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Public Assessment Report

Name of the Product:

Citamed

150 mg and 500 mg film-coated tablets

(capecitabine)

Procedure number:

HU/H/0327/001-002/DC Marketing authorisation holder:

in HU and RO: MEDISON PHARMA S.R.L., România; in SK: Medison-Iscare a.s., Slovakia.

Date: 5 November 2013

National Institute of Pharmacy Directorate

of the National Institute for Quality- and Organiza-tional Development in Healthcare and Medicines

Budapest, Hungary

National Institute of Pharmacy Citamed Directorate 150 mg and 500 mg film-coated tablets of the National Institute for Quality- Public Assessment Report and Organizational Development in Healthcare and Medicines Budapest, Hungary

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CONTENT LAY SUMMARY .............................................................................................................................. 3 SCIENTIFIC DISCUSSION ............................................................................................................... 9 I. Introduction .................................................................................................................................. 10 II. Quality aspects

II.1 Introduction ................................................................................................................... 11 II.2. Drug substance .............................................................................................................. 11 II.3 Medicinal product .......................................................................................................... 12 II.4 Discussion on chemical, pharmaceutical and biological aspects ...................................... 14

III. Non-clinical aspects

III.1 Introduction .................................................................................................................. 15 III.2 Pharmacology ............................................................................................................... 15 III.3 Pharmacokinetics .......................................................................................................... 15 III.4 Toxicology ........................................................................................................ 16 III.5 Ecotoxicity/environmental risk assessment ........................................................ 16 III.6 Discussion on the non-clinical aspects ............................................................... 16

IV. Clinical aspects

IV.1 Introduction .................................................................................................................. 17 IV.2 Pharmacokinetics .......................................................................................................... 17 IV.3 Pharmacodynamics ....................................................................................................... 19 IV.4 Clinical efficacy............................................................................................................ 19 IV.5 Clinical safety ............................................................................................................... 19 IV.6 Discussion on clinical aspects ....................................................................................... 19

V. Overall conclusion, benefit/risk assessment and recommendation ................................................. 21 V.1 Conditions for the marketing authorisation .................................................................... 21 V.2 Summary of Product Characteristics............................................................................... 22 V.3 Package leaflet and user testing ...................................................................................... 22

UPGRADE: STEPS TAKEN AFTER THE INITIAL PROCEDURE WITH AN INFLUENCE ON THE PUBLIC ASSESSMENT REPORT


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LAY SUMMARY After careful assessment of its quality and therapeutic benefit/risk ration, the National Insti-tute of Pharmacy Directorate of the National Institute for Quality- and Organizational Devel-opment in Healthcare and Medicines, the national competent authority for Human medicinal products decided to issue the marketing authorisation of the medicinal product Citamed 150 and 500 mg film-coated tablets. The marketing authorisation was granted in a decentralised procedure with Hungary as reference member state. The national competent authorities of member states concerned in this procedure Romania and Slovakia did agree. The holders of the marketing authorisation are as follows: in HU and RO Medison Pharma S.R.L., România; in SK Medison-Iscare a.s., Slovakia. The active substance of Citomed 150 and 500 mg film-coated tablets (further on: Citomed) is capecitabine. The other ingredients are: tablet core: lactose anhydrous, croscarmellose sodium, hypromellose, microcrystalline

cellulose and magnesium stearate; tablet coating: hypromellose, titanium dioxide (E171), yellow and red iron oxide (E172)

and talc. The Citomed

150 mg film-coated tablets are light peach coloured, oblong shaped, biconvex, de-bossed with “150” on one side and plain on other side?

500 mg film-coated tablets are peach coloured, oblong shaped, biconvex, debossed with “500” on one side and plain on other side,

packed in clear PVC / PVdC - Alu blisters and/or OPA/Al/PVC-Al. Citamed belongs to the group of medicines called "cytostatic medicine", which stops the growth of cancer cells. Capecitabine itself is not a cytostatic active substance, but, having been absorbed by the body is it changed into an active anti-cancer medicine (more in the tu-mour tissue than in normal tissues). Citamed is indicated for the treatment of colon, rectal, gastric, or breast cancers. Furthermore, Citamed is prescribed by doctors to prevent new occurrence of colon cancer after complete removal of the tumour by surgery. Citamed may be used either alone or in combination with other medicine.


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The necessary information before taking Citamed Do not take Citamed, if you are allergic to capecitabine or any of the other ingredients of this medicine. You must in-

form your doctor if you know that you have an allergy or over-reaction to this medicine; previously have had severe reactions to fluoropyrimidine therapy (a group of anticancer

medicines such as fluorouracil); are pregnant or nursing; have severely low levels of white cells or platelets in the blood (leucopenia, neutropenia

or thrombocytopenia); have severe liver or kidney problems; have a known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD) in-

volved in the metabolism of uracil and thymine; or are being treated now or have been treated in the last 4 weeks with brivudine, sorivudine

or similar classes of substance as part of herpes zoster (chickenpox or shingles) therapy. Further warnings and precautions Consult your doctor or pharmacist before taking Citamed if you have liver or kidney diseases; have or had heart problems (for example an irregular heartbeat or pains to the chest jaw and back

brought on by physical effort and due to problems with the blood flow to the heart); have brain diseases (for example. cancer that has spread to the brain, or nerve damage (neuropa-

thy); have calcium imbalances (seen in blood tests); have diabetes; have diarrhoea; are or become dehydrated; have imbalances of ions in your blood (electrolyte imbalances, seen in tests). DPD deficiency is a rare condition present at birth that is not usually associated with health problems unless you receive certain medicines. If you have an unrecognized DPD deficiency and take capecitabine, you may experience severe forms of the side effects listed under sec-tion Possible side effects. Contact your doctor immediately if you are concerned about any of the side effects including such not listed in the package leaflet. Children and adolescents: Citamed is not indicated to them. Do not give Citamed to children and adolescent.


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Other medicines and Citamed Before starting the treatment, tell your doctor if you are taking or have recently taken any other medicines. This is extremely important, for they may interact with each other by strengthening or weakening the effect of the medicines. You need to be particularly careful if you are taking any of the following: gout medicines (allopurinol), blood-thinning medicines (coumarin, warfarin), certain anti-viral medicines (sorivudine and brivudine), or medicines for seizures or tremors (phenytoin), interferon alpha or radiotherapy and certain medicines used to treat cancer (folinic acid, oxaliplatin, bevaci-

zumab).

Taking Citamed with food and drink It should not be taken later than 30 minutes after meals. Pregnancy and breast-feeding Before starting treatment, you must tell your doctor if you are pregnant, or think you are pregnant or if you intend to become pregnant. You should not take Citamed if you are preg-nant. You should also not breast-feed if you are taking Citamed. Driving and using machines: Citamed may make you feel dizzy, nauseous or tired. It is therefore possible that Citamed could affect your ability to drive a car or operate machinery. Citamed contains anhydrous lactose This medicinal product contains anhydrous lactose as an excipient. If you have been told by your doctor that you have intolerance to certain sugars such as lactose, contact your doctor before taking Citamed. How to take Citamed Citamed tablets should be swallowed whole with water and within 30 minutes of a meal. The dose of Citamed is based on the body surface area. This is calculated from the height and weight. The usual dose for adults is 1250 mg/m2 of body surface area, taken twice daily (morning and evening).


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Citamed tablets are usually taken for 14 days followed by a 7 day rest period (when no tablets are taken). This 21 day period is one treatment cycle. When taken in combination with other medicinal products the usual dose for adults may be less than 1250 mg/m2 of body surface area, and you may need to take the tablets over a differ-ent time period (e.g. every day, with no rest period). Your doctor may prescribe combination of different strength of Citamed. Take the tablets in the combination prescribed by your doctor for your morning and eve-

ning doses. Take the tablets within 30 minutes after the end of a meal (breakfast and dinner). If you take more Citamed than you should, contact your doctor before taking the next dose. You might experience the following side effects if you take a much more capecitabine than you should: feeling or being sick, diarrhoea, inflammation or ulceration of the gut or mouth, pain or bleeding from the intestine or stomach, or bone marrow depression (reduction in cer-tain kinds of blood cells). Tell your doctor immediately if you experience any of these symp-toms. If you forget to take Citamed: do not take the missed dose at all and do not double the next one. Instead, continue your regular dosing schedule and check with your doctor. If you stop taking Citamed There are no specific side effects occurring when stopping capecitabine treatment. However, if you are using concomitantly coumarin anticoagulants (containing e.g. phenprocoumon), stopping capecitabine might require that your doctor adjusts your anticoagulant dose. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. Stop taking Citamed immediately and contact your doctor if any of these symptoms occur: diarrhoea: if you have an increase of 4 or more bowel movements in addition to your

normal bowel movements during the day or any diarrhoea at night; vomiting: if you vomit more than once in a 24-hour time period; nausea: if you lose your appetite, and the amount of food you eat each day is much less

than usual; stomatitis: if you have pain, redness, swelling or sores in your mouth and/or throat; hand-and-foot skin-reaction: if you have pain, swelling, redness or tingling of hands

and/or feet; fever: if you have a temperature of 38°C or greater; infection: if you experience signs of infection caused by bacteria or virus, or other organ-

isms;


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chest pain: if you experience pain localized to the centre of the chest, especially if it oc-curs during exercise.

If recognised at an early stage, these side effects usually improve within 2 to 3 days after dis-continuation of the treatment. If these side effects continue, however, contact your doctor immediately. Your doctor may instruct you to restart treatment at a lower dose. In addition to the above mentioned, when Citamed is used alone, very common (that may af-fect more than 1 person of 10) side effects are: abdominal pain, rash, dry or itchy skin, tiredness, loss of appetite (anorexia). These side effects can become severe; therefore, it is important that you always contact your doctor immediately when you start to experience a side effect. Your doctor may instruct you to decrease the dose and/or temporarily discontinue treatment with Citamed. This will help reduce the likelihood that the side effect continues or becomes severe. Other possible side effects are: common (that may affect up to 1 of 10 people):

decreases in the number of white blood cells or red blood cells (seen in tests), dehydration, weight loss, sleeplessness (insomnia), depression, headache, sleepiness, dizziness, abnormal sensation in the skin (numbness or tingling sensation), taste changes, eye irritation, increased tears, eye redness (conjunctivitis), inflammation of the veins (thrombophlebitis), shortness of breath, nose bleeds, cough, runny nose, cold sores or other herpes infections, infections of the lungs or respiratory system (e.g. pneumonia or bronchitis), bleeding from the gut, constipation, pain in upper abdomen, indigestion, excess wind,

dry mouth, skin rash, hair loss (alopecia), skin reddening, dry skin, itching (pruritus), skin discol-

ouration, skin loss, skin inflammation, nail disorder, pain in the joints, or in the limbs (extremities), chest or back, fever, swelling in the limbs, feeling ill, problems with liver function (seen in blood tests) and increased blood bilirubin (ex-

creted by the liver); uncommon (that may affect up to 1 in 100 people):

blood infection, urinary tract infection, infection of the skin, infections in the nose and throat, fungal infections (including those of the mouth), influenza, gastroenteritis, tooth abscess,

lumps under the skin (lipoma), decreases in blood cells including platelets, thinning of blood (seen in tests),


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allergy, diabetes, decrease in blood potassium, malnutrition, increased blood triglycerides, confusional state, panic attacks, depressed mood, decreased libido, difficulty speaking, impaired memory, loss of movement coordination, balance disor-

der, fainting, nerve damage (neuropathy) and problems with sensation, blurred or double vision, vertigo, ear pain, irregular heartbeat and palpitations (arrhythmias), chest pain and heart attack (infarc-

tion), blood clots in the deep veins, high or low blood pressure, hot flushes, cold limbs (ex-

tremities), purple spots on the skin, blood clots in the veins in the lung (pulmonary embolism), collapsed lung, coughing

up blood, asthma, shortness of breath on exertion, bowel obstruction, collection of fluid in the abdomen, inflammation of the small or

large intestine, the stomach or the oesophagus, pain in the lower abdomen, abdominal dis-

comfort, heartburn (reflux of food from the stomach), blood in the stool, jaundice (yellowing of skin and eyes), skin ulcer and blister, reaction of the skin with sunlight, reddening of palms, swelling

or pain of the face, joint swelling or stiffness, bone pain, muscle weakness or stiffness, fluid collection in the kidneys, increased frequency of urination during the night, in-

continence, blood in the urine, increase in blood creatinine (sign of kidney dysfunc-tion),

unusual bleeding from the vagina, swelling (oedema), chills and rigors.

Some of these side effects are more common when capecitabine is used with other medicines for the treatment of cancer. Other side-effects seen in this setting are the following: common:

decrease in blood sodium, magnesium or calcium, increase in blood sugar, nerve pain, ringing or buzzing in the ears (tinnitus), loss of hearing, vein inflammation, hiccups, change in voice, pain or altered/abnormal sensation in the mouth, pain in the jaw, sweating, night sweats, muscle spasm, difficulty in urination, blood or protein in the urine, bruising or reaction at the injection site (caused by medicines given by injection con-

comitantly; very rare (that may affect up to 1 in 10,000 people):

narrowing or blockage of tear duct (lacrimal duct stenosis),


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liver failure, inflammation leading to dysfunction or obstruction in bile secretion (cholestatic hepa-

titis), specific changes in the electrocardiogram (QT prolongation), certain types of arrhythmia (including ventricular fibrillation, torsade de pointes, and

bradycardia). How to store Citamed If in OPA/Al/Al/PVC-Al blister packs this medicinal product does not require any special storage condition. If in PVC-PvdC-Alu pack, do not store it above 25oC. Keep this medicine out of the sight and reach of children.


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Scientific discussion

This module reflects the scientific discussion for the approval of Citamed 150 mg and 500 mg film-coated tablets. The procedure was finalised at 12 March 2013. For information on changes

after this date please refer to the module ‘Update’.


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I. INTRODUCTION

In accordance to the Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, im-plemented by the Act CXV of 2005 on Medicinal Products for Human Use and on the Amendment of Other Regulations Related to Medicinal Products as well as by the Decree 52/2005 (IX. 18.) of the Minister of Health on placing medicinal products for human use on the market in Hungary, an application has been submitted to the reference and competent au-thorities of the Member States concerned. This Decentralised Procedure application (Reference member state, RMS: Hungary, con-cerned member states, CMS: Romania and Slovakia) related the generic version of capacit-abine 150 and 500 mg film-coated tablets, submitted under Article 10(1) of above Directive. The originator (reference) products were Xeloda® 150 and 500 mg film-coated tablets (Roche Registration Ltd., UK), authorised for marketing in the European Economic Area via central-ized procedure in 2001. Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Citamed 150 mg and 500 mg film-coated tablets. The holder of the marketing authorisation is Medison Pharma S.R.L., România (in HU and RO) and Medi-son-Iscare a.s., Slovakia (in SK). Citamed tablets are indicated for

the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) co-lon cancer,

the treatment of metastatic colorectal cancer, first-line treatment of advanced gastric cancer in combination with a platinum based

regimen, the treatment of patients with locally advanced or metastatic breast cancer after failure

of cytotoxic chemotherapy in combination with docetaxel. Previous therapy should have included an anthracycline.

Citamed is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline containing chemo-therapy regimen or for whom further anthracycline therapy is not indicated A comprehensive description of the indications and posology is given in the Summary of Product Characteristics.


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II. QUALITY ASPECTS II.1 Introduction This chemical-pharmaceutical assessment report concerns the application of Citamed 150 mg and 500 mg film-coated tablets via a decentralized procedure according to Article 10.1 of Di-rective 2001/83/EC (i.e. a generic application). The products have been developed by Intas Pharmaceuticals Ltd. Reference products are Xeloda® tablets (containing 150 mg and 500 mg capecitabine as ac-tive ingredient), original products of Hoffmann La Roche AG, Germany and marketed by Roche Registration Ltd., UK. II.2 Drug Substance Data on the quality and manufacture of the active substance were provided in the applicant’s submission using the Active Substance Master File (ASMF) procedure for both active sub-stance manufacturers with additional data in the marketing authorization dossier. The Quality Overall Summary is adequate. INN name: capecitabine Chemical names: - carbamic acid, [1-(5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-

oxo-4-pyrimidinyl]-, pentyl ester, - 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, - pentyl 1-(5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-

pyrimidine carbamate, - N(4)-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine

Structure:

The active substance is a white or off-white, not hygroscopic powder, freely soluble in methanol, soluble in acetonitrile and in alcohol and sparingly soluble in water. The active substance does not exhibit polymorphism. The ASMF holders presented complete details of the manufacturing process. Description of the manufacturing process of the active substance provided by both manufacturers is ade-quate.


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Evidence of the structure has been confirmed by IR spectroscopy, UV spectroscopy, 1H-NMR, 13C-NMR, elemental analysis, mass spectroscopy, XRD and DSC. The impurity profile of the API contains detailed information about genotoxic impurities, residual solvents and catalysts. Capecitabine is not official in the European Pharmacopoeia (Ph. Eur.). Therefore, the sub-stance is specified according to the USP monograph supplemented with several additional requirements which include the following tests: description, solubility, identification by IR and HPLC, water content, specific rotation, sulphated ash, heavy metals, assay by HPLC, re-lated substances by HPLC, residual solvents and microbiological purity. The presented specification is in accordance with the Ph. Eur. general monograph on Sub-stances for Pharmaceutical Use and the International Conference on Harmonisation (ICH) Q6A guideline. The specifications reflect all relevant quality attributes of the active substance and were found to be adequate to control the quality of the drug substance. The limits set are properly justified. Testing methods not described in details in the Pharmacopoeia are adequately drawn up and sufficiently validated. Reference materials used by the active substance manufacturers and the drug product manufacturer for the control of the substance are adequately characterised. The substance complies with the requirements of the European Medicines Agency (EMA) guideline on genotoxic impurities. Batch analysis data justify the limits, indicate the good performance of testing methods and demonstrate the batch to batch consistency of the production. Stability studies have been performed with the drug substance. According to the presented stability data retest periods of 3 years packed in polyethylene bag in polyethylene roll in HDPE drum and 2 years packed in double polyethylene bag in HDPE container, stored in tight containers, at controlled room temperature, is acceptable. Good Manufacturing Practice (GMP) compliance of the active substance manufacture is dem-onstrated by the applicant. II.3 Medicinal Product The aim of the product development is to formulate robust, essentially similar, and stable and bioequivalent generic formulation of Capecitabine film-coated tablets 150 mg and 500 mg to that of the innovator product Xeloda® tablets 150 mg and 500 mg manufactured by Hoff-mann La Roche AG, Deutschland and marketed by Roche Registration Ltd.UK. A satisfactory package of data on development pharmaceutics has been presented. Brief dis-cussion on reasons for inclusion and quantity of excipients has been provided. As regards dissolution and impurity profile the products are shown to be similar to the refer-ence products.


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The compositions and the pharmaceutical tests evaluated during development of the final formulation are included in the documentation. As a result of development studies the following products were obtained.

150 mg film-coated tablets: light peach coloured, oblong shaped, biconvex, film-coated tablets of approximately 11.4 mm in length and 5.3 mm in width, debossed with “150” on one side and plain on other side,

500 mg film-coated tablets: peach coloured, oblong shaped, biconvex, film-coated tab-lets of approximately 15.9 mm in length and 8.4 mm in width, debossed with “500” on one side and plain on other side.

The excipients used in the finished product are anhydrous lactose, microcrystalline cellulose (E460), croscarmellose sodium, hypromellose, magnesium stearate, talc, titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172). All excipients used comply with their respective Ph. Eur. monograph, with exception of iron oxides, which comply with USP. Compliance of the products with the general monograph of the Ph. Eur. on the Products with the risk of TSE has been demonstrated by the applicant. A description and flow chart of the manufacturing method have been provided. Appropriate in-process controls are included in the manufacturing process. Satisfactory batch formulae were also presented. GMP compliance of the manufacturing site has been demonstrated The finished product specification is satisfactory. Acceptance criteria have been justified with respect to conventional pharmaceutical requirements as prescribed in the relevant dosage form monograph of the Ph. Eur. and the ICH Q6A guideline. Appropriate control strategy was es-tablished. The test methods have been described and have been adequately validated, as ap-propriate. Batch data have been provided and complied with the specification. Certificates of analysis for the batches involved in the bioequivalence study are presented. Certificates of analysis were also provided for the working standard used. The container closure system of the product is OPA/Al/PVC//Al blister or clear PVC/PVDC//Al blister and cardboard box. Specification and analytical test methods are de-scribed. IR spectra and certificates of analysis justifying the conformity to the Ph. Eur. mono-graph 3.1.11. and relevant EC Directives are provided. Finished product stability studies have been conducted in accordance with the current guide-lines. Based on the results, a shelf-life of 3 years with storage condition of ‘‘Do not store above 25°C” for PVC/PVDC//Al blister and “This medicinal product does not require any spe-cial storage condition” for OPA/Al/PVC//Al blister is approved. The Summary of Product Characteristics, patient Information Leaflet and label texts are pharmaceutically acceptable.


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II.4 Discussion on chemical, pharmaceutical and biological aspects The product has been shown to consistently meet the current regulatory requirements with respect to qualitative and quantitative content of the active substance and pharmaceutical form until the end of the approved shelf-life. The manufacture and the quality standards applied adequately support the safe use and efficacy of the product. From chemical-pharmaceutical points of view Citamed 150 and 500 mg film-coated tablets are approvable.


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III. NON-CLINICAL ASPECTS III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of capecitabine are well known. As it is a widely used, well-known active substance, and the submission was based on the bioequivalence to the reference film-coated tablets, the applicant has not provided addi-tional studies and such studies are not required. An overview based on literature review is thus appropriate. III.2 Pharmacology Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, that functions as an orally ad-ministered precursor of the cytotoxic moiety 5-fluorouracil (5-FU). Capecitabine is activated via several enzymatic steps. The enzyme involved in the final conversion to 5-FU, thymidine phosphorylase (ThyPase), is found in tumour tissues, but also in normal tissues, albeit usually at lower levels. In human cancer xenograft models capecitabine demonstrated a synergistic effect in combination with docetaxel, which may be related to the upregulation of thymidine phosphorylase by docetaxel. There is evidence that the metabolism of 5-FU in the anabolic pathway blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thereby interfering with the synthesis of deoxyribonucleic acid (DNA). The incorporation of 5-FU also leads to inhibition of RNA and protein synthesis. Since DNA and RNA are essential for cell division and growth, the effect of 5-FU may be to create a thymidine deficiency that provokes unbalanced growth and death of a cell. The effects of DNA and RNA deprivation are most marked on those cells which prolifer-ate more rapidly and which metabolise 5-FU at a more rapid rate. III.3 Pharmacokinetics The pharmacokinetics of capecitabine has been evaluated over a dose range of 502-3514 mg/m2/day. The parameters of capecitabine, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR) measured on days 1 and 14 were similar. The AUC of 5-FU was 30%-35% higher on day 14. capecitabine dose reduction decreases systemic exposure to 5-FU more than dose-proportionally, due to non-linear pharmacokinetics for the active me-tabolite. Absorption: after oral administration, capecitabine is rapidly and extensively absorbed, fol-lowed by extensive conversion to the metabolites, 5'-DFCR and 5'-DFUR. Administration with food decreases the rate of capecitabine absorption, but only results in a minor effect on the AUC of 5'-DFUR, and on the AUC of the subsequent metabolite 5-FU. Protein binding: in vitro human plasma studies have determined that capecitabine, 5'-DFCR, 5'-DFUR and 5-FU are 54%, 10%, 62% and 10% protein bound, mainly to albumin.


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Metabolism: capecitabine is first metabolised by hepatic carboxylesterase to 5'-DFCR, which is then converted to 5'-DFUR by cytidine deaminase, principally located in the liver and tu-mour tissues. Further catalytic activation of 5'-DFUR then occurs by thymidine phosphorylase (ThyPase). The enzymes involved in the catalytic activation are found in tumour tissues but also in normal tissues, albeit usually at lower levels. The sequential enzymatic biotransforma-tion of capecitabine to 5-FU results in higher concentrations within tumour tissues. In the case of colorectal tumours, 5-FU generation appears to be in large part localised in tumour stromal cells. Thymidine phosphorylase activity was measured and found to be 4 times greater in primary colorectal tumour than in adjacent normal tissue. 5-FU is further catabolised by the enzyme dihydropyrimidine dehydrogenase (DPD) to the much less toxic dihydro-5-fluorouracil (FUH2). Deficiency of DPD may lead to increased toxicity of capecitabine (see section 4.3 and 4.4). Elimination: the elimination half-life (t1/2 in hours) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU and FBAL were 0.85, 1.11, 0.66, 0.76 and 3.23 respectively. capecitabine and its metabo-lites are predominantly excreted in urine; 95.5% of administered capecitabine dose is recov-ered in urine. Faecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL, which represents 57% of the administered dose. About 3% of the administered dose is excreted in urine as unchanged drug. III.4 Toxicology Toxicological properties of Capecitabine are well known. No new data submitted or needed. III.5 Ecotoxicity/environmental risk assessment (ERA) Since Citamed 150 mg and 500 mg film-coated tablets are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assess-ment is therefore not deemed necessary. III.6 Discussion on the non-clinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of Capecitabine are well known. As Capecitabine is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is thus appropriate.


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IV. CLINICAL ASPECTS IV.1 Introduction Citamed is indicated for the adjuvant treatment of patients following surgery of stage III (Dukes’ stage C) colon cancer. Citamed is indicated for the treatment of metastatic colorectal cancer. Citamed is indicated for first-line treatment of advanced gastric cancer in combination with a platinum based regimen. Citamed in combination with docetaxel is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous ther-apy should have included an anthracycline. Citamed is also indicated as monotherapy for the treatment of patients with locally advanced or metastatic breast cancer after failure of taxanes and an anthracycline containing chemo-therapy regimen or for whom further anthracycline therapy is not indicated IV.2 Pharmacokinetics This application concerns film-coated tablets containing capecitabine. To support the market-ing authorisation submission the applicant conducted one bioequivalence study with cross-over design under fed conditions. This study was the pivotal study for the assessment. It was a multicentre, randomised, open label, single-dose, two-period, two-treatment, two-way crossover, bioequivalence study in male and female cancer patients under fed conditions. The study lasted through one treatment cycle of capecitabine (2 weeks of daily treatment fol-lowed by 1 week rest period); period-I was the first day of the first chemotherapy cycle of the study and Period-II was the first day of the next chemotherapy cycle of the study. Citamed was administered in doses of 2500 mg/m2/day in two divided doses. The patients were admin-istered either the reference or the test product only as the first morning dose of each chemo-therapy cycle as per randomisation schedule as a single dose of 1500 mg. Metastatic breast cancer or metastatic colorectal cancer patients were enrolled. Patients were on an overnight fast prior to serving of a standardised non high-fat breakfast prior to dosing in each period then were administered a single oral dose of 1500 mg (3x500 mg) of either the test or reference product with water. Blood samples were collected predose and at suitable intervals following dose administration.


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The applicant confirmed that the bioequivalence study has been performed in accordance with the principles of GCP. The test 500 mg film-coated tablets have been compared with Xeloda 500 mg tablets (Roche) as reference product. Plasma concentrations of capecitabine and the active metabolite 5-FU were determined with a validated LC/MS/MS method. The following pharmacokinetic parameters of capecitabine and 5-FU were estimated:

primary efficacy variables o Cmax: maximum plasma concentration. o AUC0-t: area under the plasma concentration curve from administration to last

observed concentration at time t, o AUC0-∞ : area under the plasma concentration curve extrapolated to infinite

time secondary efficacy variables

o Tmax: time of maximum plasma concentration, o T1/2: half-life of drug elimination during the terminal phase. o Kd: terminal elimination rate constant.

These parameters were derived individually for each analysed patient. The statistical analysis was performed on log-transformed AUC0-t and Cmax using ANOVA. The protocol stated that bioequivalence was to be concluded if the 90% confidence intervals for the test/reference ratio of the population geometric means fell within 80.00-125.00% for capecitabine AUC0-t and Cmax. Results are presented in the Tables below.

Table 1. Statistical analysis for capecitabine (ln-transformed values) Geometric Mean Ratio

Test/Reference Confidence Intervals

AUC0-t 100.9 95.68-106.46 Cmax 102.1 90.55-115.12

Table 2. Pharmacokinetic parameters for 5-FU (non-transformed values)

Test Reference Arithmetic mean SD Arithmetic mean SD

AUC(0-t) 416.7 207.9 391.3 177.8 C max 240.8 177.6 225.2 161.1 Tmax 2.333 2.333


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The test product Citamed 500 mg film-coated tablet when compared with the reference product meets the bioequivalence criteria with respect to the rate and extent of absorption of capecitabine.

Biowaiver

One bioequivalence study was submitted which employed the 500 mg strength. The applicant claimed that bioequivalence for the 150 mg strength could be concluded since all conditions for biowaiver of additional strength according to the Guideline on the investigation of Bio-equivalence (CHMP/QWP/EWP/1401/98 Rev. 1) were fulfilled for Citamed 150 mg and 500 mg tablets are manufactured by the same manufacturer and the qualitative composition of Citamed 150mg tablets is the same as that of Citamed 500mg tablets. The claim was accept-able.

IV.3 Pharmacodynamics No novel pharmacodynamic data were supplied or required for this application, based on the bioequivalence of an established product. The pharmacodynamic claims in the SPC are ap-propriately consistent with the innovator product. IV.4 Clinical efficacy No new efficacy data were supplied or required for this generic application. However, the applicant provided a review of clinical trials published in the literature. The clinical overview described several clinical trials establishing efficacy of Capecitabine in the treatment of colon cancer, colorectal cancer, gastric cancer and breast cancer. IV.5 Clinical safety The safety profile of capecitabine is known for the approved indications. No new data has been submitted or needed. No new adverse effects occurred during the bioequivalence study. The literature data collected by the applicant support the clinical safety of capecitabine in the approved indications.


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IV.6 Discussion on the clinical aspects The use of capecitabine is well established. It has recognised efficacy and acceptable safety. With regards to the current application, sufficient clinical information has been submitted which includes adequate review of published clinical data. The claim of essential similarity can be accepted. From clinical points of view Citamed 150 and 500 mg film-coated tablets are approvable.


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V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

The reference medicinal products Xeloda 150 mg and 500 mg film-coated tablets by Roche contain the widely used and well-known active substance capecitabine with an established favourable benefit-risk profile. With regards to the current generic application, sufficient clinical information has been sub-mitted which includes adequate review of published clinical data. The bioequivalence be-tween the test and reference 500 mg tablets has been successfully established. The biowaiver for the 150 mg tablets is acceptable. Thus, the claim of essential similarity between the sub-mitted and the reference medicinal products, based on the relevant European guideline, can be accepted. The therapeutic benefit/risk ratio is therefore favourable. The application for Citamed 150 mg and 500 mg film-coated tablets in the treatment of pa-tients with colon cancer, colorectal cancer, gastric cancer and breast cancer is approvable. V.1 Conditions for the marketing authorisation

V.1 Requirements for specific post-marketing obligations Not needed.

V.1.2 Pharmacovigilance system The RMS considers that the Pharmacovigilance system submitted by the applicant ful-fils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the neces-sary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. V.1.3 Risk Management Plan

Submission of a risk management plan including a summary thereof was not required for this product, since the marketing authorisation application had been submitted before the new pharmacovigilance legislation came into force (21 July 2012) and the applica-tion concerned a medicinal product containing a known active substance for which no safety concern requiring additional risk minimisation activities has been identified.


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V.1.4 Periodic Safety Update Report (PSUR) As capacitabine is included in the EURD list, PSUR submission should be aligned with the requirement published on the list. As of 28 February 2013, (EMA/630645/2012 Rev.5) the European Union reference Date (EURD) is 30/04/1998, the PSUR cycle is yearly and the next harmonized Data Lock Point (DLP) is 29.04.2013 for capacitabine. However, PSUR submission is not requested for products referred to in Article 10 (1) (generics) of 2001/83/EC as amended. Thus the MAH does not have to submit PSUR but should follow the List continuously to detect any changes. V.1.5 Legal status in the RMS

Prescription-only medicine. Citamed should only be prescribed by a doctor experienced in the use of anticancer medicines. It may be administered exclusively following diagnosis made by a specialist physician or in a hospital as well as under continuous supervision of a specialist physi-cian.

V.2 Summary of Product Characteristics (SmPC) The SmPC is, both from pharmaceutical and medical points of view, acceptable and ade-quately harmonised with that of the reference product. V.3 Package Leaflet and user consultation The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of the Directive 2001/83/EC with satisfactory re-sults. The language used for the purpose of user testing the PIL was Hungarian.

National Institute of Pharmacy Citamed Directorate of GYEMSZI 150 mg and 500 mg film-coated tablets Budapest, Hungary Public Assessment Report VI. Upgrade: steps taken after the initial procedure with an influence on the Public Assessment Report

This module reflects the procedural steps and scientific information after the finalisation of the initial procedure.

Scope Procedure number

Product information affected

Date of start of the procedure

Date of end of procedure

Approval or non approval

Assessment report

attached

Y/N (version)

citamed - magyarorszag · 2013-11-25 · citamed is indicated for the treatment of colon, rectal,...

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