Evidence Table 15Adverse events from efficacy trials in adults

Internal validity
Method and timing of assessing adverse eventsAdverse eventsTotal withdrawals; withdrawals due to adverse eventsNon-biased selection?Low overall loss to follow-up?Adverse events pre-specified and defined?Ascertainment techniques adequately described?Non-biased and adequate ascertainment methods?Statistical analysis of potential confounders?Adequate duration of follow-up?
Seasonal allergic rhinitis
Patients were seen on an outpatient basis on days .7, 1, 7, and 14. A diary card in which to record symptom severity was given on day −7.Most common AEs per treatment:
Bitter taste: 11% azelastine, 4% azelastine + loratadine
Headache: desloratadine 3%, placebo 7%4%
Pharyngitis: desloratadine 4:
Somnolence: desloratadine 1%, azelastine 2%, azelastine + loratadine 1%, placebo 1%
Withdrawals for AEs
Azelastine: 2 patients (moderate chest pain; lightheadedness)
Desloratadine: 1 patient (headache and nausea) Placebo: 1 patient (rash)
Pt evaluated AEs from daily diary cards and investigator rated AEs at clinic visitsAll AEs data given as loratadine 10 mg vs fluticasone spray vs placebo

Incidence of AEs: 42% vs 44% vs 40%
Headache: 18% vs 17% vs 12%
Discontinuation due to AEs: 4% vs 3% vs 2%
Total withdrawals: 13% from loratadine, 6% from fluticasone, 9% from placebo; discontinuation due to AEs: 4% vs 3% vs 2%Unclear, methods NRYesNoNoUnclearNRYes (4 weeks)
NRNo significant AEs reported.0/0YesYesYesYes, diaryYesNRYes, all patients completed
Tolerability assessed in terms of AEs and vital signs, and heart and respiration rates, all of which were measure at baseline and at end of study.Most common AEs, with ≥ 1% pts reporting these, cetirizine 10 mg vs azelastine spray:
 Bitter taste: <1% vs 3.3%
 Epitasis: <1% vs 2.0%
 Somnolence: 2.6% vs 1.3%
 Nasal discomfort: <1% vs 1.3%
Discontinuation due to AEs: 2 cetrizine pt (1 each: somnolence and skin rash) vs 4 azelastine patients (1 each: sleeplessness, sinus infection, nausea, and allergy exacerbation)
8; 6 (2 in cetirizine, 4 in azelastine)Unclear, methods NRYesNoYesUnclearNRYes (2 weeks)
Pts recorded daily severity of symptoms and other relevant comments in diary. These were returned on days 3, 7 and 14 of treatment for investigator evaluation of efficacy and safety. Blood pressure, body temperature, pulse and respiration rate determinations were repeated at clinical visits while clinical laboratory tests, ECG, and body weight were repeated at study completion. Any clinically meaningful changes from baseline were noted. In addition, AEs were elicited at each visit. Date, time of onset and duration of any AE were recorded and severity of any AE was graded as mild, moderate or severe by standard definition.More AEs (considered probably or possibly treatment-related) in clemastine 2mg group: clemastine 2mg 37%, loratadine 10mg 21%, placebo 20% (p<0.01)
Sedation: clemastine 22% vs loratadine 6% (p<0.01)
D/C treatment: NR
NR; NRYesYesNoYesYesNoYes
Pts recorded AEs in daily and symptoms were evaluated at each study visit; pts asked to self-evaluate drowsiness and motivation daily at 7am, 10am, and 3pm using a VAS (0–100, with 100= extremely sleepy or not motivated at all).16.8% AEs observed: 16.8%: fexofenadine 16.9%, cetirizine 16.6%
4.4% drug related AEs: 4.0% fexofenadine, 4.8% cetirizine
No serious AEs reported
Drowsiness: significantly greater with fexofenadine than with cetirizine (p=0.0110)
Overall change from baseline in drowsiness correlated with the change from baseline in motivation
D/C treatment: 16 (7 fexofenadine 180mg vs 9 cetirizine 10mg ); 6 of 16 due to AEs
total withdrawals=16; 6/16 for AEsYesYesYesYes, diaryYesNRYes
Pts were provided with a daily diary card, recording took place every morning and evening, pts recorded any AEs throughout the study period.223 pts (29.8% report 410 AEs; NSD between study groups in # of pts who reported ≥ 1 AE.
Data on AEs given as loratadine 10mg vs ebastine 10 mg vs ebastine 20 mg vs placebo
AEs related to body as whole system: 15.3% vs 11.2% vs 11.8%
AEs associated with respiratory system: 12.2% vs 8.5% vs 7.5% vs 10.2% (72 pts (9.6%) reported 101 respiratory system AEs; all unrelated to study drug)
Headache: 5.8% vs 4.3% vs 3.2% vs 4.3%
Dyspepsia: 0% vs 0% vs 3.2% vs 0%
Pharyngitis: 0% vs 0% vs 0% vs 4.3%
Serious AEs: 8 pts vs 14 pts vs 5 pts vs 13 pts
No deaths reported
Prolonged QTc intervals: 1.6% vs 3.2% vs 2.2% vs 0.5% (all mild and none resulted in discontinuation)
Slight increase in heart rate for all 4 treatment groups; 1 report of palpitation in a Loratadine pt.
CNS AEs: 33 (4.4%) of pts reported 44 CNS AEs
Somnolence: 0 vs 1.6% vs 3.2% vs 0%
100 pts; 20 pts (2.7%)Unclear, methods NR13%NoNoUnclearBaseline variables used as covariates in analysesYes (4 weeks)
UK, US, France
AEs recorded daily along with symptoms; pts self-assessed somnolence on VAS every evening before bed. Blood samples taken at baseline and end of studyTreatment-related AEs:
 fexofenadine 120mg 23%; fexofenadine 180mg 23%; cetirizine 10mg 25%; placebo: 25%;
D/C treatment: 117 (14% of total), similar among groups (numbers per group not reported)
22 pts; 13 pts Withdrawals for AEs by group: placebo − 2%, 2% for both groups of fexofenadine combined, and <1% for cetirizineYesYesYesYesYesNoNR
AEs reported by pts or observed by investigatorsData given as cetirizine 10 mg vs rupatadine 10 mg
Related (possible, probable, or definite) AEs: 42.7% vs 39.5%, NSD
headache: 19.7% vs 15.3%, NSD
fatigue/asthenia: 6.8% vs 10.5%, NSD
somnolence: 8.5% vs 9.6%, NSD
37/12Unclear, methods NRNo (15%)NoNoUnclearYesYes (2 weeks)
2004, 2005
Any unfavorable signs and symptoms observed during the period of administration of the study drug were classified as AEs. Safety items included data obtained and symptoms experienced during the study period. AEs described in the allergy diary were not reported; only those reported at physician’s examinationsNo serious adverse events were reported. There was no significant difference in the number of adverse events between the two groups (P= 0.568). A high white blood cell count and headache occurred most frequently.3/NRUnclear, methods NRYes (3/210)NoNoUnclear; AEs recorded in patients’ diaries were not recorded in studyYesYes (2 weeks)
NRAdverse events: 22.1% of fexofenadine 120mg and 18.2% of loratadine 10mg group had ≥ 1 adverse events.
AEs considered treatment related in 8.3% of fexofenadine 120mg, 5.3% of loratadine 10mg
Discontinued treatment: NR
Discontinued due to AEs: NR
NR; NRYesYesNoNoYesNoYes
Patients recorded any AEs; these were classified and summarized.No significant difference among the three groups in % of pts who reported >1 AEs: 29.4% ebastine, 33.3% loratadine, 25.4% placebo
Total number of AEs reported: 146 ebastine, 138 loratadine, 53 placebo
89.9% of AEs mild or moderate intensity, 10.1% severe (most unrelated to treatment)
Headache (reported by >2 loratadine pts)
Nervous system: ebastine 4.6%, no clinically significant trends
Digestive system: 3.2% ebastine, 3.5% placebo, no clinically significant trends
Cardiovascular system: 2.8% ebastine, 2.5% loratadine, 4.2% placebo
Prolonged QTc interval was the most frequently cardiovascular AE: 3.9% ebastine, 3.6% loratadine, 5.6% placebo; all increases in QTc were mild w/o resulting in discontinuation of treatment.
Discontinued treatment: 85
Discontinued due to AEs: 18 (3.2% ebastine, 2.2% loratadine, 2.1% placebo)
18 patients (2.6%) withdrew due to AEsUnclear; no data on selection of patients85/703 (12.5%)NoYesUnclear; blinding of assessor NRYes, baseline groups differed on duration of allergy symptoms; baseline factors used as covariatesYes (4 weeks)
Patients reported AEs in daily diary; no other details. Reported to investigators day 7 and 14Patients reporting at least 1 AE: rupatadine 10mg 64.9%; rupatadine 20mg 53.6%;
loratadine 10mg 49.1%; NSD among groups;
headache most frequent AE; others; somnolence, asthenia, coughing.
Only significant difference was somnolence between rupatadine 10mg vs rupatadine 20mg and rupatadine 10mg vs loratadine 10mg.
Other AEs with incidence rate <5%: back pain, dry mouth, pharyngitis (NSD among groups)
Overall 11 patients (3.2%);
rupatadine 10mg 4 patients, rupatadine 20mg 5 patients, loratadine 2 patients; NSD among groups.
Unclear, methods NRNo, 65+19 lost to follow-upNoNoUnclearYes, center and basal SS used as covariatesYes (2 weeks)
van Adelsberg
Safety and tolerability were assessed by adverse events monitoring, physical examinations, and laboratory testingLoratadine=montelukast for discontinuations because of AEs.
 There were no clinically meaningful differences between treatment groups in the incidence of clinical or laboratory adverse experiences.
1 withdrawal for clinical adverse experience in loratadin e group, reason NR
79; 1 withdrawal in loratadine group for clinical AE, 0 for laboratory AE
Montelukast = 11 withdrawals dues to clinical AEs
Placebo = 14 due to clinical
AEs and 1 due to lab AEs
Unclear, methods NRYesNoNoUnclearNoYes (4 weeks)
van Cauwenberge
Europe and South Africa
AEs assessed at each visit at each week of study, and were contacted 7 d after study to find out if AEs had occurred after treatment.AE data given as loratadine 10mg vs fexofenadine 120mg vs placebo
AEs: 16.4% of total
AEs by group: 17.5% vs 16.8% vs 14.7%

D/C treatment: 10% of total
D/C treatment by group: 12% vs 9% vs 11%
71; 15YesYesNoYesNoNoYes
Clinical lab tests performed at baseline and at end of study. All AEs were volunteered or observed and recorded at day 1, at the ends of weeks 1, 2, 3, and 4.Sedation significantly different hydroxyzine 75mg vs placebo p=0.001
D/C for somnolence: cetirizine 10mg 1 pt, hydroxyzine 75mg 4 pts, placebo 1 pt.
3 more placebo pts discontinued.
43; 3YesYesYesYes, diaryYesNRYes
Pts seen at 3, 7, 14, and 28 d after treatment start when evaluations were made of clinical symptoms and any side effectsNS difference in Total AEs:
Loratadine 15.8%, cetirizine 27.5%, placebo 15.8%.
One cetirizine patient withdrew due to gastralgia.
NR ; 1 pt withdrew due to AEsYesNoYesNRYesNRYes
Handa 2004
Patients self-report AEs; no details providedCetirizine 10 mg: drowsiness: 7.7%, constipation: 5.8%, epigastric pain: 3.8%, cough: 3.8%
Fexofenadine 180mg: drowsiness: 4.5%, and 2.2% reported headache, feet swelling and abdominal pain.
19; NRUnclear, methods NRNo; 19/116 left the study (16%)NoNoUnclear if assessor blinded and how AEs elicitedNRYes (2 weeks)
Kaplan, 2005
Patient-reported AE; 12-lead ECG; clinical lab tests at baseline and final visitSafety evaluation population = 259 (167 in fexofenadine vs 92 in placebo)
Treatment-associated AEs: fexofenadine 180mg 31% vs placebo 37%, NSD
Total headache: fexofenadine 180mg 5%, placebo 3%
Headache related to study drug: fexofenadine 180mg 2%, placebo 0%
Serious AEs: 1 patient in group fexofenadine 180mg had asthma requiring hospitalization;
no considered related to the study drug

“No clinically relevant changes from baseline to end of treatment seen in clinical laboratory data, vital signs, or ECGs”
25; NRSee QA tableSee QA tableSee QA tableSee QA tableSee QA tableSee QA tableSee QA table
Monroe, 2003
Vital signs recorded at all visits, ECGs and laboratory tests performed at screening and visit 7. All AEs were recorded and graded for severity and potential relation to study medication.
Safety evaluations included the incidence of treatment-emergent AEs, discontinuations due to AEs, and changed from baseline in vital signs, laboratory parameters, and ECG intervals.
Overall AE profile of desloratadine was similar to placebo (data not reported).Total: 16.4% desloratadine vs 31.8% placebo;
Due to AEs: 3 desloratadine, vs 2 placebo
YesYesNoYesYesYes (RCT)Yes (6 weeks)
Perennial allergic rhinitis
AEs obtained by asking the same general question at each evaluation; details recorded by clinician. Lab test done at baseline and endpoint; lab test with abnormal results were repeated.AEs significantly less with loratadine 10mg than clemastine 1mg or placebo (p<0.05). AE of sedation significant with clemastine 1mg.
loratadine 10 mg qd: 8/53 AEs. 5 d/c not from AE
clemastine 1 mg: 30/51 AEs, d/c, 1 AE and 2 failures.
placebo: 13 d/c, 9 due to failures
25 pts; 1 ptYesYesYesYes, diaryYesNRYes
US and Canada
Vital signs and AEs assessed at each study visit. All AEs graded according to severity and the potential relationship to study medication. Blood chemistry and hematology tests, urinalysis, and 12-lead ECGs with reporting of ventricular rate and PR, QRS, QT, and QTc intervals were performed at screening and end of study;Incidence of treatment emergent AEs (desloratadine vs placebo):
Overall: 25.8% vs 31.6%
Headache: 7.4% vs 7.1%
Infection, viral: 3.3% vs 5.3%
Pharyngitis: 3.0% vs 1.5%
URTI: 2.7% vs 2.7%
Dry mouth: 2.4% vs 1.8%
No clinically significant differences in vital signs, clinical laboratory test results, or ECGs, including QTc intervals compared with baseline or between groups.
Total: 5.93% desloratadine vs 6.48% placebo
Due to AEs: 3.3%
desloratadine vs 2.1% placebo (NSD)
YesYesNo, except for ECG resultsYesYesYes (RCT)Yes (4 weeks)

From: Evidence Tables

Cover of Drug Class Review: Newer Antihistamines
Drug Class Review: Newer Antihistamines: Final Report Update 2 [Internet].
Carson S, Lee N, Thakurta S.
Portland (OR): Oregon Health & Science University; 2010 May.
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