Clozapin ratiopharm

Hauptinformation

  • Handelsname:
  • Clozapin ratiopharm 200 mg Tabletten
  • Verschreibungstyp:
  • Arzneimittel zur einmaligen Abgabe auf aerztliche Verschreibung
  • Verwenden für:
  • Menschen
  • Art der Medizin:
  • allopathic Droge

Dokumenten

Lokalisierung

  • Erhältlich in:
  • Clozapin ratiopharm 200 mg Tabletten
    Österreich
  • Sprache:
  • Deutsch

Therapeutische Informationen

  • Produktbesonderheiten:
  • Abgabe durch eine (öffentliche) Apotheke

Weitere Informationen

Status

  • Quelle:
  • AGES
  • Zulassungsnummer:
  • 137427
  • Berechtigungsdatum:
  • 13-02-2017
  • Letzte Änderung:
  • 09-08-2017

Öffentlichen Beurteilungsberichts

CMDh/223/2005

February 2014

Public Assessment Report

Scientific discussion

Clozapin ratiopharm 25/100/200 mg Tabletten

CLOZAPIN

AT/H/0636/001-003/DC

Date: 30.08.2017

This module reflects the scientific discussion for the approval of Clozapin ratiopharm

25/100/200 mg Tabletten. The procedure was finalised at 18.01.2017.

For information on

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

I.

INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a

marketing authorisation for Clozapin ratiopharm 25/100/200 mg Tabletten, from ratiopharm

Arzneimittel Vertriebs-GmbH.

The product is indicated for:

Treatment-resistant schizophrenia

Clozapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia

patients who have severe, untreatable neurological adverse reactions to other antipsychotic

agents, including atypical antipsychotics.

Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use

of adequate doses of at least two different antipsychotic

agents, including an atypical

antipsychotic agent, prescribed for adequate duration.

Only for 25 and 100 mg tablets:

Psychosis during the course of Parkinson's disease

Clozapine is also indicated in psychotic disorders occurring during the course of Parkinson's

disease, in cases where standard treatment has failed.

A comprehensive description of the indications and posology is given in the SmPC.

The marketing authorisations have been granted pursuant to Article 10(1) of Directive

2001/83/EC for the 25 and 100 mg strengths and Article 10(3) of Directive 2001/83/EC for

the 200 mg strength.

Clozapine

been

shown

antipsychotic

agent

that

different

from

classic

antipsychotics.

Clinically clozapine produces rapid and marked sedation and exerts antipsychotic effects in

schizophrenic patients resistant to other drug treatment. In such cases, clozapine has proven

effective in relieving both positive and negative schizophrenic symptoms mainly in short-term

trials.

In an open clinical trial performed in 319 treatment resistant patients treated for 12 months, a

clinically relevant improvement was observed in 37% of patients within the first week of

treatment and in an additional 44% by the end of 12 months. The improvement was defined as

about 20% reduction from baseline in Brief Psychiatric Rating Scale Score. In addition,

improvement in some aspects of cognitive dysfunction has been described.

Compared to classic antipsychotics, clozapine produces fewer major extrapyramidal reactions

such as acute dystonia, parkinsonian-like side effects and akathisia. In contrast to classic

antipsychotics, clozapine produces little or no prolactin elevation, thus avoiding adverse

effects such as gynaecomastia, amenorrhoea, galactorrhoea and impotence.

A potentially serious adverse reaction caused by clozapine therapy is granulocytopenia and

agranulocytosis occurring at an estimated incidence of 3% and 0.7%, respectively. In view of

this risk, the use of clozapine should be limited to patients who are treatment-resistant or

patients with psychosis in Parkinson's disease when other treatment strategies have failed

(only for 25 and 100 mg tablets) and in whom regular haematological examinations can be

performed.

II.

QUALITY ASPECTS

II.1

Introduction

Clozapin ratiopharm 25/100/200 mg Tabletten are tablets which are presented in Aluminium -

PVC/PVDC blister packs.

II.2

Drug Substance

The active substance in Clozapin ratiopharm 25/100/200 mg Tabletten is clozapine. The

specification of the active substance/s meets the current scientific requirements. The adequate

quality of the active substance has been shown by submitting the appropriate control data. The

stability of the active substance has been tested under ICH conditions. The results of the

stability studies support the established retest-period.

II.3

Medicinal Product

Clozapin ratiopharm 25/100/200 mg Tabletten contain the following excipients:

Lactose monohydrate

Maize starch

Povidone K30

Silica, colloidal anhydrous

Magnesium stearate

Talc

Lactose:

25 mg: Each tablet contains 46 mg lactose.

100 mg: Each tablet contains 182 mg lactose.

200 mg: Each tablet contains 365 mg lactose.

The development of the product has been sufficiently made and deemed appropriate. The

usage of all the excipients has been described.

The release specification includes the check of all parameters relevant to this pharmaceutical

form. Appropriate data concerning the control of the finished product support the compliance

with the release specifications.

The packaging of the medicinal product complies with the current legal requirements.

Stability studies under ICH conditions have been performed and data presented support the

shelf life claimed in the SmPC, with a shelf life of 36 months.

The pharmaceutical quality of Clozapin ratiopharm 25/100/200 mg Tabletten has been

adequately shown.

II.4

Discussion on chemical, pharmaceutical and biological aspects

Information on development, manufacture and control of active substance and medicinal

product has been presented in a satisfactory manner. The results of tests carried out indicate

satisfactory consistency and uniformity of important product quality characteristics.

III.

NON-CLINICAL ASPECTS

Pharmacodynamic,

pharmacokinetic

toxicological

properties

clozapine

well

known. As clozapine 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.

III.1

Ecotoxicity/environmental risk assessment (ERA)

Since Clozapin ratiopharm 25/100/200 mg Tabletten is intended for generic substitution, this

will not lead to an increased exposure to the environment. An environmental risk assessment

is therefore not deemed necessary.

III.2

Discussion on the non-clinical aspects

non-clinical

overview

pre-clinical

pharmacology,

pharmacokinetics

toxicology is adequate.

IV.

CLINICAL ASPECTS

IV.1

Introduction

To support the application, the applicant has submitted as report two bioequivalence studies.

The studies were conducted with the lowest possible dose of 12.5 mg clozapine (one half

tablet of the lowest dose strength of 25 mg) due to safety/tolerability reasons in healthy

volunteers.

IV.2

Pharmacokinetics

Biowaiver

A biowaiver of strengths was requested and granted for the 100 mg and 200 mg strengths.

Bioequivalence studies

Study 1: An open label, balanced, randomized, two-treatment, two-period, two-sequence,

single oral dose, crossover, bioequivalence study of two products of clozapine tablets 25 mg

following administration of 12.5 mg dose (one half tablet) in normal, healthy, adult, human

subjects under fasting condition.

Table 1.

Pharmacokinetic

parameters

(non-transformed

values;

arithmetic

mean ± SD, t

max

median, range)

Treatment

AUC

0-t

ng/ml/h

AUC

0-∞

ng/ml/h

C

max

ng/ml

t

max

h

Test

426.735

± 178.2627

455.105

± 205.5401

32.533

± 11.1274

1.667

(1.000 – 4.500)

Reference

454.349

± 205.0957

482.163

± 227.3427

32.367

± 10.9138

1.667

(1.000 – 4.517)

*Ratio (90% CI)

94.6

(88.12 – 101.65)

94.8

(88.30 – 101.84)

101.2

(94.72 – 108.03)

AUC

0-t

Area under the plasma concentration curve from administration to last observed concentration at time t.

0-72h

be reported instead of AUC

, in studies with sampling period of 72 h, and where the concentration

at 72 h is quantifiable. Only for immediate release products

AUC

0-∞

Area under the plasma concentration curve extrapolated to infinite time.

0-∞

does not need to be reported when

0-72h

is reported instead of AUC

C

max

Maximum plasma concentration

t

max

Time until C

is reached

*ln-transformed values

Study 2: An open label, balanced, randomized, two-treatment, four-period, two-sequence,

single oral dose, fully replicate, crossover, bioequivalence study of two products of Clozapine

Tablets 25 mg following administration of 12.5 mg dose (one half tablet) in normal, healthy,

adult, human subjects under fasting condition.

Table 2.

Pharmacokinetic

parameters

(non-transformed

values;

arithmetic

mean ± SD, t

max

median, range)

Treatment

AUC

0-t

ng/mL/h

AUC

0-∞

ng/mL/h

C

max

ng/mL

t

max

h

Test

(N = 137

observations)

326.898

(± 161.1109)

343.622

(± 175.4411)

26.355

(± 10.1719)

1.667

(1.000 - 5.000)

Reference

(N = 138

observations)

315.261

(± 157.4109)

332.704

(± 172.3380)

24.770

(± 9.0676)

2.000

(1.000 - 6.000)

*Ratio (90% CI)

104.3

(100.13 - 108.59)

103.9

(99.76 - 108.13)

106.2

(101.60 - 110.92)

AUC

0-t

Area under the plasma concentration curve from administration to last observed concentration at time t.

0-72h

be reported instead of AUC

, in studies with sampling period of 72 h, and where the concentration

at 72 h is quantifiable. Only for immediate release products

AUC

0-∞

Area under the plasma concentration curve extrapolated to infinite time.

0-∞

does not need to be reported when

0-72h

is reported instead of AUC

C

max

Maximum plasma concentration

t

max

Time until C

is reached

*ln-transformed values

Conclusion on bioequivalence studies:

Based on the additionally submitted bioequivalence study Clozapin ratiopharm (test product)

is considered bioequivalent with Leponex (originator product).

The results of the study 2 with half a tablet (corresponding to 12.5 mg clozapine) of 25 mg

formulation can be extrapolated to other strengths 100 mg and 200 mg, according to

conditions in Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98

Rev. 1/Corr**), section 4.1.6.

IV.3

Pharmacodynamics

pharmacodynamic

profile

clozapine

well

established.

additional

pharmacodynamic study has been submitted by the applicant and none is required.

IV.4

Clinical efficacy/safety

Efficacy and safety of clozapine in the proposed indications are known and assessed as being

scientifically based considering recent knowledge, guidelines, and recommendations.

The safety profile of the test product is comparable with the safety profile of the reference

product.

IV.5

Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of

Directive

2001/83/EC

amended,

describing

pharmacovigilance

activities

interventions designed to identify, characterise, prevent or minimise risks relating to Clozapin

ratiopharm 25/100/200 mg Tabletten.

Summary table of safety concerns as approved in RMP

Important identified risks

• Agranulocytosis

• Epilepsy/Seizures

• Cardiovascular disorders including Orthostatic

hypotension, Myocarditis and Cardiomyopathy,

Pericarditis/Pericardial Effusion, QT prolongation,

Myocardial infarction, Thromboembolism,

Circulatory collapse

• Anticholinergic effects

• Metabolic disorders including Hyperglycaemia,

Dyslipidemia, Weight gain

• Acute withdrawal reactions

• Fulminant hepatic necrosis

• Neuroleptic malignant syndrome

• Hypersensitivity

• Excessive sedation

Important potential risks

• Cerebrovascular adverse events and increased risk

of death in elderly patients with dementia related

psychosis

• Sudden unexplained death

• Renal Failure

• Interaction with drugs which are either inhibitor or

inducer of CYP450 isoenzymes including

antiepileptics like phenytoin

• Interaction with valproic acid

• Interaction with citalopram

• Drug withdrawal syndrome neonatal

• Interaction with highly protein bound substances

(e.g. warfarin and digoxin)

Missing information

• Use in children and adolescent under age of 16

• Use in pregnant and lactating populations

Routine pharmacovigilance activities are regarded to be sufficient to identify and characterise

the risks of the product. Additional risk minimisation measures (educational material as

proposed in the RMP) shall be agreed with the national competent authority.

IV.6

Discussion on the clinical aspects

The dossier contains an adequate review of published clinical data and bioequivalence has

been shown for the 25 mg strength.

A biowaiver of strengths was requested and granted for the 100 mg and 200 mg strengths.

V.

USER CONSULTATION

A user consultation with target patient groups on the package information leaflet (PIL) has

been performed on the basis of a bridging report making reference to Leponex 25/100 mg

tablets and Solifenacin succinate 5/10 mg film-coated tablets. The bridging report submitted

by the applicant has been found acceptable.

VI.

OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

Concerning additional risk minimisation measures:

Educational material as additional risk minimisation measure shall be agreed with national

competent authorities.

The pharmaceutical quality of Clozapin ratiopharm 25/100/200 mg Tabletten has been

adequately shown.

There are no non-clinical or clinical concerns.

The benefit/risk relation is considered positive.

Public Assessment Report

Update

Clozapin ratiopharm 25/100/200 mg Tabletten

CLOZAPIN

AT/H/0636/001-003

This module reflects the procedural steps and scientific information after the finalisation

of the initial procedure.

Procedure

number*

Scope

Product Information

affected

Date of end

of procedure

Approval/

non approval

Summary/ Justification for

refuse

*Only procedure qualifier, chronological number and grouping qualifier (when applicable)

Packungsbeilage

Bundesamt für Sicherheit im Gesundheitswesen, Traisengasse 5, A-1200 Wien

www.ages.at, DVR: 2112611, Konto Nr.: 50670 871 619

BLZ: 12000, IBAN: AT971200050670871619; UID: ATU 54088605, BIC/SWIFT: BKAUATWW

1 von 1

Die gegenständliche Arzneispezialität wurde in einem europäischen Zulassungsverfahren

geprüft.

Die Vermarktung des Produktes in Österreich ist derzeit seitens des Zulassungsinhabers nicht

geplant, daher liegen zur Zeit keine deutschsprachigen Übersetzungen der Fach- und

Gebrauchsinformation vor.

Traisengasse 5, 1200 Wien

11-9-2018

Broschüre für den Apotheker

Broschüre für den Apotheker

Bortezomib - Bortezomib-ratiopharm® - Information für Ärzte

Deutschland - BfArM - Bundesinstitut für Arzneimittel und Medizinprodukte

11-9-2018

Poster

Poster

Bortezomib - Bortezomib-ratiopharm® - Information für Ärzte

Deutschland - BfArM - Bundesinstitut für Arzneimittel und Medizinprodukte

29-6-2018

Medicines Safety Update, Volume 9, Number 2, June 2018

Medicines Safety Update, Volume 9, Number 2, June 2018

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