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LEVOCETIRIZINE DIHYDROCHLORIDE 5MG FILM-COATED TABLET

Active substance(s): LEVOCETIRIZINE DIHYDROCHLORIDE / LEVOCETIRIZINE DIHYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Levocetirizine Dihydrochloride 5 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated Tablet contains Levocetirizine Dihydrochloride 5 mg (equivalent to
4.2 mg of Levocetirizine).
Also contains 63.50 mg of lactose monohydrate.
For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Film-coated tablet.
White colored oval shaped biconvex film-coated tablet debossed with ‘I’ and ‘12’ on
one side and score line on the other side.
Score line is for aesthetic purposes only and not to facilitate dosing.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Symptomatic treatment of allergic rhinitis (including persistent allergic rhinitis) and
urticaria.

4.2

Posology and method of administration
The film-coated tablet must be taken orally, swallowed whole with liquid and may be
taken with or without food. It is recommended to take the daily dose in one single
intake.
Adults and adolescents 12 years and above
The daily recommended dose is 5 mg (one film-coated tablet).
Elderly:
Adjustment of the dose is recommended in elderly patients with moderate to severe
renal impairment (see Patients with renal impairment below).

Children aged 6 to 12 years
The daily recommended dose is 5 mg (one film-coated tablet).
For children aged 2 to 6 years no adjusted dosage is possible with the film-coated
tablet formulation. It is recommended to use a paediatric formulation of
levocetirizine.
Patients with renal impairment:
The dosing intervals must be individualized according to renal function. Refer to the
following table and adjust the dose as indicated. To use this dosing table, an estimate
of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr (ml/min)
may be estimated from serum creatinine (mg/dl) determination using the following
formula:

Dosing Adjustments for Patients with Impaired Renal Function:

Group

Creatinine
clearance
(ml/min)

Dosage and
frequency

Normal

≥ 80

1 tablet once
daily

Mild

50 – 79

1 tablet once
daily

Moderate

30 – 49

1 tablet once
every 2 days

Severe

< 30

1 tablet once
every 3 days

End-stage renal
disease – Patients
undergoing dialysis

< 10 -

Contra-indicated

In paediatric patients suffering from renal impairment, the dose will have to be
adjusted on an individual basis taking into account the renal clearance of the patient
and his body weight. There are no specific data for children with renal impairment.
Patients with hepatic impairment
No dose adjustment is needed in patients with solely hepatic impairment. In Patients
with hepatic impairment and renal impairment adjustment of the dose is
recommended (see Patients with moderate to severe renal impairment above).
Duration of use:

Intermittent allergic rhinitis (symptoms <4days/week or during less than 4 weeks) has
to be treated according to the disease and its history; it can be stopped once the
symptoms have disappeared and can be restarted again when symptoms reappear. In
case of persistent allergic rhinitis (symptoms >4days/week and during more than 4
weeks), continuous therapy can be proposed to the patient during the period of
exposure to allergens. Clinical experience with 5 mg levocetirizine as a film-coated
tablet formulation is currently available for a 6-month treatment period. For chronic
urticaria and chronic allergic rhinitis, up to one year's clinical experience is available
for the racemate.

4.3

Contraindications
Hypersensitivity to levocetirizine, to other piperazine derivatives or to any of the
excipients.
Patients with severe renal impairment at less than 10 ml/min creatinine clearance.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose- galactose malabsorption should not take levocetirizine filmcoated tablets.

4.4

Special warnings and precautions for use
The use of the film-coated tablet formulation is not recommended in children aged
less than 6 years since this formulation does not allow for appropriate dose
adaptation. It is recommended to use a paediatric formulation of levocetirizine.
The administration of levocetirizine to infants and toddlers aged less than 2 years is
not recommended.
Precaution is recommended with intake of alcohol (see Interactions).

4.5

Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with levocetirizine (including no studies
with CYP3A4 inducers); studies with the racemate compound cetirizine demonstrated
that there were no clinically relevant adverse interactions (with pseudoephedrine,
cimetidine, ketoconazole, erythromycin, azithromycin, glipizide and diazepam). A
small decrease in the clearance of cetirizine (16%) was observed in a multiple dose
study with theophylline (400 mg once a day); while the disposition of theophylline
was not altered by concomitant cetirizine administration.
The extent of absorption of levocetirizine is not reduced with food, although the rate
of absorption is decreased.
In sensitive patients the simultaneous administration of cetirizine or levocetirizine and
alcohol or other CNS depressants may have effects on the central nervous system,
although it has been shown that the racemate cetirizine does not potentiate the effect
of alcohol.

4.6

Fertility, pregnancy and lactation
For levocetirizine no clinical data on exposed pregnancies are available. Animal
studies do not indicate direct or indirect harmful effects with respect to pregnancy,
embryonal/fetal development, parturition or postnatal development. Caution should
be exercised when prescribing to pregnant or lactating women.

4.7

Effects on ability to drive and use machines
Comparative clinical trials have revealed no evidence that levocetirizine at the
recommended dose impairs mental alertness, reactivity or the ability to drive.
Nevertheless, some patients could experience somnolence, fatigue and asthenia under
therapy with Levocetirizine. Therefore, patients intending to drive, engage in
potentially hazardous activities or operate machinery should take their response to the
medicinal product into account.

4.8

Undesirable effects
In therapeutic studies in women and men aged 12 to 71 years, 15.1% of the patients in
the levocetirizine 5 mg group had at least one adverse drug reaction compared to
11.3% in the placebo group. 91.6 % of these adverse drug reactions were mild to
moderate.
In therapeutic trials, the drop out rate due to adverse events was 1.0% (9/935) with
levocetirizine 5 mg and 1.8% (14/771) with placebo.
Clinical therapeutic trials with levocetirizine included 935 subjects exposed to the
drug at the recommended dose of 5 mg daily. From this pooling, following incidence
of adverse drug reactions were reported at rates of 1 % or greater (common: >1/100,
<1/10) under levocetirizine 5 mg or placebo:

Preferred Term

Placebo

Levocetirizine 5mg

(WHOART)

(n = 771)

(n = 935)

Headache

25 (3.2 %)

24 (2.6 %)

Somnolence

11 (1.4 %)

49 (5.2 %)

Mouth dry

12 (1.6 %)

24 (2.6 %)

Fatigue

9 (1.2 %)

23 (2.5 %)

Further uncommon incidences of adverse reactions (uncommon>1/1000, <1/100) like
asthenia or abdominal pain were observed.
The incidence of sedating adverse drug reactions such as somnolence, fatigue, and
asthenia was altogether more common (8.1 %) under levocetirizine 5 mg than under
placebo (3.1%).

In addition to the adverse reactions reported during clinical studies and listed above,
very rare cases of the following adverse drug reactions have been reported in postmarketing experience.
• Immune system disorders: hypersensitivity including anaphylaxis
• Psychiatric disorders: aggression, agitation
• Nervous system disorders: convulsion
• Eyes disorders: visual disturbances
• Cardiac disorders: palpitations
• Respiratory, thoracic, and mediastinal disorders: dyspnoea
• Gastrointestinal disorders: nausea
• Hepatobiliary disorders: hepatitis
• Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruption,
pruritus, rash, urticaria
• Musculoskeletal, connective tissues, and bone disorders: myalgia
• Investigations: weight increased, abnormal liver function tests

4.9

Overdose
Symptoms
Symptoms of overdose may include drowsiness in adults and initially agitation and
restlessness, followed by drowsiness in children.
Management of overdoses
There is no known specific antidote to levocetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended.
Gastric lavage should be considered following short-term ingestion
Levocetirizine is not effectively removed by haemodialysis.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Antihistamine for systemic use, piperazine derivatives,
ATC Code: R06A E09
Levocetirizine, the (R) enantiomer of cetirizine, is a potent and selective antagonist of
peripheral H1-receptors.
Binding studies revealed that levocetirizine has high affinity for human H1-receptors
(Ki = 3.2 nmol/l). Levocetirizine has an affinity 2-fold higher than that of cetirizine
(Ki = 6.3 nmol/l). Levocetirizine dissociates from H1-receptors with a half-life of 115

± 38 min. After single administration, levocetirizine shows a receptor occupancy of
90% at 4 hours and 57% at 24 hours.
Pharmacodynamic studies in healthy volunteers demonstrate that, at half the dose,
levocetirizine has comparable activity to cetirizine, both in the skin and in the nose.
The pharmacodynamic activity of levocetirizine has been studied in randomised,
controlled trials:
In a study comparing the effects of levocetirizine 5mg, desloratadine 5mg, and
placebo on histamine-induced wheal and flare, levocetirizine treatment resulted in
significantly decreased wheal and flare formation which was highest in the first 12
hours and lasted for 24 hours, (p<0.001) compared with placebo and desloratadine.
The onset of action of levocetirizine 5 mg in controlling pollen-induced symptoms
has been observed at 1 hour post drug intake in placebo controlled trials in the model
of the allergen challenge chamber.
In vitro studies (Boyden chambers and cell layers techniques) show that levocetirizine
inhibits eotaxin-induced eosinophil transendothelial migration through both dermal
and lung cells. A pharmacodynamic experimental study in vivo (skin chamber
technique) showed three main inhibitory effects of levocetirizine 5 mg in the first 6
hours of pollen-induced reaction, compared with placebo in 14 adult patients:
inhibition of VCAM-1 release, modulation of vascular permeability and a decrease in
eosinophil recruitment.
The efficacy and safety of levocetirizine has been demonstrated in several doubleblind, placebo controlled, clinical trials performed in adult patients suffering from
seasonal allergic rhinitis or perennial allergic rhinitis, or persistent allergic rhinitis.
Levocetirizine has been shown to significantly improve symptoms of allergic rhinitis,
including nasal obstruction in some studies.
A 6-month clinical study in 551 adult patients (including 276 levocetirizine-treated
patients) suffering from persistent allergic rhinitis (symptoms present 4 days a week
for at least 4 consecutive weeks) and sensitized to house dust mites and grass pollen
demonstrated that levocetirizine 5 mg was clinically and statistically significantly
more potent than placebo on the relief from the total symptom score of allergic
rhinitis throughout the whole duration of the study, without any tachyphylaxis.
During the whole duration of the study, levocetirizine significantly improved the
quality of life of the patients.
The paediatric safety and efficacy of levocetirizine tablets has been studied in two
placebo controlled clinical trials including patients aged 6 to 12 years and suffering
from seasonal and perennial allergic rhinitis, respectively. In both trials, levocetirizine
significantly improved symptoms and increased health-related quality of life.
In a placebo-controlled clinical trial including 166 patients suffering from chronic
idiopathic urticaria, 85 patients were treated with placebo and 81 patients with
levocetirizine 5mg once daily over six weeks. Treatment with levocetirizine resulted
in significant decrease in pruritus severity over the first week and over the total
treatment period as compared to placebo. Levocetirizine also resulted in a larger
improvement of health-related quality of life as assessed by the Dermatology Life
Quality Index as compared to placebo.
Chronic idiopathic urticaria was studied as a model for urticarial conditions. Since
histamine release is a causal factor in urticarial diseases, levocetirizine is expected to
be effective in providing symptomatic relief for other urticarial conditions, in addition
to chronic idiopathic urticaria.
Pharmacokinetic / pharmacodynamic relationship

The action on histamine-induced skin reactions is out of phase with the plasma
concentrations.
ECGs did not show relevant effects of levocetirizine on QT interval.

5.2

Pharmacokinetic properties
The pharmacokinetics of levocetirizine are linear with dose- and time-independent
with low inter-subject variability. The pharmacokinetic profile is the same when
given as the single enantiomer or when given as cetirizine. No chiral inversion occurs
during the process of absorption and elimination.
Absorption:
Levocetirizine is rapidly and extensively absorbed following oral administration.
Peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved
after two days. Peak concentrations are typically 270ng/ml and 308 ng/ml following a
single and a repeated 5 mg o.d. dose, respectively. The extent of absorption is doseindependent and is not altered by food, but the peak concentration is reduced and
delayed.
Distribution:
No tissue distribution data are available in humans, neither concerning the passage of
levocetirizine through the blood-brain-barrier. In rats and dogs, the highest tissue
levels are found in liver and kidneys, the lowest in the CNS compartment.
Levocetirizine is 90% bound to plasma proteins. The distribution of levocetirizine is
restrictive, as the volume of distribution is 0.4 l/kg.
Biotransformation
The extent of metabolism of levocetirizine in humans is less than 14% of the dose and
therefore differences resulting from genetic polymorphism or concomitant intake of
enzyme inhibitors are expected to be negligible. Metabolic pathways include aromatic
oxidation, N- and O- dealkylation and taurine conjugation. Dealkylation pathways are
primarily mediated by CYP 3A4 while aromatic oxidation involved multiple and/or
unidentified CYP isoforms. Levocetirizine had no effect on the activities of CYP
isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 at concentrations well above peak
concentrations achieved following a 5 mg oral dose.
Due to its low metabolism and absence of metabolic inhibition potential, the
interaction of levocetirizine with other substances, or vice-versa, is unlikely.
Elimination
The plasma half-life in adults is 7.9 ± 1.9 hours. The mean apparent total body
clearance is 0.63 ml/min/kg. The major route of excretion of levocetirizine and
metabolites is via urine, accounting for a mean of 85.4% of the dose. Excretion via
feces accounts for only 12.9% of the dose. Levocetirizine is excreted both by
glomerular filtration and active tubular secretion.

Renal impairment
The apparent body clearance of levocetirizine is correlated to the creatinine clearance.
It is therefore recommended to adjust the dosing intervals of levocetirizine, based on
creatinine clearance in patients with moderate and severe renal impairment. In anuric
end stage renal disease subjects, the total body clearance is decreased by
approximately 80% when compared to normal subjects. The amount of levocetirizine
removed during a standard 4-hour hemodialysis procedure was < 10%.

5.3

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies
of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential
or toxicity to reproduction.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Tablet core
Lactose monohydrate,
Cellulose microcrystalline (E460),
Colloidal anhydrous silica (E551),
Magnesium stearate (E572),
Film-coating
Opadry white (Y-1-7000) consisting of
Hypromellose (E464)
Titanium dioxide (E 171)
Macrogol 400

6.2

Incompatibilities
Not applicable

6.3

Shelf life
36 months

6.4

Special precautions for storage
No special requirements

6.5

Nature and contents of container
Aluminium – Aluminium blister pack
Pack size of 1, 2, 4, 5, 7, 10, 14, 15, 20, 21, 28, 30, 40, 50, 60, 70, 90, 100, 120’s per
pack.
Not all pack sizes may be marketed

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Brown & Burk UK Limited
5 Marryat Close, Hounslow West, Middlesex, TW4 5DQ, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 25298/0014

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/09/2012

10

DATE OF REVISION OF THE TEXT
21/09/2012

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Source: Medicines and Healthcare Products Regulatory Agency

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