Comparison of the Sedating Effects of Levocetirizine and Cetirizine: a Randomized, Double-blind, Placebo-controlled Trial

Design

Single-center, randomized, double-blind, placebo-controlled, crossover trial

N= 29

Objective

To determine whether levocetirizine is less sedating than cetirizine

Study Groups

Placebo (n = 29)

Cetirizine (n = 29)

Levocetirizine (n = 29)

Inclusion Criteria

Age 18 to 77 years; perennial allergic rhinitis to dust mite, cat, or dog with or without seasonal allergic rhinitis, reported moderate (only being able to tolerate 5 mg of cetirizine or a 10 mg dose only at night) or severe (unable to tolerate continued cetirizine use even at lower than normal doses or with nighttime use) sedation with cetirizine after taking the medication for at least 1 week before stopping its use

Exclusion Criteria

Any condition that required ongoing antihistamine or steroid treatment for which the patient was unable or unwilling to stop use of antihistamines during washout periods, recent sinusitis, nonallergic rhinitis, or the presence of a sleep disorder, such as sleep apnea.

Methods

In this crossover design, patients were initially randomized to receive either levocetirizine 5 mg daily for 1 week, cetirizine 10 mg daily for 1 week, or matching placebo for 1 week. Then patients underwent 5-day washout periods between each week of treatment. Sedation or sleepiness was measured via a questionnaire at baseline and days 5, 12, 17, 24, 29, and 36 using the modified Epworth Sleepiness Scale (mESS, 0 to 24), a Likert scale to measure global sedation (0 to 9), and total rhinitis symptom score (TRSS, 0 to 12). Each scale were similar in that 0 indicated absence of symptoms and the highest number indicated severe symptoms or sedation.

Duration

Duration of therapy: 1 week per treatment arm, duration of follow-up: 36 days

Outcome Measures

Assessing patient-reported levels of sedation and allergy symptoms through the ESS, Likert scale, and TRSS.

Baseline Characteristics

Study Participants (N= 29)

Mean age, years

Female

Patient-reported level of sedation experienced with cetirizine prior to study:

Unable to take the medication

Only able to take the medication at night

Only able to take half (5 mg) the usual dose

55%

34%

10%

Results

Endpoint

Placebo (n= 29)

Cetirizine (n= 29)

Levocetirizine (n= 29)

*p-Value

Mean mESS score

Mean Likert scale score

Mean TRSS

*p-Values are compared in the following manner: cetirizine vs. placebo, levocetirizine vs. placebo, cetirizine vs. levocetirizine

Adverse Events

N/A

Study Author Conclusions

In patients with a perceived history of sedation with cetirizine, most were able to tolerate levocetirizine. However, this controlled trial also suggests that many of these patients would tolerate cetirizine if given in a masked manner. Therefore, patients with a history of mild to moderate sedation with cetirizine are unlikely to experience a different sedation profile with levocetirizine.

InpharmD Researcher Critique

A small patient population may overestimate or be unable to detect the true effect size of treatment. Some included patients reported being able to tolerate cetirizine while others did not, which is a confounding factor that can skew results. The single-center design limits the generalizability of the results as different locations vary by environmental allergants.

Levocetirizine in Children: Evidenced Efficacy and Safety in a 6-week Randomized Seasonal Allergic Rhinitis Trial

Design

Multi-center, randomized, double-blind, placebo-controlled trial

N= 177

Objective

To assess the efficacy of levocetirizine 5 mg once daily in reducing seasonal allergic rhinitis (SAR)

Study Groups

Placebo (n= 88), levocetirizine 5 mg (n= 89)

Inclusion Criteria

Male and female children between the ages of 6 and 12 years old with confirmed and documented SAR (to grass and/or weed pollen) of at least a year's duration, as measured by Total Four Symptom Score (T4SS, sum of sneezing, rhinorrhea, nausea, and ocular pruritus) ≥ 6.

Exclusion Criteria

Children who had perennial allergic rhinitis resulting in erratic symptoms; any ear, nose, or throat (ENT) infection during the 2 week time period preceding the baseline visit or any associated ENT disease; a temperature ≥ 38.5°C at the baseline visit; the presence of any clinically significant disease or other diseases that might affect the absorption, distribution, metabolism, or excretion of the investigational medication.

Methods

In order for these patients to be diagnosed with SAR, they had to have a history of allergic rhinitis, pollen sensitization (confirmed by a positive skin test or positive Radio-Allergo-Sorbent test [RAST]), and presence of symptoms at inclusion. They were not permitted to take the following medications (days before study start): corticosteroids or desensitization in the ascending phase (30 days); ketotifen, nedocromil, or cromoglycate (14 days); loratadine (10 days); leukotriene antagonists or synthesis inhibitors (7 days); other H1-antihistamines (3 days); decongestants (3 days). The children were required to attend the clinic on five occasions, weeks 0, 2, 4, and 6. Disease-specific quality of life questionnaire, Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ), was completed by the investigator via subject interview at the beginning of all visits. At visit 3, a global evaluation of disease evolution was made separately by the subject, guardian, and investigator.

Duration

Duration of therapy: 6 weeks, duration of follow-up: 6 weeks

Outcome Measures

Primary: to assess the efficacy of levocetirizine 5 mg once daily in reducing SAR symptoms, as measured by T4SS, over the first 2 weeks of treatment

Secondary: the T4SS score, nasal congestion score, PRQLQ, and global evaluation of the illness evolution regarding weeks 2 through 6.

Baseline Characteristics

Placebo (n= 88)

Levocetirizine (n= 89)

Mean age, years

Female

White

T4SS

Results

Endpoint

Placebo (n= 88)

Levocetirizine (n= 89)

p-Value

T4SS over:

2 weeks (95% CI)

4 weeks (95% CI)

6 weeks (95% CI)

6.27 ± 0.23

5.69 ± 0.24

5.29 ± 0.24

4.98 ± 0.23

4.37 ± 0.24

4.06 ± 0.24

< 0.001

< 0.001

< 0.001

Side effects:

Asthenia

Fatigue

Headache

Irritability

Somnolence

Anorexia

2.3%

0%

2.3%

0%

0%

1.1%

1.1%

1.1%

1.1%

1.1%

1.1%

0%

Adverse Events

Common Adverse Events: see results table

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: 0.11% vs. 0%

Study Author Conclusions

In conclusion, this study demonstrates that levocetirizine is safe and efficacious in reducing the symptoms of SAR (including nasal congestion) in children, 6–12 yr of age. It also confirms the need for continuous (throughout the pollen season) treatment of SAR in children with a potent antihistamine to ensure good overall symptom control and increased quality of life.

InpharmD Researcher Critique

The duration of the trial, 6 weeks, was also an improvement from previous trials, 2 to 4 weeks. However, the study lacked a clinical comparator and relied on parent/guardian reported data.

The Acute and Sub-chronic Effects of Levocetirizine, Cetirizine, Loratadine, Promethazine, and Placebo on Cognitive Function, Psychomotor Performance, and Weal and Flare

Design

Single-center, double-blinded, crossover study

N= 18

Objective

To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (L-CTZ), cetirizine (CTZ), loratadine (LOR), and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction.

Study Groups

Placebo (n= 18), promethazine 30 mg (n= 18), loratadine 10 mg (n= 18), cetirizine 10 mg (n= 18), levocetirizine 5 mg (n= 18)

Inclusion Criteria

Patients who were in good health without a significant clinical history of physical or mental illness

Exclusion Criteria

Patients taking concomitant medications likely to interfere with the study measures and procedures

Methods

The use of alcohol and nicotine were forbidden and products containing caffeine were prohibited on test days; food consumption was strictly controlled and only allowed at specific times. On each of the test days (days 1 and 4 of each treatment cycle), subjects attended the study center where a breath alcohol reading was taken. Each treatment cycle was separated by a washout period of 6 days or more. Pre-treatment baseline recordings were then made of each of the psychometrics (Weal and Flare [W & F], Critical Flicker Fusion Threshold [CFF], Choice Reaction Time [CRT], Continuous Tracking Task [CTT], and Line Analogue Rating Scales for Sedation [LARS]), after which medications were administered and further testing carried out at 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose. Additionally, peripheral reactivity to histamine was assessed at each of hte test times by means of the weal and flare test. Assessments of sedation using subjective rating scales were made at each time point prior to the performance of the psychometric test battery. Lastly, adverse events and concomitant medications were recorded at each visit.

Duration

Duration of therapy: 4 days per arm, duration of follow-up: ~ 50 days

Outcome Measures

Primary: assessment of change in various psychometric measurements (stated in methods section)

Baseline Characteristics

All patients
(N = 18)

Mean age, years

Results

Endpoint

Placebo (N = 18)

Promethazine 
(N = 18)

Loratadine 
(N = 18)

Cetirizine 
(N = 18)

Levocetirizine 
(N = 18)

*Sedation assessments on day 1, **LARS:

Baseline

+ 1 hour (h)

+ 2 h

+ 3 h

+ 4 h

+ 6 h

+ 8 h

+ 10 h

+ 12 h

52 ± 1

2 ± 2

2 ± 2

1 ± 2

-2 ± 1

1 ± 1

2 ± 3

-1 ± 2

-4 ± 2

51 ± 1

4 ± 2

10 ± 3^{^}

16 ± 3^{^^^}

12 ± 4^{^^}

11 ± 4^{^}

8 ± 4

3 ± 4

-1 ± 3

53 ± 1

1 ± 2

-2 ± 1

-3 ± 1

-3 ± 1

0 ± 2

0 ± 1

-2 ± 1

-2 ± 1

56 ± 3

2 ± 2

2 ± 2

-1 ± 4

-1 ± 3

2 ± 3

0 ± 2

-2 ± 3

-2 ± 3

52 ± 1

-1 ± 1

-1 ± 1

0 ± 1

1 ± 1

1 ± 1

-1 ± 1

0 ± 1

-2 ± 1

*Sedation assessments on day 4, **LARS:

Baseline

+ 1 hour (h)

+ 2 h

+ 3 h

+ 4 h

+ 6 h

+ 8 h

+ 10 h

+ 12 h

54 ± 3

2 ± 2

1 ± 1

-3 ± 2

-4 ± 3

-3 ± 4

-1 ± 3

-1 ± 1

-1 ± 1

54 ± 3

2 ± 2

1 ± 2

4 ± 2

0 ± 4

5 ± 2

1 ± 4

-5 ± 3

-5 ± 3

55 ± 3

-2 ± 1

-4 ± 2

-3 ± 3

-3 ± 3

1 ± 2

-2 ± 3

-3 ± 3

-3 ± 3

51 ± 3

0 ± 2

0 ± 3

1 ± 2

0 ± 2

5 ± 2

3 ± 3

2 ± 3

1 ± 2

51 ± 1

0 ± 1

0 ± 1

0 ± 1

0 ± 1

4 ± 2

5 ± 2

-1 ± 1

-1 ± 1

*Sedation assessments listed as the presenting baseline mean of that day, followed by the change in mean for each time

**LARS is scaled as

^{^}Indicates a significant difference from placebo scores at p < 0.05^{^}, at p < 0.01^{^^}, and at p < 0.001^{^^^}

Adverse Events

N/A

Study Author Conclusions

There were no noticeable overall differences between L-CTZ, CTZ, LOR and placebo on LARS ratings.

InpharmD Researcher Critique

Strengths of this study include double-blinding as well as crossover design, both contributing greatly to the elimination of confounding factors. The use of multiple psychometric assessments studied was also a remarkable part of this study. Limitations included sample size and single-center design.