-11 – one 2.5 mg orally-disintegrating tablet daily or one teaspoonful (2.5 mg) of syrup daily.1 Children ages 12 months-5 years – one half teaspoonful (1.25 mg) once daily.1 Children ages 6-11 months – two mL (1 mg) once daily.1 Dosage adjustments for renal patients: Adult patients should take 5 mg every other day. No data has been established in children for dosing.1 Dosage adjustment for hepatic impairment: Adult patients should take 5 mg every other day. No data has been established in children for dosing.1 The orally-disintegrating tablets should be placed on top of the tongue, with or without water, and be allowed to disintegrate completely.1,8 The syrup should be drawn up with a properly calibrated syringe to deliver either 2 mL or 2.5 mL to a child.1,8 Table 6: Failure Modes and Effects Analysis (FMEA)1,5,8,13 Desloratadine Look-alike/Sound-alike Celecoxib, Claritin, loratadine Pregnancy Category C Overdose/Toxicity Tachycardia, lethargy, vomiting somnolence, and headache found in adults. Extrapyramidal side effects and heart palpitations in children. Treatment is supportive. Consider activated charcoal. Administration Oral tablets, disintegrating tablet, syrup

Storage

Specific Monitoring

25º C (77º F), Protect from moisture and excessive heat. Use orally-disintegrating tablet immediately after opening blister package. Not needed

COST EVALUATION: Desloratadine cost ranged from $126.92 for a 4 week regimen of the oral tablets up to $136.19 for the orally-disintegrating tablets. The cost of the syrup formulation for 1 month of therapy was in between at $132.00. Costs of desloratadine and other 2 nd generation antihistamines are compared in the table below using average wholesale price (AWP).14 Table 7: Cost Comparison between 2nd generation antihistamines14 Drug Usual Dosage AWP Cost/Month or Regimen Desloratadine

2.5-5 mg daily x 4 weeks

$126.92-$136.19

Loratadine

10 mg daily x 4 weeks

$22.36

Cetirizine

10 mg daily x 4 weeks

$18.72

Fexofenadine

180 mg daily x 4 weeks

$72.90

SUMMARY AND RECOMMENDATIONS: Desloratadine is the major metabolite of loratadine and is approved by the FDA for similar indications related to allergic rhinitis and chronic urticaria as other 2nd generation antihistamines. Its pharmacokinetics are representative of similar drugs in its category, however onset of action and its half-life are the longest. Adverse effects seen are similar to others compared in its category differing along with loratadine and fexofenadine from cetirizine, with a lower incidence of somnolence being reported. Desloratadine is extensively metabolized by the liver, like its parent compound loratadine, and therefore subject to similar drug-drug interactions with the absence of some clinically significant interactions. Clinical studies have consistently showed efficacy and safety in comparison to placebo for treatment of allergic rhinitis and acute allergic reaction. It is clear however, that cetirizine performs well in comparison to desloratadine in these acute reactions. This can allow for a possible conclusion that desloratadine has a slower onset of action and may not achieve high enough therapeutic responses in these patients. It is recommended that desloratadine not be added to the formulary at this time. Although clinical trials and results show effectiveness in comparison to placebo for common FDA indications of the compared 2nd generation antihistamines, there are still areas in which current formulary drugs such as cetirizine are shown to be superior. Furthermore, by looking at the AWP pricing, it is very evident that other therapies currently on formulary provide a significant cost benefit in comparison to utilizing desloratadine at similar treatment regimens without incurring extra costs. Appropriate treatment for allergic rhinitis and idiopathic chronic urticaria is appropriately managed with current formulary products. References: (Use AMA Referencing) 1. Clarinex [package insert]. Kenilworth, NJ: Schering Corperation; 2004. 2. Claritin [package insert]. Kenilworth, NJ: Schering Corperation; 2000.

3. Zyrtec [package insert]. New York, NY: Pfizer Labs; 2006. 4. Allegra [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S LLC; 2007. 5. Micromedex Healthcare Series Web site. http://www.thomsonhc.com.cuhsl.creighton.edu/ hcs/librarian. Accessed Sep 25, 2009. 6. Devillier P, Roche N, Faisy C. Clinical Pharmacokinetic and Pharmacoynamics of Desloratadine, Fexofenadine and Levocetirizine. Clin Pharmacokinet. 2008;47(4):217-230. 7. Bendetti MS, Diquet B, Molimard M. Comparison of pharmacokinetics and metabolism of desloratadine, Fexofenadine, levocetrizine and mizolastine in humans. Fundam Clin Pharmacol. 2004;18(4):399-411 8. Lexi-Comp (Lexi-Drugs) [computer program]. Lexi-Comp; Sep 22, 2003. 9. Meltzer E, Nayak A, Prenner B. Efficacy and Tolerability of Once-Daily 5 mg Desloratadine, an H1-Receptor Antagonist, in Patients with Seasonal Allergic Rhinitis Assessment during the Spring and Fall Allergy Seasons. Clin Drug Investig. 2001;21(1):25-32. 10. Berger W, Mansfield L, Schenkel E. Safety and efficacy of desloratadine 5 mg in asthma patients with seasonal allergic rhinitis and nasal congestion. Ann Allergy Asthma Immunol. 2002;89(5):485-491. 11. Frossard N, Melac M, Pauli G, Purohi A. Comparative activity of cetirizine and desloratadine on histamine-induced wheal-and-flare responses during 24 hours. Ann Allergy Asthma Immunol. 2004;92(6):635-639. 12. U.S. National Library of Medicine LactMed Search Web site.http://toxnet.nlm.nih.gov/cgibin/sis/search/f?./temp/~gLIAQS:1. Accessed Sept 28, 2008 13. ePocrates (ePocrates Rx ) [computer program]. ePocrates, Inc; Ver 2.71/Sept 19, 2009 14. Drug Topics Red Book. 2009 edition. Montvale:Thomson Reuters;2009.