SMPC

SUMMARY OF PRODUCT CHARACTERISTICS OF BILASTINE TABLETS 20 MG
1. Name of the medicinal product

Ilaxten 20 mg tablets
2. Qualitative and quantitative composition

Each tablet contains 20 mg of bilastine.
3. Pharmaceutical form
Tablet
 Oval biconvex scored white tablets (length 10 mm, width 5 mm).
 The score line is only to facilitate breaking for ease of swallowing and not to divide
into equal doses.
4. Clinical particulars
4.1 Therapeutic indications : Symptomatic treatment of allergic rhino-conjunctivitis (seasonal
and perennial) and urticaria.
Ilaxten is indicated in adults and adolescents (12 years of age and over).
4.2 Posology and method of administration

Posology: Adults and adolescents (12 years of age and over)
20 mg bilastine (1 tablet) once daily for the relief of symptoms of allergic rhinoconjunctivitis
(SAR and PAR) and urticaria
The tablet should be taken one hour before or two hours after intake of food or fruit juice
Special populations
 Elderly: No dosage adjustments are required in elderly patients (see sections 5.1 and
5.2).
 Renal impairment: No dosage adjustment is required in patients with renal
impairment. (see section 5.2).
 Hepatic impairment: There is no clinical experience in patients with hepatic
impairment. Since bilastine is not metabolized and renal clearance is its major
elimination route, hepatic impairment is not expected to increase systemic exposure
above the safety margin. Therefore, no dosage adjustment is required in patients with
hepatic impairment (see section 5.2).
 Paediatric population: There is no relevant use of bilastine in children aged 0 to 2
years for the indications of allergic rhino-conjunctivitis and urticaria. The safety and
efficacy in children below 12 years have not yet been established.
 Duration of treatment: For allergic rhinitis the treatment should be limited to the
period of exposure to allergens. For seasonal allergic rhinitis treatment could be
discontinued after the symptoms have resolved and reinitiated upon their
reappearance. In perennial allergic rhinitis continued treatment may be proposed to
the patients during the allergen exposure periods. For urticaria the duration of
treatment depends on the type, duration and course of the complaints.
Method of administration: Oral use.
The tablet is to be swallowed with water. It is recommended to take the daily dose in one
single intake.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use

Paediatric population
Efficacy and safety of bilastine in children under 12 years of age have not been established.
In patients with moderate or severe renal impairment coadministration of bilastine

with P-glycoprotein inhibitors, such as e.g, ketoconazole, erythromycin, cyclosporine,
ritonavir or diltiazem, may increase plasmatic levels of bilastine and therefore increase the
risk of adverse reactions of bilastine. Therefore, coadministration of bilastine and P-
glycoprotein inhibitors should be avoided in patients with moderate or severe renal
impairment.
4.5 Interaction with other medicinal products and other forms of interaction
 Interaction with food: Food significantly reduces the oral bioavailability of bilastine
by 30%.
 Interaction with grapefruit juice: concomitant intake of bilastine 20 mg and grapefruit

juice decreased bilastine bioavailability by 30%. This effect may also apply to other
fruit juices. The degree of bioavailability decrease may vary between producers and
fruits. The mechanism for this interaction is an inhibition of OATP1A2, an uptake
transporter for which bilastine is a substrate (see section 5.2). Medicinal products that
are substrates or inhibitors of OATP1A2, such as ritonavir or rifampicin, may
likewise have the potential to decrease plasma concentrations of bilastine.
 Interaction with ketoconazole or erythromycin: Concomitant intake of bilastine and

ketoconazole or erythromycin increased bilastine AUC 2-fold and Cmax 2-3 fold.
These changes can be explained by interaction with intestinal efflux transporters,
since bilastine is substrate for P-gp and not metabolised (see section 5.2). These
changes do not appear to affect the safety profile of bilastine and ketoconazole or
erythromycin, respectively. Other medicinal products that are substrates or inhibitors
of P-gp, such as cyclosporine, may likewise have the potential to increase plasma
concentrations of bilastine.
 Interaction with diltiazem: Concomitant intake of bilastine 20 mg and diltiazem 60

mg increased Cmax of bilastine by 50%. This effect can be explained by interaction
with intestinal efflux transporters (see section 5.2), and does not appear to affect the
safety profile of bilastine.
 Interaction with alcohol: The psychomotor performance after concomitant intake of
alcohol and 20 mg bilastine was similar to that observed after intake of alcohol and
placebo.
 Interaction with lorazepam: Concomitant intake of bilastine 20 mg and lorazepam 3

mg for 8 days did not potentiate the depressant CNS effects of lorazepam.
Interaction studies have only been performed in adults. Extent of interaction with other
medicinal products and other forms of interaction is expected to be similar in paediatric
population from 12 to 17 years of age.
4.6 Fertility, pregnancy and lactation

Pregnancy: There are no or limited amount of data from the use of bilastine in pregnant
women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive
toxicity, parturition or postnatal development (see section 5.3). As a precautionary measure, it
is preferable to avoid the use of Ilaxten during pregnancy.
Breast-feeding: The excretion of bilastine in milk has not been studied in humans. Available
pharmacokinetic data in animals have shown excretion of bilastine in milk. A decision on
whether to discontinue/abstain from Ilaxten therapy must be made taking into account the
benefit of breast-feeding for the child and the benefit of bilastine therapy for the mother.
Fertility: There are no or limited amount of clinical data. A study in rats did not indicate any
negative effect on fertility (see section 5.3).
4.7 Effects on ability to drive and use machines

A study performed to assess the effects of bilastine on the ability to drive demonstrated that
treatment with 20 mg did not affect the driving performance. However, patients should be
informed that very rarely some people experience drowsiness, which may affect their ability
to drive or use machines.
4.8 Undesirable effects

Summary of safety profile
 The incidence of adverse events in patients suffering from allergic rhinoconjunctivitis
or chronic idiopathic urticaria treated with 20 mg bilastine in clinical trials was
comparable with the incidence in patients receiving placebo (12.7% versus 12.8%).
 The phase II and III clinical trials performed during the clinical development included
2525 patients treated with different doses of bilastine, of which 1697 received
bilastine 20 mg. In these trials 1362 patients received placebo. The ADRs most
commonly reported by patients receiving 20 mg bilastine for the indication of allergic
rhinoconjunctivitis or chronic idiopathic urticaria were headache, somnolence,
dizziness, and fatigue. These adverse events occurred with a comparable frequency in
patients receiving placebo.
 ADRs at least possibly related to bilastine and reported in more than 0.1% of the
patients receiving 20 mg bilastine during the clinical development (N = 1697) are
tabulated below.
Frequencies are assigned as follows:

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
Description of selected adverse reactions

 The most frequently reported adverse reactions were two common (somnolence and
headache) and two uncommon (dizziness and fatigue). Their frequencies in bilastine
vs. placebo were 3.06 % vs. 2.86% for somnolence; 4.01% vs. 3.38% for headache;
0.83% vs. 0.59% for dizziness, and 0.83% vs. 1.32% for fatigue.
 Almost all the adverse reactions, included in the above table, were observed either in
patients treated with bilastine 20 mg or with placebo with a similar incidence.
 The information collected during the post-marketing surveillance has confirmed the
safety profile observed during the clinical development.
Paediatric population: During the clinical development the frequency, type and severity of
adverse reactions in adolescents (12 years to 17 years) were the same seen in adults. The
information collected in this population (adolescents) during the post-marketing surveillance
has confirmed clinical trial findings.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after

authorisation of the medicinal product is important. It allows continued monitoring of the
benefit/risk balance of the medicinal product. Healthcare professionals are asked to report
any suspected adverse reactions via the Yellow Card Scheme. Website:
www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or
Apple App Store.
4.9 Overdose
Information regarding acute overdose of bilastine is retrieved from the experience of clinical
trials conducted during the development and the post-marketing surveillance. In clinical
trials, after administration of bilastine at doses 10 to 11 times the therapeutic dose (220 mg as
single dose; or 200 mg/day for 7 days) to healthy volunteers frequency of treatment emergent
adverse events was two times higher than with placebo.
 The adverse reactions most frequently reported were dizziness, headache and nausea.
No serious adverse events and no significant prolongation in the QTc interval were
reported. The information collected in the post-marketing surveillance is consistent
with that reported in clinical trials.
 Critical evaluation of bilastine's multiple dose (100 mg x4 days) effect on ventricular

repolarization by a “thorough QT/QTc cross-over study” involving 30 healthy
volunteers did not show significant QTc prolongation.
 In the event of overdose symptomatic and supportive treatment is recommended.
 There is no known specific antidote to bilastine.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmaco therapeutic group: Antihistamines for systemic use, other antihistamines for
systemic use
 Bilastine is a non-sedating, long-acting histamine antagonist with selective peripheral

H1 receptor antagonist affinity and no affinity for muscarinic receptors.
 Bilastine inhibited histamine-induced wheal and flare skin reactions for 24 hours
following single doses.
 In clinical trials performed in adult and adolescent patients with allergic

rhinoconjunctivitis (seasonal and perennial), bilastine 20 mg, administered once daily
for 14-28 days, was effective in relieving symptoms such as sneezing, nasal
discharge, nasal itching, nasal congestion, ocular itching, tearing and ocular redness.
Bilastine effectively controlled symptoms for 24 hours.
 In two clinical trials performed in patients with chronic idiopathic urticaria, Bilastine
20 mg, administered once daily for 28 days was effective in relieving the itching
intensity and the number and size of wheals, as well as the patients discomfort due to
urticaria. Patients improved their sleep conditions and their quality of life.
 No clinically relevant prolongation of QTc interval or any other cardiovascular effect

has been observed in the clinical trials performed with Bilastine, even at doses of 200
mg daily (10 times the clinical dose) for 7 days in 9 subjects, or even when
coadministered with P-gp inhibitors, such as ketoconazole (24 subjects) and
erythromycin (24 subjects). Additionally a thorough QT study including 30 volunteers
has been performed.
 In controlled clinical trials at the recommended dose of 20 mg once daily, the CNS
safety profile of bilastine was similar to placebo and the incidence of somnolence was
not statistically different from placebo. Bilastine at doses of up to 40 mg q.d. did not
affect psychomotor performance in clinical trials and did not affect driving
performance in a standard driving test.
 Elderly patients (≥ 65 years) included in phase II and III studies showed no difference
in efficacy or safety with respect to younger patients. A post-authorization study in
146 elderly patients showed no differences in the safety profile with respect to the
adult population.
Adolescents (12 years to 17 years) were included in the clinical development. 128
adolescents received bilastine during the clinical studies (81 in double blind studies in
allergic rhino-conjunctivitis). A further 116 adolescent subjects were randomised to active
comparators or placebo. No differences in efficacy and safety between adults and adolescents
were seen.
The European Medicines Agency has deferred the obligation to submit the results of studies
with Ilaxten in one subset of the paediatric population in the treatment of allergic rhino-
conjunctivitis and the treatment of urticaria (see section 4.2 for information on paediatric
use).
5.2 Pharmacokinetic properties
 Absorption: Bilastine is rapidly absorbed after oral administration with a time to

maximum plasma concentration of around 1.3 hours. No accumulation was observed.
The mean value of bilastine oral bioavailability is 61%.
 Distribution: In vitro and in vivo studies have shown that bilastine is a substrate of
Pgp (see section 4.5 “Interaction with ketoconazole, erythromycin and diltiazem”) and
OATP (see section 4.5 “Interaction with grapefruit juice”). Bilastine does not appear
to be a substrate of the transporter BCRP or renal transporters OCT2, OAT1 and
OAT3. Based on in vitro studies, bilastine is not expected to inhibit the following
transporters in the systemic circulation: P-gp, MRP2, BCRP, BSEP, OATP1B1,
OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and NTCP, since only mild
inhibition was detected for P-gp, OATP2B1 and OCT1, with an estimated IC50 ≥ 300
µM, much higher than the calculated clinical plasma Cmax and therefore these
interactions will not be clinically relevant. However, based on these results inhibition
by bilastine of transporters present in the intestinal mucosa, e.g. P-gp, cannot be
excluded.
 At therapeutic doses bilastine is 84-90% bound to plasma proteins.
 Biotransformation: Bilastine did not induce or inhibit activity of CYP450 isoenzymes

in in vitro studies.
 Elimination: In a mass balance study performed in healthy volunteers, after

administration of a single dose of 20 mg 14C-bilastine, almost 95% of the
administered dose was recovered in urine (28.3%) and faeces (66.5%) as unchanged
bilastine, confirming that bilastine is not significantly metabolized in humans. The
mean elimination half-life calculated in healthy volunteers was 14.5 h.
 Linearity: Bilastine presents linear pharmacokinetics in the dose range studied (5 to

220 mg), with a low interindividual variability.
 Renal impairment: In a study in subjects with renal impairment the mean (SD) AUC0-
∞ increased from 737.4 (±260.8) ngxhr/ml in subjects without impairment (GFR: > 80
ml/min/1.73 m2) to: 967.4 (±140.2) ngxhr/ml in subjects with mild impairment (GFR:
50-80 ml/min/1.73 m2), 1384.2 (±263.23) ngxhr/ml in subjects with moderate
impairment (GFR: 30 - <50 ml/min/1.73 m2), and 1708.5 (±699.0) ngxhr/ml in
subjects with severe impairment (GFR: < 30 ml/min/1.73 m2). Mean (SD) half-life of
bilastine was 9.3 h (± 2.8) in subjects without impairment, 15.1 h (± 7.7) in subjects
with mild impairment, 10.5 h (± 2.3) in subjects with moderate impairment and 18.4 h
(± 11.4) in subjects with severe impairment. Urinary excretion of bilastine was
essentially complete after 48 -72 h in all subjects. These pharmacokinetic changes are
not expected to have a clinically relevant influence on the safety of bilastine, since
bilastine plasma levels in patients with renal impairment are still within the safety
range of bilastine.
 Hepatic impairment: There are no pharmacokinetic data in subjects with hepatic

impairment. Bilastine is not metabolized in human. Since the results of the renal
impairment study indicate renal elimination to be a major contributor in the
elimination, biliary excretion is expected to be only marginally involved in the
elimination of bilastine. Changes in liver function are not expected to have a clinically
relevant influence on bilastine pharmacokinetics.
 Elderly: Only limited pharmacokinetic data are available in subjects older than 65
years. No statistically significant differences have been observed with regard to PK of
bilastine in elderly aged over 65 years compared to adult population aged between 18
and 35 years.
 Paediatric population: No pharmacokinetic data are available in adolescents (12 years

to 17 years) as the extrapolation from adult data was deemed appropriate for this
product.
5.3 Preclinical safety data
 Non-clinical data with bilastine reveal no special hazard for humans based on
conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and
carcinogenic potential.
 In reproduction toxicity studies effects of bilastine on the foetus (pre-and post-

implantation loss in rats and incomplete ossification of cranial bones, sternebrae and
limbs in rabbits) were only observed at maternal toxic doses. The exposure levels at
the NOAELs are sufficiently in excess (> 30 fold) to the human exposure at the
recommended therapeutic dose.
 In a lactation study, bilastine was identified in the milk of nursing rats administered a
single oral dose (20 mg/kg). Concentrations of bilastine in milk were about half of
those in maternal plasma. The relevance of those results for humans is unknown.
 In a fertility study in rats, bilastine administered orally up to 1000 mg/kg/day did not
induce any effect on female and male reproductive organs. Mating, fertility and
pregnancy indices were not affected.
 As seen in a distribution study in rats with determination of drug concentrations by

autoradiography, bilastine does not accumulate in the CNS.
6. Pharmaceutical particulars
6.1 List of excipients

 Microcrystalline Cellulose
 Sodium Starch glycolate type A (derived from potato)
 Colloidal anhydrous Silica
 Magnesium Stearate
6.2 Incompatibilities: Not applicable.
6.3 Shelf life: 5 years
6.4 Special precautions for storage This medicinal product does not require any special
storage conditions.
6.5 Nature and contents of container:
 The medicinal product is packaged in a blister, consisting of two parts:
 laminate, consisting of oriented polyamide (outer side of laminate), aluminium and

PVC (inner side of laminate)
 Aluminium foil: The aluminium foil is thermosealed with a heat-seal lacquer (PVC-
PVAC copolymer and resins of butylmethacrylate) to the laminate after molding and
filling of the tablets.
 Each blister contains 10 tablets. The blisters are packaged in cardboard boxes.
 Pack sizes: 10, 20, 30, 40 or 50 tablets. Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local
requirements.
SUMMARY OF PRODUCT CHARACTERISTICS OF CETIRZINE TABLETS ODT
10MG
1. Introduction
McNeil submitted this 505(b) (1) NDA for a new non-prescription orally disintegrating tablet
(ODT) formulation for cetirizine HCl 10 mg The product temporarily relieves these
symptoms due to hay fever or other upper respiratory allergies:
• Runny nose
• Sneezing
• Itchy, watery eyes
• Itching of the nose or throat
Cetirizine HCl is metabolite of hydroxyzine. It is a second generation antihistamine (selective

inhibitor of peripheral H1 receptors) which is currently marketed as a nonprescription product
for adults and children 2 years and older for this indication in several formulations (5 mg and
10 mg tablets and chewable tablets and 1 mg/mL syrup). This new ODT formulation is
intended to provide an alternative dosing option for consumers that does not necessitate
swallowing a tablet and that allows for consumption with or without water.
Cetirizine HCl is also approved OTC for the temporary relief of the itching due to hives in
adults and children ages 6 years and older. The applicant does not seek this indication for the
orally disintegrating tablet. The Agency has approved second generation antihistamines for
each of the two nonprescription indications as separate products (either labeled for upper
respiratory allergies or for itching due to hives) because of concerns over the complexity of
the resultant Drug Facts if all of the information for each indication were to be crammed into
one product label.
Cetirizine HCl has not been labeled for children < 2 years of age as a nonprescription product
because of concern that caregivers may not be able to properly diagnose allergic rhinitis in
younger children. Also, conventional medical thinking is that seasonal allergic rhinitis (such
as hay fever) does not actually exist in children until they have had at least two seasons to be
exposed and sensitized to an allergen.
2. Background
Cetirizine HCl was approved for prescription use in 1995 for seasonal allergic rhinitis,
perennial allergic rhinitis, and chronic idiopathic urticaria. It was approved for non-
prescription use in 2007 for the upper respiratory allergies and itching due to hives
indications. It has been marketed internationally for two decades and is available worldwide
for nonprescription use in children down to the age of two years.
For this NDA, the sponsor sought approval based upon the demonstration of bioequivalence
to a reference drug rather than providing clinical efficacy and safety studies on the new
formulation. During the drug development process, the agency told the sponsor that this
would be an acceptable approach if bioequivalence was actually demonstrated. The sponsor
provided a summary of postmarketing safety data starting from January 16, 2007 which was
the end date of the four-month safety update submitted in support of the OTC switch of
cetirizine HCl in 2007.
3. Cetirizine HCl ODT formulation

The drug substance, cetirizine dihydrochloride, is commonly referred to as cetirizine
hydrochloride or cetirizine HCl. The molecular formula is C21H25ClN2O3.2HCl. The
molecular weight is 461.82. Cetirizine HCl has three ionizable moieties resulting in pKa
values of 2.2, 2.9 and 8.0. At physiological pH, it predominantly exists as a zwitterion or an
anion. Cetirizine HCl is a white or almost white powder that is freely soluble in water,
practically insoluble in acetone and in methylene chloride. It has a pH of 1.2 to 1.8 and a
relatively high melting range of 214°C to 221°C. The analyses of cetirizine powder did not
show any change in crystalline form or any tendency to exhibit polymorphism.
4. Formulation
Cetirizine HCl is a bitter drug substance that requires flavour when used in a dosage form that
disintegrates in the oral cavity. Therefore, an ODT formulation was developed that
disintegrates rapidly and passes a pleasant taste and mouth-feel. The 10 mg cetirizine ODT
formulation is provided as a citrus flavored, white to off-white, round, flat-faced, beveled
edge tablet, which weighs 325 mg. The drug product will be debossed with “Z10” on one side
of the tablet. The ODT consists of cetirizine HCl (a form of the drug substance) incorporated
in an immediate-release tablet. The ODT formulation will be packaged in 6 counts child-
resistant peelable blister package that will be commercially distributed in cartons.
Reference to quality
Component
standard
Cetirizine HCL IH
Mannitol USP
Microcrystalline cellulose NF
Sucrose NF
Crospovidone NF
Colloidal silicon dioxide NF
Sodium bicarbonate USP
Anhydrous citric acid USP
Citrus flavour -
Magnesium stearate NF
5. Analytical Section
Bioanalytical Method Validation (Final-May 2001)] of not exceeding 15% (20% for the
lowest Quality Control Samples (QCSs)) for precision and accuracy. Study samples were
analyzed in runs containing calibrators and QC samples, as recommended in the FDA
guidance. The bioanalytical laboratory at determined the concentrations of cetirizine in
human plasma (K3 EDTA) by HPLC-MS/MS detection using a validated method. The limit
of reliable quantification was 0.5 mg/mL. The dynamic calibration range was 0.5 to 400
ng/mL and required a 50 μL human plasma aliquot containing K3 EDTA. Interday precision
and accuracy of the method were evaluated using the results of the QCSs assayed daily
alongside the clinical samples. QCSs accuracy was between 98% and 100.4% of the nominal
concentrations. No interfering peaks were observed showing selectivity/specificity of the
method. Overall recovery of the QCSs was 93.3%. Following table summarizes the details of
the method validation
6.Clinical Pharmacology
Previous studies in adults have demonstrated that cetirizine undergoes rapid absorption where
the maximum plasma concentration was reached at ~1 hour following oral administration of
tablets, chewable tablets, and syrup. Comparable bioavailability was found between the tablet
and syrup dosage forms. No accumulation was observed following multiple dosing of
cetirizine HCI (10 mg tablets once daily for 10 days) in healthy subjects. Cetirizine
pharmacokinetics is linear for oral doses ranging from 5 to 60 mg. The mean plasma protein
binding of cetirizine hydrochloride is 93%, independent of concentration in the range of 25 to
1000 ng/mL, which includes the therapeutic plasma concentrations. The mean elimination
half-life is 8.3 hours and the apparent total body clearance for cetirizine is ~53 mL/min
following oral administration of cetirizine in healthy subjects. The plasma PK parameters of
cetirizine obtained in the bioequivalence study submitted with this supplement are not
different from that known
previously (Zyrtec labels).
6.1 General Biopharmaceutics

The bioequivalence of Zyrtec 10 mg ODT with the Zyrtec 10 mg reference tablet was
demonstrated with or without water under fasted conditions by the observation that the 90%
CIs for the ratios of the geometric means for AUCLAST, AUCINF and CMAX were within
the limits for bioequivalence (80-125%) for cetirizine ODT
A significant food effect was observed with the cetirizine ODT formulation for CMAX,
but not for AUC
7.Nonclinical Pharmacology/Toxicology
I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
no outstanding pharmacology/toxicology issues that preclude approval.
8.Clinical Pharmacology/Biopharmaceutics
To support this application, the sponsor submitted one combined bioequivalence and foo
effect study (CETALY1003). This was a two-part, open-label, single dose, four-way
randomized and five-way crossover study in 28 healthy male and female adults. The
reference listed drug (RLD) for this study was the U.S. currently approved cetirizine 10 mg
tablet taken with 240 mL of water.
 Part I:
 Treatment A: A single 10 mg dose of cetirizine ODT with 240 mL water
 Treatment B: A single 10 mg dose of cetirizine ODT without water
 Treatment C: (U.S. marketed product): A single 10 mg dose of the currently marketed
US cetirizine tablet (ZYRTEC®) with 240 mL water
 Treatment D (Canadian marketed product): a single 10 mg dose of the currently
marketed Canadian cetirizine tablet (REACTINE®) with 240 mL water, All study subjects
received Treatment E under fed condition in Period 5. (This was Study PartII).
 Part II:
 Treatment E: A single 10 mg dose of cetirizine ODT administered approximately 30
minutes after the start of a high-fat breakfast with 240 mL water. Each period was
separated by a 4 – 7 day washout.
9.Clinical Microbiology: Not applicable.
10 Clinical/Statistical-Efficacy
No clinical efficacy studies were conducted for this NDA. Efficacy was supported by clinical
pharmacology study CETALY1003, described above, which demonstrated bioequivalence to
the RLD, cetirizine HCl 10 mg tablets (NDA 19-835/S-022).
The clinical team agreed that the changes in the clinical pharmacology profile when taken
with food (which were not seen in the AUC) were not likely to impact the overall efficacy of
cetirizine, a once-daily use product, and so no admonitions against using with food were
recommended for the labeling. I think that this is acceptable.
11. Safety
 Dr. Raffaelli performed an excellent, detailed review of the safety data for this
Pregnancy Category B drug. This section summarizes his findings but, for more
detail, refer to his review.
 McNeil estimated that during the two years comprising the submitted postmarketing
safety database, there were approximately doses of cetirizine consumed, representing
about 36 million patient-years of use. Approximately one third of cetirizine use was in
the United States.
 Safety was supported by the demonstration of bioequivalence of the new ODT to the
RLD.
Additionally, the sponsor provided safety data from the bioequivalence study
CETALY1003 and postmarketing safety data from the following sources: Safety data
from McNeil’s database accumulated since the most recent safety update report for
Zyrtec® sNDA 19-835 (01/17/07 – 01/16/09)
 There were 4778 case reports in this database of which 52 were deaths. Dr. Raffaelli
found that most deaths were of unknown cause or associated with confounding
factors. Refer to page 34 of his review. In two of the deaths cetirizine may or may not
have played a role. One patient, a 23-year-old male, took cetirizine, clemastine, and
alcohol and died after an 8-story fall. Cetirizine and clemastine are labeled not to be
taken with alcohol because each of these three agents has sedating properties. The
second patient had several miscarriages while taking cetirizine, a few of which were
linked to lethal chromosomal abnormalities; however, since miscarriage is common
on or off medication, it is hard to know if there was any relationship to the drug.
Among the serious reports, those most commonly reported were:

 Drug exposure during pregnancy (2.1%)
 Convulsion (2%): Many of these subjects had a history of an underlying seizure
disorder.
 Hypersensitivity (1.7%)
 Somnolence (1.7%)
 Death (1.7%)
Regarding hypersensitivity, the OTC cetirizine product labels already have a warning not to
use if the consumer has had a previous allergic reaction to cetirizine or hydroxyzine. The
labels also have the standard OTC Drug Facts pregnancy warning to ask a health professional
before use (21 CFR 201.63). Cetirizine product labels state that drowsiness may occur and
that alcohol and sedatives should be avoided. The relationship of cetirizine with convulsions,
cardiac arrhythmias, and thrombocytopenia, has been explored in many reviews, including at
the time of the prescription to OTC switch, when new NDAs have been reviewed, and also in
2001 for a response to a Citizen Petition requesting that 3 nonsedating antihistamines
(including cetirizine) be switched from prescription to OTC. Convulsions are common
medical occurrences with a high background rate and the reviews, including Dr. Raffaelli’s,
have been unable to draw a clear association between cetirizine and convulsions. Prescription
cetirizine labeling does include the adverse event terms “convulsion,” “thrombocytopenia,”
and “tachycardia” but, even if there is a possible association with these events, this
association has been considered too rare to appear on the OTC labeling.
 FDA Adverse Event Reporting System (AERS) data (01/01/01 – 12/31/08)

No new safety signals for cetirizine were noted in this database, which substantially
overlapped McNeil’s database.
 World Health Organization (WHO) database (01/01/07 – 05-20/09)
No new safety signals were noted.
 American Association of Poison Control Centers (AAPCC) (01/01/07 – 06/15/09)
Division Director Review
safety data on cetirizine continue to support OTC marketing of this drug and support the
approval of this new NDA. The safety database does not suggest the need to change the
warnings as they exist currently on the OTC cetirizine products.
12. Pediatrics
The sponsor requested a waiver of pediatric studies for children < 6 years of age. DNCE and
the PeRC agreed with the regulatory rationale for this waiver, the reasons being:
 Seasonal allergic rhinitis does not exist in children < 2 years of age. (Further, FDA
has previously determined that dosing of antihistamines for this age group should
remain via prescription, independent of the formulation. This would be, for example,
because of the difficulty nonprofessional caregivers could have in making an
appropriate allergic rhinitis diagnosis in these young children.)
 For children 2 - < 6 years of age, the product fails to represent a meaningful
therapeutic benefit over existing therapies and is unlikely to be used in a substantial
number of these children
 For children 6 – 17 years old, the product is appropriately labeled based on studies
and extrapolation
13. Other Relevant Regulatory Issues

There are no unresolved relevant regulatory issues associated with this NDA.
14. Labeling
Trade Name: The trade name for this ODT product will be Zyrtec® Allergy. This is the name
which DMEPA found suitable in their review dated 06/10/10. (There was communication
with the sponsor over the trade name, which, by contrast, they thought was Zyrtec®.) The
ODT is a new dosage form for an already approved product line with the trade name
appearing on the Principal Display Panel as "Zyrtec®" and with the term "Allergy" appearing
as a modifier. Specifically, there are many approved OTC Zyrtec® products with different
dosage forms (liquid, tablets and chewable tablets) and strengths (5 mg and 10 mg) in the
market with "Zyrtec®" appearing as the trade name and "Allergy" appearing as a modifier (in
that the two words are of different font specifications/color and do not necessarily appear
right next to each other).
To avoid consumer confusion, we plan to send a supplement request letter to the sponsor to
give the sponsor time to reconfigure the labels across the entire product line to properly
account for the two-word trade name, which should apply to all OTC Zyrtec® products
labeled to treat allergy. It is important to note that the sponsor did not request the “itching due
to hives” indication for the ODT formulation, but an analogous trade name situation exists for
the Zyrtec® Hives Relief products.
Other Labeling Issues:
 After the sponsor made several modifications to their proposed labeling, which FDA
requested and which are discussed in the labeling reviews, the labeling reviewers
recommended that the labeling could be approved in their review dated 08/12/10.
There are no outstanding labelling issues.
15. Decision/Action/Risk Benefit Assessment

Regulatory Action: Approval
Risk Benefit Assessment
Division Director Review

The efficacy and safety for this product were demonstrated based upon the demonstration of
bioequivalence with the RLD in study CETALY1003 and the absence of new safety signals
in the postmarketing safety data. The data support that this new cetirizine ODT product will
be safe and effective for the OTC consumer for the temporary relief these symptoms due to
hayfever or other upper respiratory allergies:
• Runny nose
• Sneezing
• Itchy, watery eyes
• Itching of the nose or throat
There are no postmarketing commitments needed. There are no pediatric study requirements
SUMMARY OF PRODUCT CHARACTERISTICS OF LEVOCETERZINE SYRUP

Xyzal 0.5 mg/ml oral solution

1 ml of oral solution contains 0.5 mg levocetirizine dihydrochloride.
Excipients with known effect

0.675 mg methyl parahydroxybenzoate/ml
0.075 mg propyl parahydroxybenzoate/ml
0.4 g maltitol liquid/ml
Oral solution.
Clear and colourless solution.
4.1 Therapeutic indications
Xyzal 0.5 mg/ml oral solution is indicated for symptomatic treatment of allergic rhinitis
(including persistent allergic rhinitis) and urticaria in adults and children aged 2 years and
above.

 Posology
Adults and adolescents 12 years and above:
The daily recommended dose is 5 mg (10 ml of solution).
 Elderly
Adjustment of the dose is recommended in elderly patients with moderate to severe renal
impairment (see Renal impairment below).
 Renal impairment
The dosing intervals must be individualised 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:
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.
 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 Renal
impairment above).
 Paediatric population
Children aged 6 to 12 years:
The daily recommended dose is 5 mg (10 ml of solution).
 Children aged 2 to 6 years:

The daily recommended dose is 2.5 mg to be administered in 2 intakes of 1.25 mg (2.5 ml of
solution twice daily).
Even if some clinical data are available in children aged 6 months to 12 years (see section
4.8, 5.1 and 5.2), these data are not sufficient to support the administration of levocetirizine to
infants and toddlers aged less than 2 years
 Method of administration
An oral syringe is included in the package. The appropriate volume of oral solution should be
measured with the oral syringe, and poured in a spoon or in a glass of water. The oral solution
must be taken orally immediately after dilution, and may be taken with or without food.
 Duration of use:
Intermittent allergic rhinitis (symptoms experienced for less than four days a week or for less
than four weeks a year) 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 experienced for more than four
days a week or for more than four weeks a year), continuous therapy can be proposed to the
patient during the period of exposure to allergens.
There is clinical experience with the use of levocetirizine for treatment periods of at least 6
months. In chronic urticaria and chronic allergic rhinitis, there is clinical experience of use of
cetirizine (racemate) for up to one year.
Hypersensitivity to the active substance, to cetirizine, to hydroxyzine, to any other piperazine
derivatives or to any of the other excipients
Severe renal impairment at less than 10 ml/min creatinine clearance.
Precaution is recommended with concurrent intake of alcohol
 Xyzal contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which

may cause allergic reactions (possibly delayed).
 Caution should be taken in patients with epilepsy and patients at risk of convulsion as
levocetirizine may cause seizure aggravation.
 Xyzal contains maltitol liquid
 Patients with rare hereditary problems of fructose intolerance should not take this
medicine.
 Caution should be taken in patients with predisposing factors of urinary retention (e.g.
spinal cord lesion, prostatic hyperplasia) as levocetirizine may increase the risk of
urinary retention.
 Response to allergy skin tests are inhibited by antihistamines and a wash-out period
(of 3 days) is required before performing them.
 Pruritus may occur when levocetirizine is stopped even if those symptoms were not
present before treatment initiation. The symptoms may resolve spontaneously. In
some cases, the symptoms may be intense and may require treatment to be restarted.
The symptoms should resolve when the treatment is restarted.
Even if some clinical data are available in children aged 6 months to 12 years (see sections
4.8, 5.1 and 5.2), these data are not sufficient to support the administration of levocetirizine to
infants and toddlers aged less than 2 years.
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 antipyrine, azithromycin, cimetidine,
diazepam, erythromycin, glipizide, ketoconazole and pseudoephedrine). 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.
 In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily),
the extent of exposure to cetirizine was increased by about 40% while the disposition
of ritonavir was slightly altered (-11%) further to 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 concurrent administration of cetirizine or levocetirizine and

alcohol or other CNS depressants may cause additional reductions in alertness and
impairment of performance.

 Pregnancy
There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of
levocetirizine in pregnant women. However, for cetirizine, the racemate of levocetirizine, a
large amount of data (more than 1000 pregnancy outcomes) on pregnant women indicate no
malformative or feto/neonatal toxicity. Animal studies do not indicate direct or indirect
harmful effects with respect to pregnancy, embryo/fetal development, parturition or postnatal
development (see section 5.3).
The use of levocetirizine may be considered during pregnancy, if necessary.
 Breast-feeding
Cetirizine, the racemate of levocetirizine, has been shown to be excreted in human.
Therefore, the excretion of levocetirizine in human milk is likely. Adverse reactions
associated with levocetirizine may be observed in breastfed infants. Therefore, caution should
be exercised when prescribing levocetirizine to lactating women.
 Fertility
For levocetirizine no clinical data are available.

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.

Clinical studies
Adults and adolescents above 12 years of age
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 dropout rate due to adverse events was 1.0% (9/935) with
levocetirizine 5 mg and 1.8% (14/771) with placebo.
In two placebo-controlled studies in paediatric patients aged 6-11 months and aged 1 year to
less than 6 years, 159 subjects were exposed to levocetirizine at the dose of 1.25 mg daily for
2 weeks and 1.25 mg twice daily respectively. The following incidence of adverse drug
reactions was reported at rates of 1% or greater under levocetirizine or placebo.
ost-marketing experience
Adverse reactions from post-marketing experience are per System Organ Class and per
frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to
<1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare
(<1/10,000), not known (cannot be estimated from the available data).
• Immune system disorders:
Not known: hypersensitivity including anaphylaxis
• Metabolism and nutrition disorders:
Not known: increased appetite
• Psychiatric disorders:
Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation,

nightmare
• Nervous system disorders:
Not known: convulsion, paraesthesia, dizziness, syncope, tremor, dysgeusia
• Ear and labyrinth disorders:
Not known: vertigo
• Eyes disorders:
Not known: visual disturbances, blurred vision
• Cardiac disorders:
Not known: palpitations, tachycardia
• Respiratory, thoracic and mediastinal disorders:
Not known: dyspnoea
• Gastrointestinal disorders:
Not known: nausea, vomiting, diarrhoea
• Hepatobiliary disorders:
Not known: hepatitis
• Renal and urinary disorders:
Not known: dysuria, urinary retention
• Skin and subcutaneous tissue disorders:
Not known: angioneurotic oedema, fixed drug eruption, pruritus, rash, urticaria
• Musculoskeletal, connective tissues, and bone disorders:
Not known: myalgia, arthralgia
• General disorders and administration site conditions:
Not known: oedema
• Investigations:
Not known: weight increased, abnormal liver function tests
Methyl parahydroxybenzoate and propyl parahydroxybenzoate may cause allergic reactions

(possibly delayed).
Description of selected adverse reactions
After levocetirizine discontinuation, pruritus has been reported.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions via:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google

Play or Apple App Store.
4.9 Overdose
Symptoms
Symptoms of overdose may include drowsiness in adults. In children, agitation and

restlessness may initially occur, followed by drowsiness.
Management of overdoses
There is no known specific antidote to levocetirizine.
Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage

may be considered shortly after ingestion of the drug. Levocetirizine is not effectively
removed by haemodialysis.
Pharmacotherapeutic group: Antihistamines for systemic use, piperazine derivatives,
ATC code: R06A E09.
Mechanism of action
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.
Pharmacodynamic effects
The pharmacodynamic activity of levocetirizine has been studied in randomised, controlled

trials:
In a study comparing the effects of levocetirizine 5 mg, desloratadine 5 mg, 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.
Clinical efficacy and safety
The efficacy and safety of levocetirizine has been demonstrated in several double-blind,
placebo controlled, clinical trials performed in adult patients suffering from seasonal allergic
rhinitis, 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.
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 5 mg 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.
ECGs did not show relevant effects of levocetirizine on QT interval.
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 children below the age of 6 years, clinical safety has been established from several short-
or long -term therapeutic studies:
- one clinical trial in which 29 children 2 to 6 years of age with allergic rhinitis were treated
with levocetirizine 1.25 mg twice daily for 4 weeks
- one clinical trial in which 114 children 1 to 5 years of age with allergic rhinitis or chronic
idiopathic urticaria were treated with levocetirizine 1.25 mg twice daily for 2 weeks
- one clinical trial in which 45 children 6 to 11 months of age with allergic rhinitis or chronic
idiopathic urticaria were treated with levocetirizine 1.25 mg once daily for 2 weeks
- one long-term (18 months) clinical trial in 255 levocetirizine - treated atopic subjects aged
12 to 24 months at inclusion.
The safety profile was similar to that seen in the short-term studies conducted in children 1 to
5 years of age.

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. In adults,

peak plasma concentrations are achieved 0.9 h after dosing. Steady state is achieved after two
days. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a
repeated 5 mg o.d. dose, respectively. The extent of absorption is dose-independent 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.
In humans, 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 half-life is shorter in small children.
The mean apparent total body clearance in adults 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 faeces accounts for only 12.9% of the dose. Levocetirizine is excreted
both by glomerular filtration and active tubular secretion.
Special population
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%.
Data from a paediatric pharmacokinetic study with oral administration of a single dose of 5
mg levocetirizine in 14 children age 6 to 11 years with body weight ranging between 20 and
40 kg show that Cmax and AUC values are about 2-fold greater than that reported in healthy
adult subjects in a cross-study comparison. The mean Cmax was 450 ng/ml, occurring at a
mean time of 1.2 hours, weight-normalized, total body clearance was 30% greater, and the
elimination half-life 24% shorter in this paediatric population than in adults. Dedicated
pharmacokinetic studies have not been conducted in paediatric patients younger than 6 years
of age. A retrospective population pharmacokinetic analysis was conducted in 323 subjects
(181 children 1 to 5 years of age, 18 children 6 to 11 years of age, and 124 adults 18 to 55
years of age) who received single or multiple doses of levocetirizine ranging from 1.25 mg to
30 mg. Data generated from this analysis indicated that administration of 1.25 mg once daily
to children 6 months to 5 years of age is expected to result in plasma concentrations similar to
those of adults receiving 5 mg once daily.
Elderly
Limited pharmacokinetic data are available in elderly subjects. Following once daily repeat
oral administration of 30 mg levocetirizine for 6 days in 9 elderly subjects (65–74 years of
age), the total body clearance was approximately 33% lower compared to that in younger
adults. The disposition of racemic cetirizine has been shown to be dependent on renal
function rather than on age. This finding would also be applicable for levocetirizine, as
levocetirizine and cetirizine are both predominantly excreted in urine. Therefore, the
levocetirizine dose should be adjusted in accordance with renal function in elderly patients.
Gender
Pharmacokinetic results for 77 patients (40 men, 37 women) were evaluated for potential
effect of gender. The half-life was slightly shorter in women (7.08 ± 1.72 hours) than in men
(8.62 ± 1.84 hours); however, the body weight-adjusted oral clearance in women (0.67 ± 0.16
ml/min/kg) appears to be comparable to that in men (0.59 ± 0.12 ml/min/kg). The same daily
doses and dosing intervals are applicable for men and women with normal renal function.
Race
The effect of race on levocetirizine has not been studied. As levocetirizine is primarily
renally excreted, and there are no important racial differences in creatinine clearance,
pharmacokinetic characteristics of levocetirizine are not expected to be different across races.
No race-related differences in the kinetics of racemic cetirizine have been observed.
Hepatic impairment
The pharmacokinetics of levocetirizine in hepatically impaired subjects have not been tested.
Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given
10 or 20 mg of the racemic compound cetirizine as a single dose had a 50% increase in half
life along with a 40% decrease in clearance compared to healthy subjects.
Pharmacokinetic / pharmacodynamic relationship
The action on histamine-induced skin reactions is out of phase with the plasma
concentrations.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
Sodium acetate trihydrate (for pH adjustment)
Glacial acetic acid (for pH adjustment)
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Glycerol 85%
Maltitol liquid (E965)
Saccharin sodium
Tutti frutti flavor contains:
triacetin (E1518)
benzaldehyde
orange oil
vanillin
ethyl butyrate
orange oil concentrated
isoamyl acetate
allyl hexanoate
gamma-undecalactone
citral
geraniol
citronellol
alpha tocopherol (E307)
Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life

2 years
After first opening: 3 months
6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container

Type III amber glass bottle closed with a white polypropylene child-resistant closure in a
cardboard box also containing a 10 ml oral syringe graduated at 0.25 ml (polyethylene,
polystyrene).
Pack sizes: 75 ml, 150 ml and 200 ml.
Not all pack sizes may be marketed.

No special requirements.
SUMMARY OF PRODUCT CHARACTERISTICS OF ALLOPURINOL TABLETS
100MG
ALLOPURINOL TABLETS BP 100mg

Each tablet contains 100mg Allopurinol PhEur
Excipient with known effect: Each tablet contains 130.66 mg of lactose monohydrate
For the full list of excipients, see section 6.1.
White uncoated tablets
White, circular, biconvex, uncoated tablets impressed “C” and the identifying letters “AD” on
either side of a central division line on one face.
Allopurinol and its major metabolite, oxipurinol, act by inhibiting the enzyme xanthine
oxidase, which catalyses the end stage of the metabolism of purines to uric acid. Allopurinol
and its metabolites are excreted by the kidney but the renal handling is such that allopurinol
has a plasma half-life of about 1 hour whereas that of oxipurinol exceeds 18 hours. Thus
therapeutic effect may be achieved by once-a-day dosage.
1) Prophylactic management of gout and other conditions of excess body urate: Allopurinol is
used to reduce excessive urate levels (serum is theoretically saturated with urate at a
concentration between 0.38-0.42mmol/l). The higher levels seen in practice may be
accounted for by: a) the formation of saturated solutions; b) protein binding of urate. Excess
body urate may be indicated by hyperuricaemia and/or hyperuricosuria. It may lead to
disposition of urate in the tissues or it may be present with no obvious signs or symptoms.
The main clinical manifestations of urate disposition are gouty arthritis, skin tophi and/or
renal involvement: Excess body urate is frequently of idiopathic origin but may also be found
in association with the following other conditions: neoplastic disease and its treatment;
certain enzyme disorders which lead to overproduction of urate and involving: hypoxanthine
guanine phosphoribosyl transferase, such as Lesch-Nyhanb syndrome, glucose-6-
phosphatase, as in von Gierke's disease or fosforibosylpyrofosfaatsynthetase; renal failure;
renal calculus formation; diuretic therapy and psoriasis.
2) Calcium renal lithiasis: Allopurinol is of benefit in the prophylaxis and treatment of

calcium renal lithiasis in patients with raised serum or urinary uric acid.
Posology
Initiation of therapy: In the initial stages of treatment with allopurinol, as with uricosuric
agents, an acute attack of gouty arthritis may be precipitated. It is therefore advisable to give
a suitable anti-inflammatory agent or colchicine for at least one month prophylactically.
Adults: Initially 100-300mg daily which may be given as a single dose. Doses in excess of
300mg should be administered in divided doses. It has rarely been necessary to exceed
900mg daily. The dose should be adjusted by monitoring serum uric acid and urinary uric
acid levels at appropriate intervals in order that the dose may be adjusted until the desired
effect is attained (this may take 1-3 weeks). The maintenance dose is usually 200-600mg
daily.
Paediatric population: Use in children is mainly indicated for malignant conditions especially
leukaemia, and certain enzyme disorders (eg Lesch-Nyhan syndrome) when the dosage is 10-
20mg/kg bodyweight daily.
Use in the elderly: Dosage should be the minimum necessary to maintain normal serum and
urinary urate levels.
Use with uricosurics: Oxipurinol, allopurinol's major metabolite which is itself

therapeutically active, is excreted by the kidney in a similar way to urate. Drugs with
uricosuric activity (eg probenecid or large doses of salicylate) may therefore accelerate the
excretion of oxipurinol. This may decrease the therapeutic effect of allopurinol, however, the
significance should be assessed on an individual basis.
In order to prevent acute uric acid nephropathy in neoplastic conditions, treatment with
allopurinol should precede treatment with cytotoxic drugs.
Dose recommendations with impaired renal function: Impairment of renal function may lead
to retention of allopurinol and its metabolites (which are excreted via the kidney) with
consequent prolongation of action. Serum uric acid levels should therefore be monitored and
the dose adjusted accordingly. The following dose recommendation is for use in adults:
Creatinine clearance:
Dosage:
Over 20ml/minute
Standard dose
10-20ml/minute
100-200mg daily
Under 10ml/minute
100mg daily or less frequently
Dose recommendations in renal disease: Allopurinol and it metabolites are removed by renal
dialysis. If frequent dialysis is required, an alternative schedule of 300-400mg after each
dialysis, with none in the interim, should be considered.
Method of Administration
For oral administration
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Treatment for an acute attack of gout;
• Prophylactic therapy may be commenced when the acute attack has completely subsided,
provided anti-inflammatory agents are also taken.

Allopurinol should be withdrawn immediately when a skin rash or other evidence of
sensitivity occurs as this could result in more serious hypersensitivity reactions (including
Stevens-Johnson syndrome and toxic epidermal necrolysis) (see section 4.8).
Chronic renal impairment
Patients with chronic renal impairment and concomitant diuretic use, in particular thiazides,
may be at increased risk of developing hypersensitivity reactions including SJS/TEN
associated with allopurinol. Extra vigilance for the signs of hypersensitivity syndrome or
SJS/TEN is required and the patient should be informed of the need to stop treatment
immediately and permanently at the first appearance of symptoms (see section 4.8).
Hepatic or renal impairment
Reduced doses should be used in patients with hepatic or renal impairment (see Section 4.2).
Patients under treatment for hypertension or cardiac insufficiency, for example with diuretics
or ACE inhibitors, may have some concomitant impairment of renal function and allopurinol
should be used with care in this group.
Life-threatening cutaneous reactions (Stevens-Johnson syndrome (SJS) and toxic
epidermalnecrolysis (TEN)) have been reported with the use of allopurinol.
Patients should be advised of the signs and symptoms and monitored closely for skin
reactions.The highest risk for occurrence of SJS or TEN is within the first weeks of
treatment.
If symptoms or signs of SJS or TEN (e.g. progressive skin rash often with blisters or mucosal
lesions) are present, allopurinol treatment should be discontinued.
The best results in managing SJS and TEN come from early diagnosis and immediate
discontinuation of any suspect drug. Early withdrawal is associated with a better prognosis.
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has also been reported with
the use of allopurinol. DRESS is characterised by fever, eosinophilia, atypical circulating
lymphocites, lymphadenopathy and hepatitis.
Hypersensitivity syndrome, SJS and TEN
Allopurinol hypersensitivity reactions can manifest in many different ways, including

maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and SJS/TEN.
These reactions are clinical diagnoses, and their clinical presentations remain the basis for
decision making. If such reactions occur at any time during treatment, allopurinol should be
withdrawn immediately. Rechallenge should not be undertaken in patients with
hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming
hypersensitivity skin reactions.
HLA-B*5801 allele
The HLA-B*5801 allele has been shown to be associated with the risk of developing
allopurinol related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-
B*5801 allele varies widely between ethnic populations: up to 20% in Han Chinese
population, 8-15% in the Thai, about 12% in the Korean population and 1-2% in individuals
of Japanese or European origin. Screening for HLA-B*5801 should be considered before
starting treatment with allopurinol in patient subgroups where the prevalence of this allele is
known to be high. Chronic kidney disease may increase the risk in these patients additionally
In case that no HLA-B*5801 genotyping is available for patients with Han Chinese, Thai or
Korean descent the benefits should be thoroughly assessed and considered outweigh the
possible higher risks before starting therapy. The use of genotyping has not been established
in other patient populations. If the patient is a known carrier of HLA-B*5801 (especially in
those who are from Han Chinese, Thai or Korean descent, allopurinol should not be started
unless there are no other reasonable therapeutic options and if the benefits are thought to
exceed risks. Extra vigilance for signs of hypersensitivity syndrome or SJS/TEN is required
and the patient should be informed of the need to stop treatment immediately at the first
appearance of symptoms.
SJS/TEN can still occur in patients who are found to be negative for HLA-B*5801
irrespective of their ethnic origin.
Thyroid disorders
Increased TSH values (>5.5 μIU/mL) were observed in patients on long-term treatment with
allopurinol (5.8%) in a long term open label extension study. Caution is required when
allopurinol is used in patients with alteration of thyroid function.
Asymptomatic hyperuricaemia per se is generally not considered an indication for use of

allopurinol. Fluid and dietary modification with management of the underlying cause may
correct the condition.
Acute gouty attacks: Allopurinol treatment should not be started until an acute attack of gout
has completely subsided, as further attacks may be precipitated.
In the early stages of treatment with allopurinol, as with uricosuric agents, an acute attack of
gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a
suitable anti-inflammatory agent or colchicine for at least one month. The literature should be
consulted for details of appropriate dosage and precautions and warnings.
If acute attacks develop in patients receiving allopurinol, treatment should continue at the
same dosage while the acute attack is treated with a suitable anti-inflammatory agent.
Xanthine deposition: In conditions where the rate of urate formation is greatly increased (e.g.
malignant disease and its treatment, Lesch-Nyhan syndrome) the absolute concentration of
xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract.
This risk may be minimised by adequate hydration to achieve optimal urine dilution.
Impaction of uric acid renal stones: Adequate therapy with Allopurinol will lead to
dissolution of large uric acid renal pelvic stones, with the remote possibility of impaction in
the ureter.
Lactose intolerance: Allopurinol tablets contain lactose. Patients with rare hereditary
problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
should not take this medicine.
6-mercaptopurine and azathioprine: Azathioprine is metabolised to 6-mercaptopurine which
is inactivated by the action of xanthine oxidase. If azathioprine or 6-mercaptopurine is given
concurrently with allopurinol, the dose of these agents should only be one quarter of that
usually given as inhibition of xanthine oxidase will prolong their activity.
Vidarabine (Adenine Arabinoside): Evidence suggests that the plasma half-life of adenine
arabinoside is increased in the presence of allopurinol and hence when these two agents are
administered concomitantly, extra vigilance is required to recognise enhanced toxic effects.
There is no unequivocal evidence that allopurinol potentiates the activity of other cytotoxic
drugs.
Salicylates and uricosuric agents: oxipurinol, the major metabolite of allopurinol and itself
therapeutically active, is excreted by the kidney in a similar way to urate. Hence, drugs with
uricosuric activity such as probenecid or large doses of salicylate may accelerate the
excretion of oxipurinol. This may decrease the therapeutic activity of Allopurinol, but the
significance needs to be assessed in each case.
Coumarin anticoagulants: There have been rare reports of increased effect of warfarin and
other coumarin anticoagulants when co-administered with allopurinol, therefore, all patients
receiving anticoagulants must be carefully monitored.
Chlorpropamide: If allopurinol is given concomitantly with chlorpropamide when renal

function is poor, there may be an increased risk of prolonged hypoglycaemic activity because
allopurinol and chlorpropamide may compete for excretion in the renal tubule.
Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical
significance has not been demonstrated.
Theophylline: Inhibition of the metabolism of theophylline has been reported. The

mechanism of the interaction may be explained by xanthine oxidase being involved in the
biotransformation of theophylline in man. Theophylline levels should be monitored in
patients starting or increasing allopurinol therapy.
Ampicillin/Amoxicillin: An increase in the frequency of skin rash has been reported among
patients receiving ampicillin or amoxicillin concurrently with allopurinol compared to
patients who are not receiving both drugs. The cause of the reported association has not been
established. However, it is recommended that in patients receiving allopurinol an alternative
to ampicillin or amoxicillin is used where available.
Cytostatics: Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic

agents has been reported among patients with neoplastic disease (other than leukaemia), in
the presence of allopurinol. However, in a well-controlled study of patients treated with
cyclophosphamide, doxorubicin, bleomycin, procarbazine and/or mechloroethamine
(chlormethine hydrochloride) allopurinol did not appear to increase the toxic reaction of these
cytotoxic agents.
With administration of allopurinol and cytostatics (e.g. cyclophosphamide, doxorubicin,

bleomycin, procarbazine, alkyl halogenides), blood dyscrasias occur more frequently than
when these active substances are administered alone. Blood count monitoring should
therefore be performed at regular intervals.
Ciclosporin: Reports suggest that the plasma concentration of ciclosporin may be increased
during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin
toxicity should be considered if the drugs are co-administered.
Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine
Cmax and AUC values were approximately doubled with concomitant allopurinol treatment
(300 mg daily) without affecting terminal half life. Co-administration of these 2 drugs is
generally not recommended. If concomitant use is unavoidable, a dose reduction of
didanosine may be required, and patients should be closely monitored.
Diuretics: An interaction between allopurinol and furosemide that results in increased serum
urate and plasma oxypurinol concentrations has been reported.
An increased risk of hypersensitivity has been reported when allopurinol is given with
diuretics, in particular thiazides, especially in renal impairment.
Angiotensin-converting-enzyme (ACE) inhibitors: An increased risk of hypersensitivity has

been reported when allopurinol is given with ACE inhibitors especially in renal impairment.
Aluminium hydroxide: If aluminium hydroxide is taken concomitantly, allopurinol may have

an attenuated effect. There should be an interval of at least 3 hours between taking both
medicines.
Ace inhibitors: Concurrent use of allopurinol and ACE inhibitors may lead to an increased
risk of haematological reactions such as leucopenia, especially if there is pre-existing renal
failure.

Pregnancy
High dose intraperitoneal allopurinol in mice has been associated with foetal abnormalities
but extensive animal studies with oral allopurinol have shown none.
There is inadequate evidence of safety of Allopurinol in human pregnancy, although it has

been in wide use for many years without apparent ill consequence (see section 5.3).
Use in pregnancy only when there is no safer alternative and when the disease itself carries
risks for the mother or unborn child.
Breast-feeding
Allopurinol and its metabolite oxipurinol is excreted in the human breast milk.
Concentrations of 1.4 mg/litre allopurinol and 53.7 mg/litre oxipurinol have been
demonstrated in breast milk from a woman taking Allopurinol 300 mg/day. However, there
are no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.
Allopurinol during breastfeeding is not recommended.

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients
receiving allopurinol, patients should exercise caution before driving, using machinery or
participating in dangerous activities until they are reasonably certain that allopurinol does not
adversely affect performance.

These are usually rare and mostly of a minor nature; the incidence is higher in the presence of
renal and/or hepatic disorders.
For this product there is no modern clinical documentation which can be used as support for
determining the frequency of undesirable effects. Undesirable effects may vary in their
incidence depending on the dose received and also when given in combination with other
therapeutic agents.
The frequency categories assigned to the adverse drug reactions below are estimates: for most
reactions, suitable data for calculating incidence are not available. Adverse drug reactions
identified through post-marketing surveillance were considered to be rare or very rare. The
following convention has been used for the classification of frequency:
Very common (≥1/10 (≥10%)), Common (≥1/100 and <1/10 (≥1% and <10%)), Uncommon
(≥1/1000 and <1/100 (≥0.1% and <1%)), Rare (≥1/10,000 and <1/1000 (≥0.01% and
<0.1%)), Very rare (<1/10,000 (<0.01%))
Infections and infestations
Very rare: furunculosis,
Blood and lymphatic system disorders
Very rare: thrombocytopenia, aplastic anaemia, agranulocytosis

Frequency not known: leucopenia, eosinophilia, haemolytic anaemia
Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic
anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing
the need for particular care in this group of patients.
Reports of transient reduction in the number of circulating formed elements of the blood, are
usually in association with a renal and/or hepatic disorder reinforcing the need for particular
care in this group of patients.
Immune system disorders
A delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or

DRESS) with fever, rashes, vasculitis, lymphadenopathy, pseudo lymphoma, arthralgia,
leucopenia, eosinophilia, hepato-splenomegaly, abnormal liver function tests and vanishing
bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in
various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas,
myocardium, and colon). If such reactions do occur, it may be at any time during treatment,
Allopurinol tablets should be withdrawn immediately and permanently.
When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has
usually been present particularly when the outcome has been fatal.
Uncommon: hypersensitivity reactions
Very rare: angioimmunoblastic lymphadenopathy, anaphylactic reaction
Frequency not known: arthralgia
Associated vasculitis and tissue response may be manifested in various ways including
hepatitis, interstitial nephritis and, very rarely, epilepsy. Corticosteroids may be beneficial in
overcoming them. When generalised hypersensitivity reactions have occurred, a renal and/or
hepatic disorder has usually been present, particularly when the outcome has been fatal.
Metabolism and nutrition disorders
Very rare: diabetes mellitus, hyperlipidaemia
Frequency not known: exacerbation of gouty attacks (see section 4.4)
Psychiatric disorders
Very rare: depression,

Nervous system disorders
Very rare: ataxia, coma, headache, neuropathy, paraesthesia, paralysis, somnolence, taste
perversion, dysgeusia
Frequency not known: dizziness
Eye disorders
Very rare: cataract, macular changes, visual disorders
Ear and labyrinth disorders
Very rare: vertigo
Cardiac disorders
Very rare: angina, bradycardia
Vascular disorders
Very rare: hypertension
Frequency not known: vasculitis
Gastrointestinal disorders
Uncommon: nausea, vomiting
Very rare: changed bowel habit, stomatitis, steatorrhoea, haematemisis
Frequency not known: diarrhoea, abdominal pain,
Hepatobiliary disorders
Uncommon: asymptomatic increases in liver function tests
Rare: hepatitis (including hepatic necrosis and granulomatous hepatitis)
Skin and subcutaneous tissue disorders
Common: rash
Rare: severe cutaneous adverse reactions (SCARs): Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN) have been reported (see section 4.4). The highest risk for
SJS and TEN, or other serious hypersensitivity reactions, is within the first weeks of
treatment.
Very rare: alopecia, angioedema, discoloured hair, fixed drug eruptions.
Frequency not known: skin reaction associated with eosinophilia, urticaria.
Drug Rash with Eosinophilia and Systemic Symptoms has been reported. Some cases have
had a fatal outcome.
Skin reactions are the most common reactions and may occur at any time during treatment.
They may be pruritic, maculopapular, sometimes scaly or purpuric, associated with

exfoliation, fever, lymphadenopathy, arthralgia and/or eosinophilia resembling Stevens-
Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and/or Lyell's. Allopurinol
should be withdrawn immediately should such reactions occur.
If desired, after recovery from mild reactions, allopurinol may be reintroduced at a low dose
(eg 50mg/day) which may be gradually increased. If the rash recurs, allopurinol should be
permanently withdrawn.
The HLA-B*5801 allele has been has been identified as a genetic risk factor for allopurinol
associated SJS/TEN in retrospective, case-control, pharmacogenetic studies in patients of
Han Chinese, Japanese and European descent. Up to 20-30% of some Han Chinese, African
and Indian populations carry the HLA-B*5801 allele whereas only 1-2% of Northern
European, US European and Japanese patients are estimated to be HLA-B*5801 carriers.
However, the use of genotyping as a screening tool to make decisions about treatment with
allopurinol has not been established.
The clinical diagnosis of SJS/TEN remains the basis for decision making. If such reactions
occur at any time during treatment, allopurinol should be withdrawn immediately and
permanently.
Renal and urinary disorders
Very rare: haematuria, uraemia, azotaemia
Frequency not known: nephrolithiasis
Reproductive system and breast disorders
Very rare: gynaecomastia, impotence, infertility, erectile dysfunction

Frequency not known: nocturnal emissions
General disorders and administration site conditions
Very rare: asthenia, general malaise, oedema, pyrexia*
Investigations
Common: blood thyroid stimulating hormone increased**
*Fever has been reported to occur with and without signs and symptoms of a more
generalised Allopurinol hypersensitivity reaction (see section 4.8 Immune system disorders).
**The occurrence of increased thyroid stimulating hormone (TSH) in the relevant studies did
not report any impact on free T4 levels or had TSH levels indicative of subclinical
hypothyroidism.

product. Healthcare professionals are asked to report any suspected adverse reactions via the
Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow
Card in the Google Play or Apple App Store.
4.9 Overdose
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported.
Massive absorption of allopurinol may lead to considerable inhibition of xanthine oxidase

activity, which should have no untoward effects unless adenine arabinoside, azathioprine or
6-mercaptopurine is being taken concurrently. In this case, the risk of increased activity of
these drugs must be recognised.
Symptoms
Nausea, vomiting, diarrhoea, dizziness, headache, somnolence and abdominal pain. Rarely,
there may be renal insufficiency and hepatitis.
Treatment
The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal

dose: 50 g for adults; 1 g/ kg for children) if the patient presents within 1 hour of ingestion of
more than 50 mg/kg. If more than 50 mg/kg has been ingested check U&Es and LFTs.
Adequate hydration to maintain optimum diuresis facilitates excretion of allopurinol and its
metabolites. Other measures as indicated by the patient's clinical condition.
Haemodialysis is unlikely to be required. Hameodialysis may be considered in patients with

severe renal or hepatic impairment.
Pharmacotherapeutic group: Antigout preparations inhibiting uric acid production
ATC code – M04 AA01
Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxipurinol

lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme
catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to
the inhibition of purine catabolism in some but not all hyperuricaemic patients, de novo
purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine
phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside and
oxipurinol-7-riboside.

Absorption
Allopurinol is active when given orally and is rapidly absorbed from the upper
gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 minutes after
dosing. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of allopurinol
generally occur approximately 1.5 hours after oral administration of Allopurinol, but fall
rapidly and are barely detectable after 6 hours. Peak plasma levels of oxipurinol generally
occur after 3-5 hours after oral administration of Allopurinol and are much more sustained.
Distribution
Allopurinol is negligibly bound by plasma proteins and therefore variations in protein binding
are not thought to significantly alter clearance. The apparent volume of distribution of
allopurinol is approximately 1.6 litre/kg which, suggests relatively extensive uptake by
tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely
that allopurinol and oxipurinol will be present in the highest concentrations in the liver and
intestinal mucosa where xanthine oxidase activity is high.
Biotransformation
The main metabolite of Allopurinol is oxipurinol. Other metabolites of allopurinol include

allopurinol-riboside and oxipurinol-7-riboside.
Elimination
Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of

allopurinol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and
aldehyde oxidase, with less than 10% of the unchanged drug excreted in the urine.
Allopurinol has a plasma half-life of about 0.5 to 1.5 hours.
Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but the plasma half-
life of oxipurinol is far more prolonged. Estimates range from 13 to 30 hours in man.
Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a
single daily dose of Allopurinol. Patients with normal renal function will gradually
accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such
patients, taking 300 mg of allopurinol per day will generally have plasma oxipurinol
concentrations of 5-10 mg/litre.
Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it
undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6
hours to 29 hours. The large discrepancies in these values may be accounted for by variations
in study design and/or creatinine clearance in the patients.
Pharmacokinetics in patients with renal impairment
Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function
resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where
creatinine clearance values were between 10 and 20 ml/min, showed plasma oxipurinol
concentrations of approximately 30 mg/litre after prolonged treatment with 300 mg
allopurinol per day. This is approximately the concentration which would be achieved by
doses of 600 mg/day in those with normal renal function. A reduction in the dose of
Allopurinol is therefore required in patients with renal impairment.
Pharmacokinetics in elderly patients
The kinetics of the drug are not likely to be altered other than due to deterioration in renal
function (see section 5.2 Pharmacokinetics in patients with renal impairment).

Mutagenicity
Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human
blood cells in vitro at concentrations up to 100 micrograms/ml and in vivo at doses up to 600
mg/day for a mean period of 40 months.
Allopurinol does not produce nitroso compounds in vitro or affect lymphocyte transformation
in vitro.
Evidence from biochemical and other cytological investigations strongly suggests that
allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not
mutagenic.
Carcinogenicity
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for
up to 2 years.
Teratogenicity
One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of

gestation resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on
day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of
allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150
mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects.
An in vitro study using foetal mouse salivary glands in culture to detect embryotoxicity
indicated that allopurinol would not be expected to cause embryotoxicity without also
causing maternal toxicity.
Also contains:
Maize starch
Carmellose sodium
Cellulose
Sodium lauryl sulfate
Lactose
Magnesium stearate
None known
6.3 Shelf life

Shelf-life
Three years from the date of manufacture.
Shelf-life after dilution/reconstitution
Not applicable
Shelf-life after first opening
Not applicable

Store below 25°C in a dry place.

The product containers are rigid injection moulded polypropylene or injection blow-moulded
polyethylene containers with snap-on polyethylene lids; in case any supply difficulties should
arise the alternative is amber glass containers with screw caps.
The product may also be supplied in blister packs in cartons:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper
aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse
side.
Pack sizes: 28's, 30's, 56's, 60's, 84's, 90's, 100's, 112's, 1000's.
Product may also be supplied in bulk packs, for reassembly purposes only, in polybags
contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs
are included for temporary storage of the finished product before final packaging into the
proposed marketing containers.
Maximum size of bulk packs: 25,000.

Not applicable
SUMMARY OF PRODUCT CHARACTERISTICS OF ALLOPURINOL TABLETS
300MG
Allopurinol 300mg Tablets

Each tablet contains Allopurinol 300mg.
For the full list of excipients, see section 6.1.
White to off white, round, biconvex with beveled edge uncoated tablet with inscription "AX'
on one side and plain on the other side
Allopurinol is indicated for reducing urate/uric acid formation in conditions where urate/uric
acid deposition has already occurred (e.g. gouty arthritis, skin tophi, nephrolithiasis) or is a
predictable clinical risk (e.g. treatment of malignancy potentially leading to acute uric acid
nephropathy). The main clinical conditions where urate/uric acid deposition may occur are:
idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and
myeloproliferative disease with high cell turnover rates, in which high urate levels occur
either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to
overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase,
including Lesch-Nyhan syndrome; glucose-6-phosphatase including glycogen storage
disease; phosphoribosylpyrophosphate synthetase, phosphoribosylpyrophosphate
amidotransferase; adenine phosphoribosyltransferase. Allopurinol is indicated for
management of 2,8-dihydroxyadenine (2,8-DHA) renal stones related to deficient activity of
adenine phosphoribosyltransferase.
Allopurinol is indicated for the management of recurrent mixed calcium oxalate renal stones
in the presence of hyperuricosuria, when fluid, dietary and similar measures have failed.

Posology
Adults: Allopurinol should be introduced at low dosage e.g. 100mg/day to reduce the risk of
adverse reactions and increased only if the serum urate response is unsatisfactory. Extra
caution should be exercised if renal function is poor (see Patients with renal impairment). The
following dosage schedules are suggested:
100 to 200 mg daily in mild conditions,
300 to 600 mg daily in moderately severe conditions,

700 to 900 mg daily in severe conditions.
If dosage on a mg/kg bodyweight basis is required, 2 to 10 mg/kg bodyweight/day should be

used.
Paediatric population:
Children under 15 years: 10 to 20 mg/kg bodyweight/day up to a maximum of 400 mg daily.

Use in children is rarely indicated, except in malignant conditions (especially leukaemia) and
certain enzyme disorders such as Lesch-Nyhan syndrome.
Older people: In the absence of specific data, the lowest dosage which produces satisfactory
urate reduction should be used. Particular attention should be paid to advice in patients with
renal impairment and section 4.4.
Patients with renal impairment: Since allopurinol and its metabolites are excreted by the
kidney, impaired renal function may lead to retention of the drug and/or its metabolites with
consequent prolongation of plasma half-lives. In severe renal insufficiency, it may be
advisable to use less than 100 mg per day or to use single doses of 100mg at longer intervals
than one day.
If facilities are available to monitor plasma oxipurinol concentrations, the dose should be
adjusted to maintain plasma oxipurinol levels below 100 micromol/litre (15.2 mg/litre).
Allopurinol and its metabolites are removed by renal dialysis. If dialysis is required two to
three times a week consideration should be given to an alternative dosage schedule of 300-
400 mg Allopurinol immediately after each dialysis with none in the interim.
Patients with hepatic impairment: Reduced doses should be used in patients with hepatic
impairment. Periodic liver function tests are recommended during the early stages of therapy.
Treatment of high urate turnover conditions, e.g. neoplasia, Lesch-Nyhan syndrome: It is

advisable to correct existing hyperuricaemia and/or hyperuricosuria with Allopurinol before
starting cytotoxic therapy. It is important to ensure adequate hydration to maintain optimum
diuresis and to attempt alkalinisation of urine to increase solubility of urinary urate/uric acid.
Dosage of Allopurinol should be at the lower end of the recommended dosage schedule.
If urate nephropathy or other pathology has compromised renal function, the advice given in
Patients with renal impairment should be followed.
These steps may reduce the risk of xanthine and/or oxipurinol deposition complicating the
clinical situation. See also sections 4.5 and 4.8.
Monitoring Advice: The dosage should be adjusted by monitoring serum urate concentrations
and urinary urate/uric acid levels at appropriate intervals.
Method of administration: Allopurinol may be taken orally once a day after a meal. It is well
tolerated, especially after food. Should the daily dosage exceed 300 mg and gastrointestinal
intolerance be manifested, a divided doses regimen may be appropriate.
Allopurinol should not be administered to individuals known to be hypersensitive to
allopurinol or to any of the components of the formulation listed in section 6.1.

Hypersensitivity syndrome, SJS and TEN
Allopurinol hypersensitivity reactions can manifest in many different ways, including

maculopapular exanthema, hypersensitivity syndrome (also known as DRESS) and SJS/TEN.
These reactions are clinical diagnoses, and their clinical presentations remain the basis for
decision making. If such reactions occur at any time during treatment, allopurinol should be
withdrawn immediately. Rechallenge should not be undertaken in patients with
hypersensitivity syndrome and SJS/TEN. Corticosteroids may be beneficial in overcoming
hypersensitivity skin reactions.
HLA-B*5801 allele
The HLA-B*5801 allele has been shown to be associated with the risk of developing
allopurinol related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-
B*5801 allele varies widely between ethnic populations: up to 20% in Han Chinese
population, 8-15% in the Thai, about 12% in the Korean population and 1-2% in individuals
of Japanese or European origin.
Screening for HLA-B*5801 should be considered before starting treatment with allopurinol
in patient subgroups where the prevalence of this allele is known to be high. Chronic kidney
disease may increase the risk in these patients additionally In case that no HLA-B*5801
genotyping is available for patients with Han Chinese, Thai or Korean descent the benefits
should be thoroughly assessed and considered outweigh the possible higher risks before
starting therapy. The use of genotyping has not been established in other patient populations.
If the patient is a known carrier of HLA-B*5801(especially in those who are from Han
Chinese, Thai or Korean descent, allopurinol should not be started unless there are no other
reasonable therapeutic options and the benefits are thought to exceed risks. Extra vigilance
for signs of hypersensitivity syndrome or SJS/TEN is required and the patient should be
informed of the need to stop treatment immediately at the first appearance of symptoms.
SJS/TEN can still occur in patients who are found to be negative for HLA-B*5801
irrespective of their ethnic origin.
Chronic renal impairment
Patients with chronic renal impairment and concomitant diuretic use, in particular thiazides,
may be at increased risk of developing hypersensitivity reactions including SJS/TEN
associated with allopurinol. Extra vigilance for the signs of hypersensitivity syndrome or
SJS/TEN is required and the patient should be informed of the need to stop treatment
immediately and permanently at the first appearance of symptoms (see section 4.8).
Hepatic or renal impairment
Reduced doses should be used in patients with hepatic or renal impairment (See Section 4.2).
Asymptomatic hyperuricaemia:
Asymptomatic hyperuricaemia per se is generally not considered an indication for use of

Allopurinol. Fluid and dietary modification with management of the underlying cause may
correct the condition.
Acute gouty attacks:
Allopurinol treatment should not be started until an acute attack of gout has completely
subsided, as further attacks may be precipitated.
In the early stages of treatment with Allopurinol, as with uricosuric agents, an acute attack of
gouty arthritis may be precipitated. Therefore it is advisable to give prophylaxis with a
suitable anti-inflammatory agent or colchicine for at least one month. The literature should be
consulted for details of appropriate dosage and precautions and warnings.
If acute attacks develop in patients receiving allopurinol, treatment should continue at the
same dosage while the acute attack is treated with a suitable anti-inflammatory agent.
Xanthine deposition:
In conditions where the rate of urate formation is greatly increased (e.g. malignant disease
and its treatment, Lesch-Nyhan syndrome) the absolute concentration of xanthine in urine
could, in rare cases, rise sufficiently to allow deposition in the urinary tract. This risk may be
minimised by adequate hydration to achieve optimal urine dilution.
Impaction of uric acid renal stones:
Adequate therapy with Allopurinol will lead to dissolution of large uric acid renal pelvic
stones, with the remote possibility of impaction in the ureter.
Thyroid disorders:
Increased TSH values (>5.5 µIU/mL) were observed in patients on long-term treatment with
allopurinol (5.8%) in a long term open label extension study. Caution is required when
allopurinol is used in patients with alteration of thyroid function.
Lactose :
Allopurinol tablets contain lactose and therefore should not be administered to patients with
rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption.
Cytostatics
With administration of allopurinol and cytostatics (e.g. cyclophosphamide, doxorubicin,

bleomycin, procarbazine, alkyl halogenides), blood dyscrasias occur more frequently than
when these active substances are administered alone.
Blood count monitoring should therefore be performed at regular intervals.
Aluminium hydroxide
If aluminium hydroxide is taken concomitantly, allopurinol may have an attenuated effect.

There should be an interval of at least 3 hours between taking both medicines.
Coumarin anticoagulants: There have been rare reports of increased effect of warfarin and
other coumarin anticoagulants when co-administered with allopurinol, therefore, all patients
receiving anticoagulants must be carefully monitored.
Azathioprine and 6-mercaptopurine: Azathioprine is metabolised to 6-mercaptopurine which

is inactivated by the action of xanthine oxidase. When 6-mercaptopurine or azathioprine is
given concurrently with Allopurinol, only one-quarter of the usual dose of 6-mercaptopurine
or azathioprine should be given because inhibition of xanthine oxidase will prolong their
activity.
Vidarabine (Adenine arabinoside): Evidence suggests that the plasma half life of vidarabine
is increased in the presence of allopurinol. When the two products are used concomitantly
extra vigilance is necessary, to recognise enhanced toxic effects.
Salicylates and uricosuric agents: Oxipurinol, the major active metabolite of allopurinol, is
excreted by the kidney in a similar way to urate. Hence drugs with uricosuric activity such as
probenecid or large doses of salicylates may accelerate the excretion of oxipurinol. This may
decrease the therapeutic activity of allopurinol (but the significance needs to be assessed in
each case.).
Chlorpropamide: If allopurinol is given concomitantly with chlorpropamide when renal

function is poor, there may be an increased risk of prolonged hypoglycaemic activity,
because allopurinol and chlorpropamide may compete for excretion in the renal tubule.
Phenytoin: Allopurinol may inhibit hepatic oxidation of phenytoin but the clinical
significance has not been demonstrated.
Theophylline: Inhibition of the metabolism of theophylline has been reported. The

mechanism of the interaction may be explained by xanthine oxidase being involved in the
biotransformation of theophylline in man. Theophylline levels should be monitored in
patients starting or increasing allopurinol therapy.
Ampicillin / amoxicillin: An increase in the frequency of skin rash has been reported among
patients receiving ampicillin or amoxicillin concurrently with allopurinol compared with
patients who are not receiving both drugs. The cause of the reported association has not been
established. However, it is recommended that in patients receiving allopurinol an alternative
to ampicillin or amoxicillin is used where available.
Ciclosporin: Reports suggest that the plasma concentration of ciclosporin may be increased
during concomitant treatment with allopurinol. The possibility of enhanced ciclosporin
toxicity should be considered if the drugs are co-administered.
Cyclophosphamide, doxorubicin, bleomycin, procarbazine, mechloroethamine: Enhanced

bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported
among patients with neoplastic disease (other than leukaemia), in the presence of allopurinol.
However, in a well-controlled study of patients treated with cyclophosphamide, doxorubicin,
bleomycin, procarbazine and/or mechloroethamine (chlormethine hydrochloride) allopurinol
did not appear to increase the toxic reaction of these cytotoxic agents.
Didanosine: In healthy volunteers and HIV patients receiving didanosine, plasma didanosine
Cmax and AUC values were approximately doubled with concomitant allopurinol treatment
(300 mg daily) without affecting terminal half life. Co-administration of these 2 drugs is
generally not recommended. If concomitant use is unavoidable, a dose reduction of
didanosine may be required, and patients should be closely monitored.
Diuretics
An interaction between allopurinol and furosemide that results in increased serum urate and
plasma oxypurinol concentrations has been reported.
An increased risk of hypersensitivity has been reported when allopurinol is given with
diuretics, in particular thiazides, especially in renal impairment.
Angiotensin-converting-enzyme (ACE) inhibitors
An increased risk of hypersensitivity has been reported when allopurinol is given with ACE
inhibitors especially in renal impairment.
4.6 Pregnancy and lactation

Pregnancy:
There is inadequate evidence of safety of Allopurinol in human pregnancy, although it has

been in wide use for many years without apparent ill consequence.
Use in pregnancy only when there is no safer alternative and when the disease itself carries
risk for the mother or unborn child.
Breast-feeding:
Allopurinol and its metabolite oxipurinol is excreted in human breast milk. Allopurinol
during breastfeeding is not recommended.
Concentrations of 1.4mg/litre allopurinol and 53.7 mg/litre oxipurinol have been

demonstrated in breast milk from woman taking Allopurinol 300 mg/day. However, there are
no data concerning the effects of allopurinol or its metabolites on the breast-fed baby.

Since adverse reactions such as somnolence, vertigo and ataxia have been reported in patients
receiving allopurinol, patients should exercise caution before driving, using machinery or
participating in dangerous activities until they are reasonably certain that allopurinol does not
adversely affect performance.

For this product, there is no modern clinical documentation which can be used as support for
determining the frequency of undesirable effects. Undesirable effects may vary in their
incidence depending on the dose received and also when given in combination with other
therapeutic agents.
The frequency categories assigned to the adverse drug reactions below are estimates: for most
reactions, suitable data for calculating incidence are not available. Adverse drug reactions
identified through post-marketing surveillance were considered to be rare or very rare. The
following convention has been used for the classification of frequency:
Very common
≥1/10
Common
≥1/100 and <1/10
Uncommon
≥1/1000 and <1/100
Rare
≥1/10,000 and <1/1000
Very rare
<1/10,000
Adverse reactions in association with Allopurinol are rare in the overall treated population
and mostly of a minor nature. The incidence is higher in the presence of renal and/or hepatic
disorder.
Table 1 Undesirable effects
System Organ Class
Frequency
Adverse reaction
Infections and infestations
Very rare
Furuncle
Blood and lymphatic system disorders
Very rare
Agranulocytosis1
Aplastic anaemia1
Thrombocytopenia1
Immune system disorders
Uncommon
Hypersensitivity 2
Very rare
Angioimmunoblastic T-cell lymphoma 3, Anaphylactic reaction
Metabolism and nutrition disorders
Very rare
Diabetes mellitus
Hyperlipidaemia
Psychiatric disorders
Very rare
Depression
Nervous system disorders
Very rare
Coma
Paralysis
Ataxia
Neuropathy peripheral
Paraesthesia
Somnolence
HeadacheDysgeusia
Eye disorders
Very rare
Cataract
Visual impairment
Maculopathy
Ear and labyrinth disorders
Very rare
Vertigo
Cardiac disorders
Very rare
Angina pectoris
Bradycardia
Vascular disorders
Very rare
Hypertension
Gastrointestinal disorders
Uncommon
Vomiting4
Nausea4
Very rare
Haematemesis
Steatorrhoea
Stomatitis
Change of bowel habit
Hepatobiliary disorders
Uncommon
Liver function test abnormal5
Rare
Hepatitis (including hepatic necrosis and granulomatous hepatitis) 5
Skin and subcutaneous tissue disorders
Common
Rash
Rare
Stevens-Johnson syndrome/toxic epidermal necrolysis 6
Very rare
Angioedema7
Drug eruption
Alopecia
Hair colour changes
Renal and urinary disorders
Very rare
Haematuria
Azotaemia
Reproductive system and breast disorders
Very rare
Infertility male
Erectile dysfunction
Gynaecomastia
General disorders and administration site conditions
Very rare
Oedema
Malaise
Asthenia
Pyrexia 8
Investigations
common
blood thyroid stimulating hormone increased 9
1 Very rare reports have been received of thrombocytopenia, agranulocytosis and aplastic
anaemia, particularly in individuals with impaired renal and/or hepatic function, reinforcing
the need for particular care in this group of patients.
2 A delayed multi-organ hypersensitivity disorder (known as hypersensitivity syndrome or

DRESS) with fever, rashes, vasculitis,lymphadenopathy, pseudo lymphoma, arthralgia,
leucopenia, eosinophilia hepato-splenomegaly, abnormal liver function tests, and vanishing
bile duct syndrome (destruction and disappearance of the intrahepatic bile ducts) occurring in
various combinations. Other organs may also be affected (e.g. liver, lungs, kidneys, pancreas,
myocardium, and colon). If such reactions do occur, it may be at any time during treatment,
allopurinol should be withdrawn IMMEDIATELY AND PERMANENTLY.
Rechallenge should not be undertaken in patients with hypersensitivity syndrome and
SJS/TEN. Corticosteroids may be beneficial in overcoming hypersensitivity skin reactions.
When generalised hypersensitivity reactions have occurred, renal and/or hepatic disorder has
usually been present particularly when the outcome has been fatal.
3 Angioimmunoblastic T-cell lymphoma has been described very rarely following biopsy of a
generalised lymphadenopathy. It appears to be reversible on withdrawal of Allopurinol
tablets.
4 In early clinical studies, nausea and vomiting were reported. Further reports suggest that
this reaction is not a significant problem and can be avoided by taking Allopurinol tablets
after meals.
5 Hepatic dysfunction has been reported without overt evidence of more generalised
hypersensitivity.
6 Skin reactions are the most common reactions and may occur at any time during treatment.
They may be pruritic, maculopapular, sometimes scaly, sometimes purpuric and rarely
exfoliative, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN).
The highest risk for SJS and TEN, or other serious hypersensitivity reactions, is within the
first weeks of treatment. The best results in managing such reactions come from early
diagnosis and immediate discontinuation of any suspect drug. Allopurinol tablets should be
withdrawn immediately should such reactions occur. After recovery from mild reactions,
Allopurinol tablets may, if desired, be re-introduced at a small dose (e.g. 50 mg/day) and
gradually increased. If the rash recurs, Allopurinol tablets should be permanently withdrawn
as more severe hypersensitivity may occur (see Immune system disorders). If SJS/TEN, or
other serious hypersensitivity reactions cannot be ruled out, DO NOT re-introduce allopurinol
due to the potential for a severe or even fatal reaction. The clinical diagnosis of SJS/TEN
remains the basis for decision making. If such reactions occur at any time during treatment,
allopurinol should be withdrawn immediately and permanently.
7 Angioedema has been reported to occur with and without signs and symptoms of a more
generalised hypersensitivity reaction.
8 Fever has been reported to occur with and without signs and symptoms of a more
generalised Allopurinol tablets hypersensitivity reaction (see Immune system disorders).
9. The occurrence of increased thyroid stimulating hormone (TSH) in the relevant studies did
not report any impact on free T4 levels or had TSH levels indicative of subclinical
hypothyroidism.

product.
Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card
Scheme.
Website: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Ingestion of up to 22.5 g allopurinol without adverse effect has been reported. Symptoms and
signs including nausea, vomiting, diarrhoea and dizziness have been reported in a patient who
ingested 20 g allopurinol. Recovery followed general supportive measures. Massive
absorption of Allopurinol may lead to considerable inhibition of xanthine oxidase activity,
which should have no untoward effects unless affecting concomitant medication, especially
with 6-mercaptopurine and/or azathioprine. Adequate hydration to maintain optimum diuresis
facilitates excretion of allopurinol and its metabolites. If considered necessary haemodialysis
may be used.
Pharmacotherapeutic Group: Antigout preparations inhibiting uric acid production
ATC code: M04 AA01
Allopurinol is a xanthine-oxidase inhibitor. Allopurinol and its main metabolite oxipurinol

lower the level of uric acid in plasma and urine by inhibition of xanthine oxidase, the enzyme
catalyzing the oxidation of hypoxanthine to xanthine and xanthine to uric acid. In addition to
the inhibition of purine catabolism in some but not all hyperuricaemic patients, de novo
purine biosynthesis is depressed via feedback inhibition of hypoxanthine-guanine
phosphoribosyltransferase. Other metabolites of allopurinol include allopurinol-riboside and
oxipurinol-7 riboside.

Absorption:
Allopurinol is active when given orally and is rapidly absorbed from the upper
gastrointestinal tract. Studies have detected allopurinol in the blood 30-60 minutes after
dosing. Estimates of bioavailability vary from 67% to 90%. Peak plasma levels of allopurinol
generally occur approximately 1.5 hours after oral administration of Allopurinol, but fall
rapidly and are barely detectable after 6 hours. Peak levels of oxipurinol generally occur after
3-5 hours after oral administration of Allopurinol and are much more sustained.
Distribution:
Allopurinol is negligibly bound by plasma proteins and therefore variations in protein binding
are not thought to significantly alter clearance. The apparent volume of distribution of
allopurinol is approximately 1.6 litre/kg which suggests relatively extensive uptake by
tissues. Tissue concentrations of allopurinol have not been reported in humans, but it is likely
that allopurinol and oxipurinol will be present in the highest concentrations in the liver and
intestinal mucosa where xanthine oxidase activity is high.
Biotransformation
The main metabolite of Allopurinol tablets is oxipurinol. Other metabolites of allopurinol
include allopurinol-riboside and oxipurinol-7-riboside.
Elimination:
Approximately 20% of the ingested allopurinol is excreted in the faeces. Elimination of

allopurinol is mainly by metabolic conversion to oxipurinol by xanthine oxidase and
aldehyde oxidase, with less than 10% of the unchanged drug excreted in the urine.
Allopurinol has a plasma half-life of about 1 to 2 hours.
Oxipurinol is a less potent inhibitor of xanthine oxidase than allopurinol, but the plasma half-
life of oxipurinol is far more prolonged. Estimates range from 13 to 30 hours in man.
Therefore effective inhibition of xanthine oxidase is maintained over a 24 hour period with a
single daily dose of Allopurinol. Patients with normal renal function will gradually
accumulate oxipurinol until a steady-state plasma oxipurinol concentration is reached. Such
patients, taking 300 mg of allopurinol per day will generally have plasma oxipurinol
concentrations of 5-10 mg/litre.
Oxipurinol is eliminated unchanged in the urine but has a long elimination half-life because it
undergoes tubular reabsorption. Reported values for the elimination half-life range from 13.6
hours to 29 hours. The large discrepancies in these values may be accounted for by variations
in study design and/or creatinine clearance in the patients.
Pharmacokinetics in patients with renal impairment.
Allopurinol and oxipurinol clearance is greatly reduced in patients with poor renal function
resulting in higher plasma levels in chronic therapy. Patients with renal impairment, where
creatinine clearance values were between 10 and 20ml/min, showed plasma oxipurinol
concentrations of approximately 30mg/litre after prolonged treatment with 300 mg
allopurinol per day. This is approximately the concentration which would be achieved by
doses of 600 mg/day in those with normal renal function. A reduction in the dose of
Allopurinol is therefore required in patients with renal impairment.
Pharmacokinetics in elderly patients.

The kinetics of the drug are not likely to be altered other than due to deterioration in renal
function (see Pharmocokinetics in patients with renal impairment).
A. Mutagenicity
Cytogenetic studies show that allopurinol does not induce chromosome aberrations in human
blood cells in vitro at concentrations up to 100 micrograms/ml and in vivo at doses up to 600
mg/day for mean period of 40 months.
Allopurinol does not produce nitraso compounds in vitro or affect lymphocyte transformation
in vitro.
Evidence from biochemical and other cytological investigations strongly suggests that
allopurinol has no deleterious effects on DNA at any stage of the cell cycle and is not
mutagenic.
B. Carcinogenicity
No evidence of carcinogenicity has been found in mice and rats treated with allopurinol for
up to 2 years.
C. Teratogenicity
One study in mice receiving intraperitoneal doses of 50 or 100 mg/kg on days 10 or 13 of

gestation resulted in foetal abnormalities, however in a similar study in rats at 120 mg/kg on
day 12 of gestation no abnormalities were observed. Extensive studies of high oral doses of
allopurinol in mice up to 100 mg/kg/day, rats up to 200 mg/kg/day and rabbits up to 150
mg/kg/day during days 8 to 16 of gestation produced no teratogenic effects.
An in vitro study using foetal mouse salivary glands in culture to detect embryotoxicity
indicated that allopurinol would not be expected to cause embryotoxicity without also
causing maternal toxicity.
Lactose
Maize starch
Povidone K-30
Crospovidone
Magnesium stearate
None known.
6.3 Shelf life

3 years.

Container pack: Do not store above 25°C. Store in the original container. Keep the container
tightly closed.
Blister pack: Do not store above 25°C. Store in the original package.

Polypropylene tablet containers fitted with low density polyethylene caps.
Pack sizes: 28,100,500 and 1000 tablets.
Blister pack (clear PVC 250 micron and plain aluminium foil 20 micron)
Pack size: 28 tablets.
Not all pack sizes may be marketed.

Not applicable.
SUMMARY OF PRODUCT CHARACTERISTICS OF BETAHISTINE TABLETS

(SR/IR) 8 MG /16 MG /24 MG
Betahistine 8mg, 16mg & 24mg tablets
Package leaflet: Information for the user
Betahistine 8 mg tablets
Betahistine dihydrochloride
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to others. It may harm
them, even if their signs of illness are the same as yours.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Betahistine is and what it is used for

2. What you need to know before you take Betahistine
3. How to take Betahistine
4. Possible side effects
5. How to store Betahistine
6. Contents of the pack and other information
1. What Betahistine is and what it is used for
Betahistine is a type of medicine called a “histamine analogue”.
Betahistine is used for:
Ménière’s disease – the signs of this include:
feeling dizzy (vertigo)

ringing in the ears (tinnitus)
hearing loss or hearing difficulty
This medicine works by improving blood flow in the inner ear. This lowers the build up of
pressure.
2. What you need to know before you take Betahistine
Do not take Betahistine
if you are allergic to betahistine or to any of the other ingredients of this medicine (listed in
section 6)
if you have a pheochromocytoma, a rare tumour of the adrenal gland
Warnings and precautions
Talk to your doctor or pharmacist before taking Betahistine.
if you have a stomach ulcer (peptic ulcer)

if you have asthma
if you have nettle rash, skin rash or a cold in the nose caused by an allergy, since these
complaints may be exacerbated.
if you have low blood pressure
If you suffer from any of the above conditions, consult your doctor about whether you may
take Betahistine tablets.
These groups of patients should be monitored by a doctor during treatment.
Children
Betahistine is not recommended for those under 18 years old.
Other medicines and Bethisitine
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.
In particular, tell your doctor or pharmacist if you are taking any of the following medicines:
Anti-histamines – This is because in theory betahistine may not work properly. Also,
betahistine may lower the effect of anti-histamines.
Monoamine-oxidase inhibitors (MAOIs) – used to treat depression or Parkinson’s disease.

These may increase the exposure of betahistine.
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist
before taking Betahistine.
Taking Betahistine with food and drink

Betahistine can be taken with or without food. However, Betahistine can cause mild stomach
problems (listed in section 4). Taking betahistine with food can help reduce stomach
problems.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a
baby, ask your doctor or pharmacist for advice before taking this medicine.
Do not take betahistine dihydrochloride tablets if you are pregnant unless your doctor has
decided that it is absolutely necessary. Ask your doctor for advice.
Do not breast-feed while using betahistine dihydrochloride tablets unless instructed by your
doctor. It is not known if betahistine passes into breast milk.
Driving and using machines
Betahistine is not likely to affect your ability to drive or use tools or machinery.
However, remember that the disease for which you are being treated with Betahistine
(Ménière’s disease) can make you feel dizzy or sick, and can affect your ability to drive and
use machines.
3. How to take Betahistine
Always take this medicine exactly as your doctor or pharmacist has told you. Check with
your doctor or pharmacist if you are not sure.
Your doctor will adjust your dose, depending on your progress.

Keep taking your medicine. The medicine can take a while to start to work.
How to take Betahistine
Swallow the tablets with water.

Take the tablet with or after a meal. However, Betahistine can cause mild stomach problems
(listed in Section 4). Taking Betahistine with food can help reduce stomach problems.
How much Betahistine to take
Always follow your doctor’s instructions because your doctor might adjust your dose.
The recommended dose is:
Adults
The recommended dose is 24 mg to 48 mg per day. 8 mg tablets: one or two tablets three
times a day.
16 mg tablets: half or one tablet three times a day.
If you take more than one tablet each day, spread your tablets evenly over the day. For
example, take one tablet in the morning, one at midday and one in the evening.
Try to take your tablet at the same time each day. This will make sure that there is a steady
amount of the medicine in your body. Taking at the same time will also help you remember
to take your tablets. Betahistine is not recommended for use in children.
If you take more Betahistine than you should
If you or someone else takes too many Betahistine tablets (an overdose), you may feel sick
(nauseous), sleepy or have stomach pain. Talk to a doctor or go to a hospital immediately.
Take the Betahistine pack with you.
If you forget to take Betahistine
Wait until you have to take your next dose. Do not take a double dose to make up for a
forgotten tablet.
If you stop taking Betahistine
Keep taking your tablets until your doctor tells you to stop.
Even when you start feeling better, your doctor may want you to carry on taking the tablets
for some time to make sure that the medicine has worked completely.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very few adverse effects have been reported with betahistine.
The following serious side effects may occur during treatment with Betahistine:
Allergic reactions:
a red or lumpy skin rash or inflamed itchy skin

swelling of your face, lips, tongue or neck
a drop in your blood pressure
loss of consciousness
difficulty breathing
If any of these side effects occur you should stop treatment immediately and contact your
doctor.
Other side effects include:
Common (may affect up to 1 in 10 people):
feeling sick (nausea)

indigestion (dyspepsia)
headache.
Other side effects that have been reported with the use of betahistine
Mild stomach problems such as being sick (vomiting), stomach pain, stomach swelling
(abdominal distension) and bloating. Taking betahistine with food can help reduce stomach
problems.
Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. You can also report side effects directly (see details below).
By reporting side effects you can help provide more information on the safety of this
medicine.
Malta
ADR Reporting
The Medicines Authority
Post-Licensing Directorate
203 Level 3, Rue D’Argens
GŻR-1368 Gżira
Website: www.medicinesauthority.gov.mt
e-mail: postlicensing.medicinesauthority@gov.mt
The United Kingdom
Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard
or search for MHRA Yellow Card in the Google Play or Apple App Store.
5. How to store Betahistine
Keep this medicine out of the sight and reach of children.
This medicinal product does not require any special storage conditions.
Do not use this medicine after the expiry date which is stated on the label, carton, bottle after
(EXP).The expiry date refers to the last day of that month.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist
how to throw away medicines you no longer use. These measures will help protect the
environment.
6. Contents of the pack and other information
What Betahistine contains
The active substance is betahistine dihydrochloride.

Each tablet contains 8 mg betahistine dihydrochloride.
The other ingredients are microcrystalline cellulose, mannitol, povidone, crospovidone, citric
acid anhydrous, colloidal anhydrous silica, talc and stearic acid.
What Betahistine looks like and the contents of the pack
Tablet.
White to off-white round, flat uncoated tablets debossed with ‘X’ on one side and ‘87’ on the
other side.
White to off-white round uncoated tablets debossed with ‘X’ and a break line on one side and
‘88’ on the other side. The tablet can be divided into equal doses.
White to off-white round uncoated tablets debossed with ‘X’ and a break line on one side and
‘89’ on the other side. The tablet can be divided into equal doses.
Betahistine Tablets are available in:
Blisters of Polyamide/ Aluminium/ PVC/ Aluminium:
8 mg: 10, 20, 30, 50, 60, 84, 90, 100 & 120 tablets
16 mg: 10, 20, 30, 60, 84 & 90 tablets

24 mg: 10, 20, 30, 50, 60 & 90 tablets
White opaque round HDPE bottle with polypropylene closure containing cotton coil: 30 and
1000 tablets.
Not all pack sizes may be marketed

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SUMMARY OF PRODUCT CHARACTERISTICS OF BILASTINE TABLETS 20 MG

1. Name of the medicinal product

2. Qualitative and quantitative composition

4.2 Posology and method of administration

4.4 Special warnings and precautions for use

In patients with moderate or severe renal impairment coadministration of bilastine

 Interaction with grapefruit juice: concomitant intake of bilastine 20 mg and grapefruit

 Interaction with ketoconazole or erythromycin: Concomitant intake of bilastine and

 Interaction with diltiazem: Concomitant intake of bilastine 20 mg and diltiazem 60

 Interaction with lorazepam: Concomitant intake of bilastine 20 mg and lorazepam 3

4.6 Fertility, pregnancy and lactation

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Frequencies are assigned as follows:

Description of selected adverse reactions

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after

 Critical evaluation of bilastine's multiple dose (100 mg x4 days) effect on ventricular

 In the event of overdose symptomatic and supportive treatment is recommended.

 There is no known specific antidote to bilastine.

 Bilastine is a non-sedating, long-acting histamine antagonist with selective peripheral

 In clinical trials performed in adult and adolescent patients with allergic

 No clinically relevant prolongation of QTc interval or any other cardiovascular effect

5.2 Pharmacokinetic properties

 Absorption: Bilastine is rapidly absorbed after oral administration with a time to

 Biotransformation: Bilastine did not induce or inhibit activity of CYP450 isoenzymes

 Elimination: In a mass balance study performed in healthy volunteers, after

 Linearity: Bilastine presents linear pharmacokinetics in the dose range studied (5 to

 Hepatic impairment: There are no pharmacokinetic data in subjects with hepatic

 Paediatric population: No pharmacokinetic data are available in adolescents (12 years

 In reproduction toxicity studies effects of bilastine on the foetus (pre-and post-

 As seen in a distribution study in rats with determination of drug concentrations by

6.1 List of excipients

6.2 Incompatibilities: Not applicable.

6.3 Shelf life: 5 years

6.5 Nature and contents of container:

 The medicinal product is packaged in a blister, consisting of two parts:

 laminate, consisting of oriented polyamide (outer side of laminate), aluminium and

6.6 Special precautions for disposal and other handling

Cetirizine HCl is metabolite of hydroxyzine. It is a second generation antihistamine (selective

3. Cetirizine HCl ODT formulation

6.1 General Biopharmaceutics

Among the serious reports, those most commonly reported were:

 FDA Adverse Event Reporting System (AERS) data (01/01/01 – 12/31/08)

13. Other Relevant Regulatory Issues

15. Decision/Action/Risk Benefit Assessment

Division Director Review

1. Name of the medicinal product

2. Qualitative and quantitative composition

Excipients with known effect

4.2 Posology and method of administration

 Children aged 2 to 6 years:

 Xyzal contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which

 Xyzal contains maltitol liquid

 In sensitive patients, the concurrent administration of cetirizine or levocetirizine and

4.6 Fertility, pregnancy and lactation

The use of levocetirizine may be considered during pregnancy, if necessary.

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

• Immune system disorders:

Not known: hypersensitivity including anaphylaxis

• Metabolism and nutrition disorders:

Not known: increased appetite

Not known: aggression, agitation, hallucination, depression, insomnia, suicidal ideation,