doreta sr · 2017. 4. 11. · doreta sr prolonged-release tablet (further on: doreta sr) is a...

Public Assessment Report

Name of the Product:

Doreta SR

75 mg/650 mg prolonged release tablets

(tramadol hydrochloride/paracetamol)

Procedure number: HU/H/0190/003/DC Marketing authorisation holder: Krka d.d.

Date: 16 June 2016

National Institute of Pharmacy Doreta SR and Nutrition 75 mg/650 mg prolonged-release tablets Budapest, Hungary HU/H/0190/003/DC Public Assessment Report

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CONTENT LAY SUMMARY .............................................................................................................................. 3 SCIENTIFIC DISCUSSION during the initial phase ......................................................................... 10 I. Introduction .................................................................................................................................. 11 II. Quality aspects

II.1 Introduction ................................................................................................................... 12 II.2. Drug substances II.2.1 Tramadol hydrochloride .............................................................................................. 12 II.2.2 Paracetamol ................................................................................................................. 13 II.3 Medicinal product .......................................................................................................... 14 II.4 Discussion on chemical, pharmaceutical and biological aspects ...................................... 15

III. Non-clinical aspects

III.1 Introduction .................................................................................................................. 16 III.2 Pharmacology ............................................................................................................... 16 III.3 Pharmacokinetics .......................................................................................................... 16 III.4 Toxicology ........................................................................................................ 17 III.5 Ecotoxicity/environmental risk assessment ........................................................ 18 III.6 Discussion on the non-clinical aspects ............................................................... 18

IV. Clinical aspects

IV.1 Introduction .................................................................................................................. 19 IV.2 Pharmacokinetics

IV.2.1 Literature data ............................................................................................... 19 IV.2.2 Bioavailability studies ................................................................................... 21

IV.3 Pharmacodynamics ....................................................................................................... 24 IV.4 Clinical efficacy............................................................................................................ 25 IV.5 Clinical safety ............................................................................................................... 26 IV.6 Pharmacovigilance IV.6.1 Summary of the Pharmacovigilance System ............................................................... 26 IV.6.2 Risk Management Plan .............................................................................................. 27 IV.6.3 Periodic Safety Update Reports .................................................................................. 27 IV.7 Discussion on clinical aspects ....................................................................................... 27

V. Overall conclusion, benefit/risk assessment and recommendation V.1 Summary ....................................................................................................................... 29 V.2 Classification ................................................................................................................. 29 V.3 Package leaflet and user consultation.............................................................................. 30

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 ratio, the member states have granted the marketing authorisation of the Doreta SR (in the Czech Republic Doreta Prolong, in Estonia, Latvia, Lithuania Doreta, in the Slovak Republic Doreta SR) 75 mg/650 mg pro-longed-release tablets. The holder of the marketing authorisation is Krka, d. d. in the reference member state. The active substances are tramadol hydrochloride and paracetamol. Each prolonged-release tablet contains 75 mg tramadol hydrochloride equivalent to 65.88 mg tramadol and 650 mg paracetamol. The other ingredients are:

- tablet core: pregelatinised maize starch, hypromellose (type 2208, 100 mPa.s), copovidone, croscarmellose sodium, yellow iron oxide (E172), microcrystalline cellulose, colloidal anhydrous silica and sodium stearyl fumarate,

- film-coating: poly(vinyl alcohol), macrogol 3350 and talc. The prolonged-release tablets are oval, biconvex, bilayer, film-coated, white to off-white on one side and pale yellow on the opposite side, with dark spots (length: around 20 mm, width: 11 mm). They are available in boxes. Doreta SR prolonged-release tablet (further on: Doreta SR) is a combination of two analgesics (pain killers) tramadol and paracetamol that act together to relieve pain. It is intended for use in the treatment of moderate to severe pain when the doctor recommends that a combination of tramadol and paracetamol is needed. Doreta SR should only be taken by adults and adolescents over 12 years of age. What patients need to know before you take Doreta SR Those who - are allergic to paracetamol, tramadol or any of the other ingredients of this medicine, - are acutely intoxicated with alcohol, sleeping pills, pain relievers or other psychotropic

medicines (medicines that affect mood and emotions), - are also taking MAO inhibitors (certain medicines used for treatment of depression or

Parkinson’s disease) or have taken them in the last 14 days before treatment with Doreta SR,

- suffer from severe liver problems, - have epilepsy that is not adequately controlled on the current medicine must not take Doreta SR. Warnings and precautions


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Special care must be taken with Doreta SR if the patient - has kidney problems, - has liver problems or liver disease or have noticed the eyes and skin turning yellow, which

may suggest jaundice or problems with bile ducts, - has severe difficulties in breathing, for example, asthma or severe lung problems, - is dependent on any other medicines used to relieve pain, for example, morphine, - has epilepsy or if having already experienced fits or seizures, - has recently suffered from a head injury, shock or severe headaches associated with vom-

iting, - takes other medicines containing paracetamol or tramadol, - takes other medicines to treat pain that contain buprenorphine, nalbuphine or pentazocine, - is going to have an anaesthetic (the doctor or dentist must be informed that Doreta SR is

taken). Other medicines and Doreta SR The doctor should be informed if the patient is taking, has recently taken or might take any other medicines. This medicine contains paracetamol and tramadol. The doctor must be informed if the patient is taking any other medicine containing paracetamol or tramadol, in order to avoid exceeding the maximum daily doses. Doreta SR must not be taken together with monoamine oxidase inhibitors ("MAOIs"). Doreta SR is not recommended to be taken with the following:

˗ carbamazepine (a medicine used to treat epilepsy or some types of pain such as severe pain attacks in the face called trigeminal neuralgia),

˗ buprenorphine, nalbuphine or pentazocine (opioid-type pain relievers). The pain-reliev-ing effect may be reduced.

Doreta SR may increase the risk of side effects if the patient is also taking the following medi-cines:

˗ triptans (used for migraine) or selective serotonin re-uptake inhibitors (SSRIs, used for depression). The patient should check with the doctor if experiencing confusion, restless-ness, fever, sweating, uncoordinated movement of limbs or eyes, uncontrollable jerking of muscles or diarrhoea,

˗ tranquilizers, sleeping pills, other pain relievers such as morphine and codeine (also as cough medicine), baclofen (a muscle relaxant), medicines used to lower blood pressure, antidepressants or medicines to treat allergies. The doctor should be discussed if the pa-tient feels drowsy or feel faint,

˗ medicines which may cause convulsions (fits), such as certain antidepressants or antipsy-chotics. The risk having a fit may increase if taking Doreta SR at the same time. The doctor will tell the patient whether Doreta SR is suitable,

˗ certain antidepressants. Doreta SR may interact with these medicines and the patient may


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experience symptoms such as involuntary, rhythmic contractions of muscles, including the muscles that control movement of the eye, agitation, excessive sweating, tremor, ex-aggeration of reflexes, increased muscle tension, body temperature above 38 °C,

˗ warfarin or phenprocoumon (for blood thinning). The effectiveness of such medicines may be altered and bleeding may occur. Any prolonged or unexpected bleeding should be reported to the doctor immediately.

The effectiveness of Doreta SR may be altered if the following medicines are also taken:

˗ metoclopramide, domperidone or ondansetron (medicines used to treat nausea and vom-iting/being sick),

˗ cholestyramine (medicine used to reduce cholesterol in the blood). Doreta SR with food, drink and alcohol Doreta SR can be taken with or without food. Doreta SR may make the patient feel drowsy. Alcohol may make the patient feel drowsier, so it is best not to drink alcohol while taking Doreta SR. Pregnancy, breast-feeding and fertility Those who are pregnant or breast-feeding, think they may be pregnant or are planning to have a baby, ask the doctor for advice before taking this medicine. Since Doreta SR is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy and breast feeding. Small amounts of tramadol may pass into the breast-milk. Therefore Doreta SR should not be taken during breast-feeding. Based on human experience tramadol is suggested not to influence female or male fertility. No data on the influence of the combination of tramadol and paracetamol on fertility are available. Driving and using machines Doreta SR may make the patient feel drowsy. Until the patient knows how Doreta SR affects him/her, driving, operating machinery or performing other activities for which he/she need to be alert are not advised. How to take Doreta SR The usual starting dose is one to two tablets. If required, further doses can be taken after every twelve hours, as recommended by the doctor.


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More than 4 tablets per day (equivalent to 300 mg tramadol hydrochloride and 2600 mg para-cetamol) must not be taken. The dosage should be adjusted to the intensity of the pain and the individual pain sensitivity. In general the lowest pain-relieving dose should be taken. Severe liver disease (insufficiency) Patients with severe liver insufficiency should not take Doreta SR. In case of mild or moderate insufficiency, the doctor may recommend prolonging the dosage interval. Use in children Doreta SR is not recommended for use in children under 12 years. Elderly patients In elderly patients (above 75 years) the excretion of tramadol may be delayed. If this applies to the patient, the doctor may recommend prolonging the dosage interval. Method of administration The tablets must be swallowed whole with some liquid. The tablets should not be crushed or chewed. The tablets should be taken for as short a time as possible. If the patient thinks that the effect of Doreta SR is too strong (i.e. feeling very drowsy or having difficulty with breathing) or too weak (i.e. having inadequate pain relief), the doctor should be contacted. If the symptoms do not get any better, the doctor must be seen. What to do if more Doreta SR has been taken than it should have been? Immediate medical advice should be sought in the event of an overdose, even if the patient feels well, because of the risk of delayed, serious liver damage. If the patient takes more Doreta SR than he/she should he/she could experience severe disturbance of blood supply to organs, con-sciousness disorders up to coma, convulsions, or he/she might have difficulty breathing, feel unwell, vomit, lose weight or feel abdominal pain. What to do if taking Doreta SR has been forgotten? If a dose is missed, the next tablet should be taken at the usual time. No double dose should be


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taken to make up for a forgotten tablet. May the patient stop taking Doreta SR? If the patient has been using Doreta SR for some time, he/she should talk to the doctor if wanting to stop taking it because the body may have got used to it. If the patient does suddely stop using Doreta SR he/she may feel unwell, may experience anxiety, agitation, nervousness, sleepless-ness, hyperactivity, tremors and/or an upset stomach. Possible side effects Like all medicines, Doreta SR can cause side effects, although not everybody experiences them. Very common side effects (that may affect more than 1 in 10 people) are: - nausea, - dizziness, - drowsiness. These are usually mild and not troublesome. Common side effects (that may affect up to 1 in 10 people) are: - vomiting, - digestion problems (constipation, flatulence, diarrhoea), - abdominal pain, - dry mouth, - headache, - shaking, - confusion, - sleep disorders, - mood changes (anxiety, nervousness, euphoria (a sense of feeling "high" all the time)), - increased sweating, - itching. Uncommon side effects (that may affect up to 1 in 100 people) are: - high blood pressure, heart rhythm and heart rate disorders, - difficulty or pain on passing urine, protein in the urine, - skin reactions (hives, rashes), - ringing in the ear, - depression, - nightmares, - hallucinations (hearing, seeing or sensing things that are not really there), - loss of memory, - difficulty swallowing, - blood in the stools, - shivering, - hot flushes,


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- pain in the chest, - involuntary muscle twitching, - unusual tingling feeling ("pins and needles"), - shortness of breath, - raised liver enzymes. Rare side effects (that may affect up to 1 in 1,000 people) are: - drug dependence, - fits, difficulties in carrying out coordinated movements, - blurred vision, - transient loss of consciousness. Very rare side effect (that may affect up to 1 in 10,000 people) is drug abuse. Unknown side effect (its frequency cannot be estimated from the available data) is decrease in blood sugar level. The following are recognised side effects which have been reported by people using medicines that contain only tramadol hydrochloride or paracetamol. However, experiencing any of these while taking Doreta SR the doctor should be informed: - feeling faint when getting up from a lying or sitting position, slow heart rate, fainting,

changes in appetite, muscle weakness, slower or weaker breating, mood changes, changes in activitiy, changes in perception, worsening of asthma,

- in some rare cases a skin rash, indicating an allergic reaction, may develop with sudden swelling of the face and neck, difficulties breathing or drop of blood pressure and fainting. If this happens to the patient, the treatment must be stopped and a doctor consulted immediately. The medicine must not be taken again.

In rare cases, using a medicine of the type of tramadol may make the patient become dependent on it, making it hard to stop taking it. On rare occasions, people who have been taking tramadol for some time may feel unwell in they stop treatment abruptly. They may feel agitated, anxious, nervous or shaky. They may be hyperactive, have difficulty sleeping and have stomach or bowel disorders. Very few people may also get panic attacks, hallucinations, unusual perception such as itching, tingling, numbness and ringing in the ears (tinnitus). If noticing any of these effects, or any other unusual symptoms, the patient should consult the doctor as soon as possible. In exceptional cases blood tests may reveal certain abnormalities, for instance, low counts of blood platelets, which may result in nose bleeds or bleeding gums. Very rare cases of serious skin reactions have been reported for paracetamol containing medicines. How to store Doreta SR


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This medicine does not require any special storage conditions but keep it out of the sight and reach of children.


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Scientific discussion

during the initial phase

This module reflects the scientific discussion for the approval of Doreta SR 75 mg/650 mg pro-longed-release tablets. The procedure was finalised at 14 October 2015. 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, an application has been submitted to the reference and competent authorities of the Member State concerned.

This Decentralised Procedure application (Reference member state, RMS: Hungary, concerned member states, CMS: Bulgaria, the Czech Republic, Estonia, Latvia, Lithuania, Netherlands, Poland, Portugal, Romania, Slovenia and the Slovak Republic) concerned the combination of tramadol/paracetamol 75mg/650mg prolonged release tablets (Doreta SR prolonged-release tablets, named Doreta Prolong in the Czech Republic, Doreta in Estonia, Latvia and Lithuania while Doreta EP in Romania). This application was submitted according to Article 10(3) “hybrid application” of the Directive 2001/83/EC. The reference product for the application was Zaldiar® 37.5 mg/325 mg film-coated tablets (Grünenthal GmbH, Germany) that is available in an immediate release form. The reference product was licensed in the Community in 2002, therefore the legal basis is ac-ceptable. Marketing authorizations for Doreta 37.5 mg/325 mg and 75 mg/650 mg film-coated tablets have already been granted through decentralized procedures HU/H/0190/001/DC and HU/H/0190/002/DC as well as through two repeat use mutual recognition (MR) procedures HU/H/0190/01-02/E/01 and HU/H/0190/01-02/E/02. Therefore the current application is a line extension of the previously authorised products. Based on the review of the quality, safety and efficacy data, the Member States have granted marketing authorisations for Doreta SR prolonged-release tablets from Krka, d. d., Novo mesto, Slovenia. Doreta SR is indicated for the symptomatic treatment of moderate to severe pain in adults and adolescents over the age of 12 years. A comprehensive description of the indications and posology is given in the Summary of Prod-uct Characteristics (SmPC).


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II. QUALITY ASPECTS

II.1 Introduction The chemical-pharmaceutical assessment report concerns the application Doreta SR 75 mg/650 mg prolonged release tablets via a decentralized procedure according to Article 10 (3) of Di-rective 2001/83/EC (i.e. a hybrid application). The product has been developed by Krka, d. d., Novo mesto. The reference product was Zaldiar tablets 37.5 mg/325 mg (containing 37.5 mg tramadol hy-drochloride and 325 mg paracetamol as active ingredients) which was the original product of Laboratoires Grünenthal. II.2 Drug substances

II.2.1 Tramadol hydrochloride

Data on the quality and manufacture of the active substance were provided in the sub-mission using the European Pharmacopoeia (Ph. Eur.) Certificate of Suitability (CEP) procedures with additional data in the marketing authorization dossier. The Quality Overall Summary is adequate. INN name: tramadol hydrochloride Chemical name: (1RS, 2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cy-

clohexanol hydrochloride Structure:

The drug substance is a white or almost white, crystalline powder which is freely soluble in water and in methanol, very slightly soluble in acetone. The substance is specified according to the requirements of the current Ph. Eur. mono-graph. Additional specification has only been set for residual solvents and microbial impurities. The Ph. Eur. specification includes the following tests for tramadol hydrochloride: ap-pearance, solubility, identification (by melting point, IR, TLC, chlorides), appearance


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of solution, acidity, optical rotation, impurity E, related substances, heavy metals, water, sulphated ash and assay of tramadol hydrochloride.

Testing methods are performed in accordance with the Ph. Eur. monograph and the an-nex of the current CEPs on tramadol hydrochloride. The microbiological purity test was verified. 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. A retest period and the packaging material have been mentioned on the CEP.

Good Manufacturing Practice (GMP) compliance of the drug substance manufacture is demonstrated by the applicant. II.2.2 Paracetamol Data on the quality and manufacture of the active substance were provided in the appli-cant’s submission using the CEP procedures with additional data in the marketing au-thorization dossier. The Quality Overall Summary is adequate. INN name: paracetamol Chemical name: N-(4-hydroxypheny)acetamide Structure:

The drug substance is a white or almost white, crystalline powder which sparingly sol-uble in water, freely soluble in alcohol, very slightly soluble in methylene chloride. The substance is specified according to the requirements of the current Ph. Eur. mono-graph, additional specification has only been set for microbial impurities. The Ph. Eur. specification includes the following tests for paracetamol: appearance, sol-ubility, identification (by melting point, specific absorbance, IR, colour reaction and reaction of acetyl), related substances, heavy metals, loss on drying, sulphated ash and assay paracetamol.

Testing methods are performed in accordance with the Ph. Eur. monograph and the an-nex of the current CEP on paracetamol. The microbiological purity test was verified.


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Reference materials used by the drug substance manufacturers and the drug product manufacturer for the control of the substance are adequately characterised. The substance complies with the requirements of the EMA guideline on genotoxic im-purities. Batch analysis data justify the limits, indicate the good performance of testing methods and demonstrate the batch to batch consistency of the production. A retest period and the packaging material have been set or justified by the applicant or mentioned on the CEP. GMP compliance of the drug substance manufacture is demonstrated by the applicant.

II.3 Medicinal product The aim was to develop a dosage form which enables the delivery of paracetamol and tramadol within 12 hours to facilitate pain management over that period of time. A satisfactory package of data on development pharmaceutics has been presented. Brief discus-sion on reasons for inclusion and quantity of excipients has been provided. As regards impurity profile the product is shown to be similar to the reference product. The compositions and the pharmaceutical tests evaluated during development of the final for-mulation are included in the documentation. As a result of development studies product with the following appearance, composition and packaging was obtained. Doreta SR 75 mg/650 mg prolonged release tablets are oval, biconvex, bilayer film-coated tab-lets, white to off-white on one side and pale yellow on the opposite side, with dark spots (length: around 20 mm, width: around 11 mm). The excipients used in the finished product are pregelatinised maize starch, hypromellose, co-povidone, croscarmellose sodium, iron oxide yellow (E172), microcrystalline cellulose, colloi-dal anhydrous silica, sodium stearyl fumarate, poly(vinyl alcohol), macrogol 3350 and talc. All excipients used comply with their respective Ph. Eur. monographs, except from the colouring and film-coating agents. Iron oxide yellow (E170) meets the requirements of Regulation (EU) No 231/2012 and Opadry II consists of pharmacopoeial components which comply with their respective Ph. Eur. monographs. Compliance of the product with the general monograph of the European Pharmacopoeia on the Products with the risk of TSE has been demonstrated by the applicant. A description and flow chart of the manufacturing method has 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.


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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 International Council of Harmonisation (ICH) Q6A guide-line. Appropriate control strategy was selected. The test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and complied with the specification. Certificates of analysis for the batches involved in the bioequivalence study are presented. The container closure system of the product is PVC/PVDC//Al blister or child-resistant blister (PVC/PVDC white foil, paper/Alu foil) and box. Specifications and quality certificates for all packaging components are enclosed. Finished product stability studies have been conducted in accordance with the current guide-lines. Based on the results, a shelf-life of 2 years in blisters with the storage condition “This medicinal product does not require any special temperature storage conditions.” is approved. The SmPC, the Patient Information (Package) Leaflet and label texts are pharmaceutically ac-ceptable. II.4 Discussion on chemical, pharmaceutical and biological aspects The product has been shown to meet the current regulatory requirements with regards to its quality and content of the active substance as well as dosage-form characteristics until the end of the approved shelf-life consistently. The manufacture and the quality standards applied ad-equately support the safe use and efficacy of the product. From chemical-pharmaceutical aspects the product is approvable.


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III. NON-CLINICAL ASPECTS

III.1 Introduction Pharmacodynamic, pharmacokinetic and toxicological properties of both components are well known. The Applicant has not provided additional studies. The non-clinical overview is detailed and acceptable. As the current application is based on Article 10(3) – a hybrid application –, new non-clinical studies might be required. However, both active substances have been known for several years and their pharmacological properties are well-known. Therefore the non-clin-ical studies can be waived and granting marketing authorization can be based on a literature review from a non-clinical point of view.

III.2 Pharmacology Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is pure non- selective agonists of the μ, δ, and κ opioid receptors with a higher affinity for the µ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Un-like morphine, a broad range of analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastro-intestinal motility is not modified. The cardiovascular effects are generally slight. The potency of tramadol is considered to be one-tenth to one-sixth that of morphine. The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects. Their combination is positioned as a step II analgesic in the WHO pain ladder and should be utilised accordingly by the physician. III.3 Pharmacokinetics Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and its metab-olite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol. Racemic tramadol is rapidly and almost completely absorbed after oral administration. Paracetamol appears to be widely distributed throughout most body tissues except fat. A rela-tive small portion (~20%) of paracetamol is bound to plasma proteins. Tramadol is extensively metabolized after oral administration. Tramadol is metabolised through O-demethylation (catalysed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalysed by CYP3A) to the metabolite M2. M1


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is further metabolised through N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuron-idation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction is metabolized by cytochrome P450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by re-duced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased. Tramadol and its metabolites are eliminated mainly by the kidneys. III.4 Toxicology No new non-clinical study has been performed with the tramadol and paracetamol fixed com-bination to evaluate its carcinogenic or mutagenic effects or its effects on fertility. No teratogenic effect that can be attributed to the medicine has been observed in the progeny of rats treated orally with the combination tramadol/paracetamol. The combination tramadol/paracetamol has proven to be embryotoxic and foetotoxic in the rat at materno-toxic dose (50/434 mg/kg tramadol/paracetamol), i.e., 8.3 times the maximum ther-apeutic dose in man. No teratogenic effect has been observed at this dose. The toxicity to the embryo and the foetus results in a decreased foetal weight and an increase in supernumerary ribs. Lower doses, causing less severe materno-toxic effect (10/87 and 25/217 mg/kg tra-madol/paracetamol) did not result in toxic effects in the embryo or the foetus. Results of standard mutagenecity tests did not reveal a potential genotoxic risk for tramadol in man. Results of carcinogenicity tests do not suggest a potential risk of tramadol for man. Animal studies with tramadol revealed, at very high doses, effects on organ development, ossi-fication and neonatal mortality, associated with maternotoxicity. Fertility reproductive perfor-mance and development of offspring were unaffected. Tramadol crosses the placenta. No effect on fertility has been observed after oral administration of tramadol up to doses of 50 mg/kg in the male rat and 75 mg/kg in the female rat. Extensive investigations showed no evidence of a relevant genotoxic risk of paracetamol at therapeutic (i.e. non-toxic) doses. Long-term studies in rats and mice yielded no evidence of relevant tumorigenic effects at non-hepatotoxic dosages of paracetamol.


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Animal studies and extensive human experience to date yield no evidence of reproductive tox-icity. III.5 Ecotoxicology/environmental risk assessment Evaluation of the potential environmental risk posed by the medicinal products has not been provided. As the application concerns a product intended for substitution of the innovator and the replacement of the already indicated immediate release products, such an evaluation is deemed unnecessary since no additional amount of tramadol/paracetamol will be introduced in the environment. III.6 Discussion on the non-clinical aspects The application is based on Article 10(3) of Directive 2001/83/EC, hybrid application. Abridged applications, as a rule, avoid the need for repetitive tests on animals. Pharmacody-namics, pharmacokinetics and toxicology of tramadol and paracetamol are well-known. The non-clinical part of the application is acceptable.


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IV. CLINICAL ASPECTS

IV.1 Introduction This application concerns the combination of tramadol/paracetamol 75 mg/650 mg prolonged release tablets under trade name Doreta SR prolonged release tablets and refers to Article 10(3) “hybrid application” of Directive 2001/83/EC, as amended. To support the application, the ap-plicant has submitted the reports of two biovailability studies with the tramadol/paracetamol 75 mg/650 mg prolonged release tablets. The approval of the 75 mg/650 mg strength is based upon by showing the comparable exposure of the prolonged release formulation to the innovator immediate release Zaldiar 37.5 mg/325 mg film-coated tablets. Doreta SR is indicated for the symptomatic treatment of moderate to severe pain in adults and adolescents over the age of 12 years. IV.2 Pharmacokinetics

IV.2.1 Literature data

The PK data in this chapter refer to literature data as well as data, obtained in PK studies on Doreta SR. Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol. During pharmacokinetic studies in healthy volunteers after single and repeated oral ad-ministration of the tramadol/paracetamol combination (immediate release formulation) no clinical significant change was observed in the kinetic parameters of each active in-gredient compared to the parameters of the active ingredients used alone.

Racemic tramadol is almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75%. After repeated administration, the bioavailability is increased and reaches approximately 90%. After oral administration absorption of paracetamol is nearly complete. Following single and multiple dose administration of tramadol hydrochloride/paraceta-mol 75 mg/650 mg prolonged-release tablets under fasting conditions, the peak plasma tramadol and O-desmethyl tramadol concentrations were reached at about 4.5 hours. The oral absorption of paracetamol was rapid with peak plasma concentrations achieved at about 30 minutes following administration.


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Where tramadol hydrochloride/paracetamol immediate release and prolonged-release tablets were assessed in fasted state, the peak plasma tramadol, O-desmethyl tramadol and paracetamol concentration (Cmax) and exposure (AUC) of the same dose given within the 12-h dosing interval (i.e. tramadol hydrochloride/paracetamol 37.5 mg/325 mg immediate-release tablets given every 6 hours and tramadol hydrochloride/parace-tamol 75 mg/650 mg prolonged-release tablets given every 12 hours) were equivalent and may be used interchangeably. The administration of prolonged-release tablets causes less frequent fluctuations in the plasma concentration compared to the admin-istration of immediate release tablets. The oral administration of tramadol hydrochloride/paracetamol 75 mg/650 mg pro-longed-release tablets with food has no clinically significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol. Doreta SR can be taken independently of meal times. Tramadol has a high tissue affinity (Vd,β=203 ± 40 l). It has a plasma protein binding of about 20%. Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 l/kg. A relative small portion (~20%) of paracetamol is bound to plasma proteins. Tramadol is extensively metabolized after oral administration. About 30% of the dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as metab-olites. Tramadol is metabolised through O-demethylation (catalysed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalysed by CYP3A) to the me-tabolite M2. M1 is further metabolised through N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. The plasma con-centrations of M1 are several-fold lower than those of tramadol and the contribution to the clinical effect are unlikely to change on multiple dosing. Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased. Tramadol and its metabolites are eliminated mainly by the kidneys.


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Compared to values observed for adults, the half-life of paracetamol is shorter in chil-dren and slightly longer in the new-borns and in cirrhotic patients. Paracetamol is mainly eliminated by dose-dependent formation of glucuro- and sulpho-conjugate derivatives. Less than 9% of paracetamol is excreted unchanged in urine. In renal insufficiency, the half-life of both compounds is prolonged. Following single dose administration of tramadol hydrochloride/paracetamol 75 mg/650 mg prolonged-release tablets under fasting conditions, the mean elimination half-life was 6.4 hours and 6.9 hours for tramadol and paracetamol, respectively.

IV.2.2 Bioavailability studies

The pharmacodynamics, pharmacokinetic and toxicological properties of both tramadol and paracetamol are well-known. The developmental plan was based on the require-ments of Article 10(3) “hybrid application” of Directive 2001/83/EC, as amended and Section 4 of the Guidance on modified release oral and transdermal dosage forms: Part II (Pharmacokinetic and clinical evaluation), CPMP/EWP/280/96 Corr* London, 28 July 1999. The modified release guideline states that “the aim of the modified release formulation is therefore, in most cases, to reach a similar total exposure (AUC) to drug and/or metabolite(s) as for the immediate release formulation.” The following properties should be studied if applicable:

the rate and extent of absorption – the measured parameters in the studies fulfil this criterion,

fluctuations in drug concentrations – fluctuation was measured in a steady state study,

variability in pharmacokinetics arising from of the drug formulation, dose proportionality – not relevant in this case as only one strength is applied, factors influencing the performance of the modified drug formulation – food

effect was studied, the risk of unexpected release characteristics (e.g. dose dumping) – alcohol did

not cause dose dumping. The applicant has addressed the relevant points.

The applicant has conducted two bioavailability studies: A comparative, 3-way cross-over bioavailability study of tramadol hydrochloride/

paracetamol formulations in healthy adult volunteers under fasting and fed conditions.

A multiple-dose, randomized, two-period, two-treatment, two-sequence, crossover comparative bioavailability study of two tramadol hydrochloride/paracetamol formulations in healthy volunteers.

The reference product was the immediate release Zaldiar 37.5 mg/325 mg film-coated tablet (Grünenthal GmbH).


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Comparative, 3-way (Treatments A-C) cross-over bioavailability study of tramadol hy-drochloride/paracetamol formulations in healthy adult volunteers under fasting and fed conditions.

Treatment A: test product under fasting conditions. Treatment B: reference product (two tablets) under fasting conditions. Treatment C: test product under fed conditions.

The 90% Confidence Intervals of ratio of LS-Means (Treatment A/Treatment B) for tramadol and paracetamol primary pharmacokinetic parameter AUCt as well as Cmax are listed in the following Tables.

Tramadol

Pharmacokinetic parameter

Geometric mean ratio A/B

90% Confidence in-terval CV*

AUCt 95.39% 91.77% – 99.14% 9.38% Cmax 71.60% 66.86% – 76.68% 16.71%

*Estimated from the residual mean squares

Paracetamol Pharmacokinetic parameter

Geometric mean ratio A/B

90% Confidence in-terval CV

AUCt 98.84% 96.33% – 101.42% 6.25% Cmax 93.00% 82.14% – 105.30% 30.77%

Confidence intervals and ratio of LS-Means (Treatment C/Treatment A) for tramadol, and paracetamol pharmacokinetic parameters AUCt, AUCi and Cmax are listed in the following Tables.

Tramadol


Geometric mean ratio C/A


AUCt 103.15% 98.93% – 107.55% 9.72% AUCi 102.31% 98.05% – 106.75% 9.89% Cmax 137.62% 129.47% – 146.29% 14.25%

Paracetamol


Geometric mean ratio C/A


AUCt 104.48% 101.46% – 107.59% 6.82% AUCi 103.68% 100.32% – 107.16% 7.66% Cmax 92.29% 80.91% – 105.27% 31.27%


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The data indicate comparable exposure with both tramadol and paracetamol in both treatment arms as the AUCt geometric mean ratios fall within the bioequivalence ac-ceptance limits. However, using the term bioequivalence is not adequate in this situation since Cmax equivalence is not required and not necessarily expected either (Note For Guidance on modified release oral and transdermal dosage forms: Section II Pharma-cokinetic and clinical evaluation, CPMP/EWP/280/96 Corr * London, 28 July 1999 and the Guideline on the pharmacokinetic and clinical evaluation of modified release dos-age forms, EMA/CHMP/EWP/280/96 Corr1 coming into effect on the 1st of July, 2015). Indeed, the Cmax ratio confidence interval for tramadol is below the acceptance range indicating that the immediate release formulation reference product has a steeper ab-sorption. This is not surprising since the whole tramadol content is in the sustained re-lease part of the new formula. The absorption rates for paracetamol are comparable.

There is a food effect on tramadol absorption from the test product regarding its Cmax. The applicant claims this as insignificant since i.v. tramadol formulation may have dou-ble of the Cmax compared to the oral formulas without any clinical relevance. This argu-mentation can be accepted.

In summary there are two parameters that preclude bioequivalence between the test for-mulation and the two tablets of reference product given in 6 hours interval: the lower Cmax of tramadol and the food effect on the Cmax of tramadol. However, as the exposures with both active ingredients are comparable the study results support the acceptance of the new prolonged release formula. There was no new safety concern emerged from the clinical study.

Multiple-dose, randomized, two-period, two-treatment, two-sequence, crossover com-parative bioavailability study of two tramadol hydrochloride/paracetamol formulations in healthy volunteers 90% Confidence Intervals of ratio of LS-Means (Test/Ref) for tramadol and paracetamol primary pharmacokinetic parameter AUCtau as well as Cmax of tramadol and paracetamol and Cmin of tramadol are listed in the following Tables.

Tramadol


Geometric mean ratio Test/Ref 90% Confidence interval CV

AUCthau 98.48% 95.18% – 101.89% 8.3% Cmax 90.91% 87.37% – 94.60% 9.7% Cmin 97.78% 92.67% – 103.17% 13.1%

Paracetamol


Geometric mean ratio Test/Ref 90% Confidence interval CV

AUCthau 94.72% 92.30% – 97.21% 6.3%


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Cmax 97.68% 91.90% – 103.83% 14.9%

The 90 % confidence intervals of the ratios of LS-Means derived from analyses on the ln-transformed primary PK parameter AUCthau for tramadol and paracetamol and secondary PK parameter Cmax for paracetamol in plasma were within the 80.00-125.00% acceptance range. The acceptance criteria (i.e. ≥80%) was also achieved for the 90 % confidence intervals of the ratios of LS-Means derived from analyses on the ln-transformed secondary PK parameter Cmin for tramadol in plasma.

IV.3 Pharmacodynamics Tramadol is a centrally-acting, synthetic analgesic with a dual mechanism of action – weak opioid agonist and weak noradrenaline and serotonin reuptake inhibition. Tramadol is a racemic mixture and its mechanism of action via opioid and noradrenergic/serotonergic mechanisms is related to the independent effects of its two enantiomers: (+)-tramadol is an agonist of the μ opioid receptor and inhibits serotonin reuptake, while (-)-tramadol inhibits noradrenaline reuptake. Interestingly, the enantiomers act synergistically to achieve better antinociceptive ef-fect without enhancing side effects, and additionally lower respiratory depression and toler-ance/dependence. The O-desmethyl metabolite (M1) is also pharmacologically active. It acts as a μ opioid agonist and also contributes to the analgesic effect. Tramadol appears to produce less constipation and dependence than the equivalent doses of strong opioids. In several post-mar-keting surveillance studies tramadol is showed as effective as codeine, penthazocine, pethidine and morphine with good tolerability. Paracetamol (also known as acetaminophen) is a nonopiate, nonsalicylate analgesic. Its mech-anism of action is not clear, but it appears to act centrally via several mechanisms, including inhibition of N-methyl-D-aspartate (NMDA) – or substance P – mediated nitric oxide synthesis, and inhibition and interference with the descending serotonergic pathway. It may also inhibit the release of prostaglandin E2 in the central nervous system. Paracetamol is one of the most widely used drugs, with a wealth of experience clearly establishing it as the standard antipyretic and analgesic for mild to moderate pain states. Generally its use is limited to mild pain or as an adjuvant with opioids for more severe pain. These effects are thought to be related to inhibition of prostaglandin synthesis. Tramadol/paracetamol combination The combination of the two active substances is based on the synergistic actions on pain relief and the reduced risk of adverse effects due to the lower doses required compared to the mono-therapies. The current development may also improve the patient’s compliance as the dosage regimen requires only a double daily administration compared to the immediate release formu-lation that can be administered four times a day as a maximum.


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IV.4 Clinical efficacy The Guidance on modified release oral and transdermal dosage forms: Section II (Pharmacoki-netic and clinical evaluation), CPMP/EWP/280/96 Corr* London, 28 July 1999 Section 4.2 states:

“In general it will be necessary to carry out controlled clinical trials. However, in rare cases, if the assessment of concentration-effect relationship indicates that there is a well-defined relationship between plasma concentration (s) of the drug /active metabolite (s) and clinical response clinical trials may be considered unnecessary.”

To justify the lack of clinical efficacy studies the applicant has summarized the data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship of tramadol and paracetamol. Their conclusion is as follows (Module 5.3.4.2: Expert report on efficacy and safety data of tramadol hydrochloride and paracetamol). A PK/PD relationship undoubtedly exists for both tramadol and paracetamol, which in turn means that the tramadol and paracetamol plasma concentrations may certainly serve to forecast the efficacy profile of tramadol/paracetamol formulations. Moreover, taking into account the PK parameters, which have been proved to be important for the efficacy and safety of the con-cerned drugs (i.e. AUC, Cmax and T>MEC of paracetamol and AUC, Cmin and T>MEC of tramadol), two different formulations can be compared in terms of efficacy using only selected PK parameters. The applicant has reviewed several studies regarding the relationship between pharmacokinetic and efficacy parameters of both tramadol and paracetamol. There are data with the combina-tions and also with the monocomponent formulations. The applicant has also compared the different formulations, i.e. immediate release vs. prolonged release to the ones already mar-keted. The conclusion can be accepted, a definitive relationship can be established between PK parameters and the efficacy noting that paracetamol, - similarly to other minor analgesics and non-steroidal anti-inflammatory agents, - has a ceiling effect in the analgesia (the applicant has also noted this phenomenon). Overall, the lack of efficacy studies are considered fully justified. IV.5 Clinical safety The clinical safety of both tramadol and paracetamol, as well as the fixed combination of tra-madol and paracetamol, is well-known. In the two bioavailability studies no new safety con-cerns emerged. A general safety concern has been raised by one of the concerned member states regarding the maximum daily dose of paracetamol from the prolonged release formulation: “a justification for the single dose of two tablets of the medicinal product (equivalent to 150 mg tramadol hy-drochloride and 1300 mg paracetamol) should be provided, and safety of this dose should be discussed in detail, especially regarding paracetamol hepatotoxicity in the single dose of 1300 mg paracetamol and with regard to the fact that the dosage of the product does not depend on


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the body weight so that the proposed dose can exceed the recommended single dose of parace-tamol (15 mg/kg) in patients weighing less than 86 kg.” The applicant has answered the question very thoroughly. The arguments have been as fol-lows:

1. The total exposure with paracetamol is not higher than that after the immediate release (IR) tramadol/paracetamol products.

2. The Cmax values of paracetamol after intake of Doreta SR are lower compared to treatment with maximal allowed single doses of immediate release paracetamol containing products.

3. The combination cannot be given to patients weighing less than 43 kg. 4. The combination cannot be given to children. 5. 5 g of paracetamol may only be hepatotoxic in patients with risk factors (e.g. alcoholics,

patients using enzyme inducing medicines, etc.). 6. The 24 h dose of paracetamol is lower than 4g that is the accepted safety limit within

one day. 7. The plasma concentrations of paracetamol are way below the concentrations that require

treatment with N-acetyl-cystein. These arguments have been accepted by the member states. IV.6 Pharmacovigilance

IV.6.1 Summary of the Pharmacovigilance System

The applicant has submitted a signed Summary of the Applicant's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation 520/2012 and as detailed in the relevant Good Vigilance Practice module, the Summary is considered acceptable.

IV.6.2 Risk Management Plan

Summary of safety concerns

Important identi-fied risks

•Hepatotoxicity in patients with pre-existing hepatic conditions or us-ing high doses, •Convulsions (e.g. in patients with poorly controlled epilepsy), • Overdose, • Withdrawal syndrome, • Dependence, tolerance, abuse, • Concomitant use with anticoagulants, • Serotonin syndrome during concomitant use with serotonergic drugs, • Concomitant use with CNS depressants, • Concomitant use with enzyme inducers,


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Summary of safety concerns

Important poten-tial risks

• Use in patients with a tendency of prolonged elimination (elderly above over 75 years or hepatic/renal impairment. • Use during pregnancy (embryotoxicity, foetotoxicity and neonatal withdrawal syndrome. • Use during breastfeeding. • Medication overuse headache.

Missing infor-mation • Use in paediatric population under 16 years of age

Pharmacovigilance Plan: routine pharmacovigilance activities are considered sufficient to manage all of the safety concerns. No additional activities are proposed.

Risk Minimisation Measures: routine measures (i.e. wording in SmPC, package leaflet and classification as a prescription-only medicine) are considered sufficient to manage all of the safety concerns. No additional activities are proposed. For any further infor-mation on risk minimisation, please refer to the product information.

IV.6.3 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal.

IV.7 Discussion on the clinical aspects Based on the submitted bioavailability studies Doreta SR (tramadol/paracetamol) 75 mg/650 mg prolonged release tablets have similar exposure to two tablets of the reference product Zaldiar® 37.5mg/325mg film-coated tablets. Since there is a well-established PK-PD relationship with the analgesic compounds similarity between the pharmacokinetic parameters indicate similarity in efficacy as well, comparable ex-posure suggest equal analgesic efficacy of the test product. The fluctuation of the sustained released tramadol/paracetamol prolonged release tablet is also similar to the immediate release formula and the bioavailability studies did not indicate the appearance of any new unknown safety concern the benefit of the test product outweighs the risks. The b.i.d. administration of the test product may increase the patients’ compliance as well.


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V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT

AND RECOMMENDATION V.1 Summary The present applications concern Doreta SR 75 mg/650 mg prolonged-release tablets, fixed combination of tramadol (as hydrochloride) and paracetamol. The applicant and the future holder of authorisation is Krka, d. d., Novo mesto, Slovenia. The indication is symptomatic treatment of moderate to severe pain in adults and adolescents over the age of 12 years. This application was submitted according to Article 10(3) “hybrid application” of the Directive 2001/83/EC. The reference product for the application was Zaldiar® 37.5 mg/325 mg film-coated tablets (Grünenthal GmbH, Germany) that is available in an immediate release form. To support the application, the applicant has submitted the reports of two bioavailability studies with the tramadol/paracetamol 75 mg/650 mg prolonged release tablets. The approval of the 75 mg/650 mg strength is based upon by showing the comparable exposure with the prolonged release formulation to the innovator immediate release Zaldiar 37.5 mg/325 mg film-coated tablets. The submitted documentation is administratively adequate and scientifically sound. The quality of the product is satisfactory. There were no non-clinical concerns. The clinical safety concern, raised by one of the concerned member states during the discussion was satisfactorily answered by the applicant. The therapeutic benefit/risk assessment is, therefore, positive. Based on the review of the quality, safety and efficacy data, the Member States have granted marketing authorisation for Doreta SR 75 mg/650 mg prolonged-release tablets. V.2 Classification Prescription-only medicine.


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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 Directive 2001/83/EC. The language used for the purpose of user testing the patient information leaflet was Hungarian. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

National Institute of Pharmacy Doreta SR and Nutrition 75 mg/650 mg prolonged-release tableta

Budapest, Hungary HU/H/0190/003-/DC 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 HU/H/

Product information affected

Date of start of the procedure

Date of end of procedure

Approval or non approval

Assessment report

attached

IB z) Update of the SmPC and Package Leaflet 0190/001-003/IB/024 yes 26. 07. 2016 25. 08. 2016 approval no

doreta sr · 2017. 4. 11. · doreta sr prolonged-release tablet (further on: doreta sr) is a...

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