CMDh/223/2005

February 2014

Public Assessment Report

Scientific discussion

Allopurinol Sandoz
allopurinolum

FI/H/894/01-02/DC

Date: 9.8.2016
I. INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application
for Allopurinol Sandoz 100 mg, tablet, and Allopurinol Sandoz 300 mg, tablet, in the treatment of
hyperuricemia, in the following therapeutic indications

Adults
• All forms of hyperuricaemia not controllable by diet, including secondary hyperuricaemia of
differing origin and clinical complications of hyperuricaemic states, particularly manifest
gout, urate nephropathy and for the dissolution and prevention of uric acid stones.

• The management of recurrent mixed calcium oxalate stones in concurrent hyperuricaemia,

when fluid, dietary and similar measures have failed.

Children and adolescents

• Secondary hyperuricaemia of differing origin

• Uric acid nephropathy during treatment of leukaemia

• Hereditary enzyme deficiency disorders, Lesch-Nyhan syndrome (partial or total hypoxanthin-

guanin phosphoribosyl transferase deficiency) and adenine phosophoribosyl transferase
deficiency.

is approvable as satisfactory responses have been given to all issues in the three lists of questions.

The marketing authorisation has been granted pursuant to Article of Directive 2001/83/EC.

Allopurinol is a xanthine-oxidase inhibitor (ATC code: M04AA01). 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.

Allopurinol is widely regarded as the urate-lowering drug of choice and is the only xanthine oxidase
inhibitor on the market in European countries. Allopurinol is indicated for reducing urate/uric acid
formation in conditions where urate/uric acid deposition has already occurred or is a predictable
clinical risk for example for the prophylaxis of gout, gouty arthritis, skin tophi, nephrolithiasis; for
hyperuricaemia associated with leukaemia, radiotherapy, antineoplastic agents and during therapy with
diuretics of the thiazide or similar type; for prophylaxis of uric acid and calcium oxalate renal stones
and in certain enzyme disorders which lead to over production of urate for example Lesch-Nyhan
syndrome.

This decentralised application concerns a generic version of allopurinol under a number of trade
names. In this Assessment Report the Allopurinol Sandoz (Allopurinol Sandoz 100 mg tablet and
Allopurinol Sandoz 300 mg tablet) name is used.

Allopurinol 100 mg and 300 mg tablets from Sandoz are a generic form of an established brand of
Allopurinol 100 mg and 300 mg tablets available on the European market.

The originator product is Zyloric by Aspen Europe GmbH (Bad Oldesloe, Germany. The product is
present on the market as Zyloric 100 mg tablets and Zyloric 300 mg tablets, registered since the year
1966 and 1977, respectively. The use of European Reference Medicinal Product is applicable to the
following CMSs: BE, BG, CZ, DK, EE, ES, HU, LU, LV, PT, RO, SI and SK.

PAR Scientific discussion 2/9

The reference medicinal product against which BE has been conducted i.e. Zyloric 300 mg tablet were
originally developed by Wellcome Foundation Limited, UK (100 mg and 300 mg tablets) in 1980. The
marketing authorisation of Zyloric in the European Union is based on the complete registration
dossier. The reference product has been authorized in European Union for more than 10 years, thus the
period of data exclusivity has expired.

With Finland (FI) as the Reference Member State in this Decentralized Procedure, Sandoz
Pharmaceuticals is applying for the Marketing Authorisations for Allopurinol Sandoz in the following
member states: BE, BG, CZ, DK, EE, ES, HU, LU, LV, NL, PL, PT, RO, SE, SI, SK and NO.

This is an abridged application, according to Article 10.2(b) of Directive 2001/83/EC, as amended; a

so called ’generic’ application. It can be concluded that all requirements for an abridged application
are fulfilled and the regulatory reference to Zyloric 300 mg tablets is justified. Essential similarity to
the reference product has been shown.

Pharmacovigilance system
A pharmacovigilance system has been provided.

Environmental Risk Assessment

Since Allopurinol Sandoz is intended for generic substitution, this will not lead to an increased
exposure to the environment. Consequently, no changes in the environmental risks that are not already
known for active substance are to be anticipated. An environmental risk assessment is, therefore, not
deemed necessary.

In compiling this application the Applicant has adhered to pertinent guidance.

II. QUALITY ASPECTS

II.1 Introduction

The pharmaceutical form of Allopurinol Sandoz is tablets. One tablet contains 100 mg or 300
mg allopurinol. The primary pack of the product is either PVC/Alu blister or HDPE container.

II.2 Drug Substance

Allopurinol (C5H4N4O) used in the manufacture of the commercial batches of Allopurinol Sandoz 100
mg and Allopurinol Sandoz 300 mg tablets complies with the specifications of Ph.Eur and it has an
EDQM Certificate of Suitability (CEP) with an additional test for residual solvent, formamide.
Allopurinol has no chiral center, and does not form isomers. According to the CEP the re-test period
of the allopurinol used is 60 months if stored in double polyethylene bags placed in a fiber or
polyethylene drum.

II.3 Medicinal Product

Allopurinol 100 mg tablets are white to off white, scored, flat cylindrical tablets debossed with ‘I’ and
‘56’ on either side of the break line, on one tablet side, and plain on other side. Diameter of tablets is
approx. 8 mm.

Allopurinol 300 mg tablets are white to off white, scored, flat cylindrical tablet debossed with ‘I’ and
‘57’ on either side of the break line on one tablet side and plain on other side. Diameter of the tablets
is approx. 11 mm.
PAR Scientific discussion 3/9
The composition of Allopurinol Sandoz 100 mg tablets and Allopurinol Sandoz 300 mg tablets is as
follows in the table below:

Ingredients Allopurinol Sandoz Allopurinol Sandoz

100 mg tablets 300 mg tablets
Drug substance mg/tablet mg/ tablet quality
Allopurinol 100 mg 300 mg Ph.Eur.
Excipients
Lactose monohydrate q.s. q.s. Ph.Eur.
(as Lactose) (35 mg) (106 mg)
Maize starch q.s. q.s. Ph.Eur.
Povidone q.s. q.s. Ph.Eur.
Magnesium stearate q.s. q.s. Ph.Eur.

q.s. quantum satis = the amount needed

Ph.Eur. = European Pharmacopoeia

The pharmaceutical dosage form is tablets. The active ingredient of the Allopurinol Sandoz tablets is
Allopurinol. The active ingredient complies with the pharmacopoeia monograph (Ph.Eur.). All the
excipients are commonly used in tablet drug products. The excipients comply with the pharmacopoeia
monographs (Ph.Eur.)

Manufacturing stages and in-process controls of the drug product have been described in marketing
authorisation documentation in detail. All the used analysis methods have been adequately validated
and are stable. Batch analysis data have been presented. Release and shelf-life specifications of the
drug product have been accepted.

Two package types have been accepted for the drug product. The tablets are packed in aluminium-
plastic blister packages (PVC/Al), which are packed in a cardboard outer package or in HDPE
container with PP child resistant cap or PP non-child resistant cap with induction seal.

Based on the stability data provided, a shelf-life of 2 years has been granted for tablets packed in
PVC/Alu blister package. The tablets packed in HDPE container have a shelf-life of 1 year. After the
first opening of the HDPE container the shelf-life is 6 months.

III. NON-CLINICAL ASPECTS

Pharmacodynamic, pharmacokinetic and toxicological properties of allopurinol are well known. As
allopurinol is a widely used, well-known active substance, the applicant has not provided additional
non-clinical studies and further studies are not required. Overview based on literature review is, thus,
appropriate.

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology was on
request updated with a discussion on the impurity profile of the drug product and the safety of the
excipients. The non-clinical overview is thus considered adequate and acceptable.

There are no objections to approval of Allopurinol Sandoz 100 mg and Allopurinol Sandoz 300 mg
from a non-clinical point of view.

PAR Scientific discussion 4/9

IV. CLINICAL ASPECTS
Pharmacodynamic, pharmacokinetic and toxicological properties of allopurinol are well known. As
allopurinol is a widely used, well-known active substance, the applicant has not provided additional
non-clinical studies and further studies are not required. The provided overview based on literature
review is appropriate.

The clinical assessment report represents an evaluation of the key elements of the information
provided by the company in the dossier. As allopurinol is a widely used, well-known active substance,
with a well-known safety and efficacy profile, the applicant has not provided additional clinical
studies and further studies are not required. The provided overview based on literature review is
appropriate. The clinical overview on the clinical pharmacology, efficacy and safety is considered
adequate to support the claimed indication.

The proposed indication in adults is:

All forms of hyperuricaemia not controllable by diet including secondary hyperuricaemia of differing
origin and in clinical complications of hyperuricaemic states, particularly manifest gout, urate
nephropathy and for the dissolution and prevention of uric acid stones.
The management of recurrent mixed calcium oxalate stones in concurrent hyperuricaemia, when fluid,
dietary and similar measures have failed.

The proposed indication in children and adolescents is:

Secondary hyperuricaemia of differing origin.
Uric acid nephropathy during treatment of leukaemia.
Hereditary enzyme deficiency disorders, Lesch-Nyhan syndrome (partial or total hypoxanthin-guanin
phosphoribosyl transferase deficiency) and adenine phosophoribosyl transferase deficiency.

Posology and method of administration

Proposed Posology
Dosage in 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.

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.

Elderly
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 Dosage in renal impairment and section 4.4.

Renal impairment

PAR Scientific discussion 5/9

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.
The following schedule may serve as guidance for dose adjustments at renal impairment:
Creatinine Clearance Daily Dose
> 20 ml/min normal dose
10 to 20 ml/min 100 to 200 mg per day
< 10 ml/min 100 mg/day or longer dose intervals

In severe renal insufficiency, it may be advisable to use less than 100 mg per day or to use single
doses of 100 mg 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 100micromol/litre (15.2 mg/litre).

Dosage in 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 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 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 Dosage
in renal impairment should be followed.

Monitoring Advice: The dosage should be adjusted by monitoring serum urate concentrations and
urinary urate/uric acid levels at appropriate intervals.

The basis of the BE study has also been adequately justified. In support of its application, the applicant
has submitted one bioequivalence study: A Randomized, Open Label, Balanced, Two-Treatment, Two-
Period, Two-Sequence, Single Dose, Crossover, Bioequivalence Study of Allopurinol 300 mg tablets of
Indoco Remedies Ltd, India with Zyloric 300 mg tablets of Aspen Europe GmbH, Industriestrasse 32-
36, D- 23843, Bad Oldesloe, Germany in normal, healthy, adult, human subjects under fasting
condition. No evidence has been found of reduced bioavailability of allopurinol on co-administration
with food, thus a BE study conducted in the fasting state is adequate and sufficient to establish the
bioequivalence between the test and reference products. No statistically significant differences were
observed between Allopurinol 300 mg tablets and Zyloric 300 mg tablets for any of the
pharmacokinetic parameters AUC0-t and Cmax. The 90% confidence intervals of AUC0-t and Cmax
lie within the bioequivalence range of 80-125 %. The test and reference products were found to be
equivalent. Allopurinol 300 mg tablets were well tolerated. No new safety concern emerged from the
provided data. Overall the safety of the test product was acceptable and comparable to that of the
reference. Based on the submitted bioequivalence study ARL/13/249 Allopurinol Sandoz 300 mg is
considered bioequivalent with the originator Zyloric 300 mg. The results of the submitted BE study
with the 300 mg formulation can be extrapolated to the other strength 100 mg, according to the
conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/
Corr.

The analytical methods covered the evaluation of selectivity, lower limit of quantitation, the response
function (calibration curve performance), accuracy, precision and stability. The acceptance criteria
defined in the Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 Rev. 1

PAR Scientific discussion 6/9

Corr.) were met for the method validation. The summary of the original validation results provided by
the Applicant is acceptable. Statement on the GLP compliance was provided on request.

SmPC and PL
The SmPC of the reference medicinal product is not harmonised across the Member States. On the
basis of the current assessment, the SmPC and the PL, of this procedure were aligned with those of the
EU DC procedure UK/H/1313/001 and UK/H/1313/003. The final Product Information is acceptable.

Conclusion
In conclusion, the application contained an adequate review of published clinical and non-clinical data
and bioequivalence with the reference medicinal product was demonstrated by appropriate
bioavailability studies and a bio-waiver for the Allopurinol Sandoz 100 mg tablet has been acceptably
justified. Approval was recommended from the clinical and non-clinical point of view.

Summary Pharmacovigilance system and Risk Management Plan

The company has provided a RMP in support of its application for a generic product, which is no
different from the reference product in terms of dose or formulation that would have any implications
for safety.
Summary of safety concerns
The Applicant identifies the following safety concerns
Table Summary of safety concerns

Having considered the data in the safety specification and in line with the previous DCP process in EU
(SE/H/1394/001-002/DC), the safety specifications were aligned with the safety specification of
Allopurinol Orion 100 mg and 300 mg. The public summary of this RMP has been published on the
Danish authority website:
https://sundhedsstyrelsen.dk/da/medicin/regulering/godkendelse-af-medicin/laegemidler-godkendt-
med-et-sammendrag-af-risikostyringsplanen.aspx?letter=A&subletter=i-l
The safety specification of the above process includes the following safety concerns:
Important identified risks: Serious hypersensitivity (allergic) reactions and increased risk for certain
serious skin reactions in people of Han Chinese or Thai origin.
Important potential risks: Concomitant administration of ampicillin/amoxicillin.
Missing information: Administration during pregnancy and lactation

PAR Scientific discussion 7/9

Pharmacovigilance Plan
Routine pharmacovigilance is sufficient to identify and characterise the risks of the product.
Routine PSUR reporting Routine PSUR reporting is not required for this product.
Additional Post-authorisation Efficacy Studies
No post-authorisation efficacy studies are necessary.
Risk minimisation measures
In line with the reference product routine risk minimisation measures are sufficient to minimise the
risks of the product in the proposed indication(s).
MAH’s Summary of the RMP
The Applicant has updated the safety specification to be in line with a previously accepted safety
specification in the EU.
The RMS recommendations
The RMP is considered acceptable.
RMS advice on conditions or restrictions with regard to the safe and effective use of the medicinal
product
No other conditions of the Marketing Authorisation relating to the RMP are necessary.

Risk management system

An updated RMP should be submitted:
1. At the request of the national competent authority;
2. Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of an
important (pharmacovigilance or risk minimisation) milestone being reached.
Additional risk minimisation Measures No conditions are necessary.
Obligation to conduct post-authorisation measures No conditions are necessary.

V. USER CONSULTATION

A user consultation with target patient groups on the package information leaflet (PIL) has
been performed on the basis of a bridging report making reference to the reference PIL
Allopurinol Warren 100 mg and 300 mg tablets. The bridging report submitted by the applicant
has been found acceptable.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

The essential similarity between reference product Zyloric 300 mg tablets and the test product
Allopurinol 300 mg tablets was evaluated on the basis of the drug substance content, pharmaceutical
form, and the route of administration, dissolution profile and comparative bioavailability.

1. Quantitative and qualitative composition in terms of active drug substance is same in Zyloric 300
mg tablets and the test product Allopurinol 300 mg tablets.
2. Pharmaceutical form is the same i.e. uncoated tablets.
3. Route of administration is same i.e. oral.
4. The dissolution profiles of compared products are similar.

In support of this application, the Applicant submitted one bioequivalence study: A Randomized, Open
Label, Balanced, Two-Treatment, Two-Period, Two-Sequence, Single Dose, Crossover,
Bioequivalence Study of Allopurinol 300 mg tablets of Indoco Remedies Ltd, India with Zyloric 300
PAR Scientific discussion 8/9
mg tablets of Aspen Europe GmbH, Industriestrasse 32-36, D- 23843, Bad Oldesloe, Germany in
normal, healthy, adult, human subjects under fasting condition. No statistically significant differences
were observed between Allopurinol 300 mg tablets and Zyloric 300 mg tablets for any of the
parameters AUC0-t and Cmax. The 90% confidence intervals of AUC0-t and Cmax lie within the
bioequivalence range of 80-125 %. The test and reference products were found to be equivalent.
Allopurinol 300 mg tablets were well tolerated. No new safety concern emerged from the provided
data. Overall the safety of the test product was acceptable and comparable to that of the reference
product. Furthermore, on the basis of the justification provided by the Applicant, a bio-waiver for the
Allopurinol Sandoz 100 mg tablet appears justified and is acceptable. In the design and conduct of the
study relevant guidance has been adhered to.

Based on assessment of the provided data, Allopurinol 300 mg tablet can be considered essentially
similar to the reference medicinal product Zyloric 300 mg tablet, as it was shown to have the same
qualitative and quantitative composition in active substances and the same pharmaceutical form as the
reference medicinal product, and bioequivalence with the reference medicinal product was
demonstrated by appropriate bioavailability studies and a bio-waiver for the Allopurinol Sandoz 100
mg tablet has been acceptably justified.

In conclusion, this application contains an adequate review of published quality, non-clinical and
clinical data and bioequivalence has been shown. The risk/benefit ratio is considered positive and
approval is recommended for Allopurinol Sandoz 100 mg, tablet and Allopurinol Sandoz 300 mg,
tablet.

PAR Scientific discussion 9/9