granisetron 1mg 1ml and 3mg 3ml conc for sol for inf or ... · granisetron 3mg/3ml concentrate for...

UKPAR Granisetron 1mg/1ml and 3mg/3ml Conc for Sol for Inf or Inj PL 24668/0035-6, 0038-9

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GRANISETRON 1MG/1ML CONCENTRATE FOR SOLUTION FOR INFUSION OR INJECTION


UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

2

Steps taken after authorisation – summary

Page 13

Summary of Product Characteristics Product Information Leaflet Labelling


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LAY SUMMARY On 27th April 2009, the MHRA granted Caduceus Pharma Limited Marketing Authorisations (licences) for the medicinal products Granisetron 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection (PL 24668/0035-6, 0038-9). These are prescription only medicines (POM). Granisetron belongs to a group of medicines called serotonin (5-HT3) antagonists which act as anti-emetics. It is used to prevent and treat nausea (feeling sick) and vomiting (being sick). It is especially useful when you need to have medical treatment that may cause you to feel or be sick. In adults, Granisetron 1mg/1ml Concentrate for Solution for Infusion or Injection is used to stop you from feeling or being sick after a surgical operation. In children and adolescents aged 2-16 years Granisetron 1mg/1ml Concentrate for Solution for Infusion or Injection is used to stop you from feeling or being sick after certain types of treatment, for example, chemotherapy or radiotherapy. Granisetron 3mg/3ml Concentrate for Solution for Infusion or Injection is used to stop you from feeling or being sick after certain types of treatment, for example, chemotherapy or radiotherapy. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Granisetron 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection outweigh the risks, hence Marketing Authorisations have been granted.


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GRANISETRON 1MG/1ML CONCENTRATE FOR SOLUTION

FOR INFUSION OR INJECTION GRANISETRON 3MG/3ML CONCENTRATE FOR SOLUTION

FOR INFUSION OR INJECTION

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 7

Clinical assessment (including statistical assessment)

Page 8

Overall conclusions and risk benefit assessment Page 11


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the UK granted Marketing Authorisations for the medicinal products Granisetron 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection (PL 24668/0035-6, 0038-9) to Caduceus Pharma Limited on 27th April 2009. The products are prescription-only medicines. These are national abridged applications for Granisetron 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection claiming essential similarity to the originator products Kytril 1mg/1ml and 3mg/3ml, first licensed in the UK to Roche Products Limited in 1991. The products contain the active ingredient granisetron hydrochloride and are indicated for the:

• prevention or treatment of nausea and vomiting induced by cytostatic therapy and for the prevention and treatment of post-operative nausea and vomiting (1mg/1ml)

• prevention or treatment of nausea and vomiting induced by cytostatic therapy (3mg/3ml)

Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT3) receptors. Radioligand binding studies have demonstrated that Granisetron has negligible affinity for other receptor types including 5-HT and dopamine D2 binding sites.


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PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Granisteron hydrochloride Chemical Names: 1-Methyl-N-[(lR,3R,5S)-9-methyl-9-azabicyclo[3.3.1 ]non-3-yl]-

1H-indazole-3-carboxamide hydrochloride Structure:

Molecular formula: C18H25ClN4O Molecular weight: 348.9 Physical form: A white or almost white powder freely soluble in water, sparingly

soluble in methylene chloride, slightly soluble in methanol Granisetron hydrochloride is the subject of a European Pharmacopoeia monograph. Synthesis of the drug substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents, and these are supported by relevant certificates of analysis. No materials of animal or human origin are used in the production of the active substance. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. All impurities have been appropriately characterised and certificates of analysis have been provided for any working standards used. Batch analysis data are provided that comply with the proposed specification. Suitable specifications for all materials used in the active substance packaging have been provided. The primary packaging meets the requirements for materials in contact with food. Appropriate stability data have been generated, from studies carried out in accordance with ICH conditions. A suitable retest period has been set, based on the stability data provided. DRUG PRODUCT Other ingredients Other ingredients consist of pharmaceutical excipients sodium chloride, hydrochloric acid, sodium hydroxide, water for injections and nitrogen. All excipients are controlled to their respective European Pharmacopoeia monograph. Satisfactory certificates of analysis have been provided for all excipients. None of the excipients used contain materials of animal or human origin.


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Pharmaceutical development Suitable pharmaceutical development data have been provided for these applications. Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results appear satisfactory. Finished product specification The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used. Container Closure System Granisetron is supplied in clear glass ampoules in packs of five, with an outer carton. Specifications and certificates of analysis for the primary packaging material have been provided. These are satisfactory. All primary packaging is controlled to European Pharmacopoeia standards and complies with guidelines concerning materials in contact with parenteral products. Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 3 years has been set when the product is unopened, with the storage conditions “Keep the ampoules in the outer carton in order to protect from light. Do not freeze.” When the product has been opened and diluted, a shelf-life of 24 hours has been applied. Summary of Product Characteristics (SPC), Patient Information Leaflet (PIL) and Labelling The SPC, PIL and labelling are pharmaceutically satisfactory. The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. MAA Form The MAA form is pharmaceutically satisfactory. Expert Report The pharmaceutical expert report is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier.


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Conclusion It is recommended that Marketing Authorisations are granted for these applications.


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PRECLINICAL ASSESSMENT These applications are generic medicinal products of Kytril 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection (Roche Products Limited, UK), which has been licensed within the EEA for over 10 years. No new preclinical data have been supplied with these applications and none are required for applications of this type.


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CLINICAL ASSESSMENT CLINICAL PHARMACOLOGY No new pharmacokinetic data were submitted to support these applications and none are required for applications of this type. EFFICACY No new efficacy data were submitted to support these applications and none are required for applications of this type. SAFETY No new safety data were submitted to support these applications and none are required for applications of this type. EXPERT REPORTS A clinical expert report has been written by a suitably qualified person and is satisfactory. SUMMARY OF PRODUCT CHARACTERISTICS (SPC) These are consistent with those for the reference products and are satisfactory. PATIENT INFORMATION LEAFLETS (PIL) These are consistent with the SPC and are satisfactory. LABELLING These are satisfactory APPLICATION FORMS (MAA) These are satisfactory. DISCUSSION Bioequivalence has been satisfactorily demonstrated, in accordance with CHMP criteria. MEDICAL CONCLUSION The grant of marketing authorisations is recommended for these applications.


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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Granisetron 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY Bioequivalence has been demonstrated between the applicant’s and reference products. No new or unexpected safety concerns arise from these applications. The SPC, PIL and labelling are satisfactory and consistent with those for the reference products, where necessary. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The bioequivalence studies support the claim that the applicant’s products and the innovator products are interchangeable. Extensive clinical experience with granisetron hydrochloride is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


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STEPS TAKEN FOR ASSESMENT

1 The MHRA received the Marketing Authorisation applications on 4th January

2007

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 5th March 2007

3 Following assessment of the applications the MHRA requested further information relating to the quality dossiers on 26th June 2008 and 31st December 2008, and related to the clinical dossiers on 3rd March 2007, 13th September 2007, 15th November 2007 and 27th June 2008

4 The applicant responded to the MHRA’s requests, providing further information on 14th October 2008 and 23rd January 2009 for the quality sections, and 30th August 2007, 16th October 2007, 23rd April 2008 and 30th June 2008 for the clinical sections.

5 The applications were determined on 27th April 2009


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STEPS TAKEN AFTER AUTHORISATION - SUMMARY

Date submitted

Application type

Scope Outcome


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1 NAME OF THE MEDICINAL PRODUCT Granisetron 1mg/1ml concentrate for solution for infusion or injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains 1 mg of granisetron (as the hydrochloride)

For full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM

A glass ampoule containing a sterile, clear, colourless or slightly straw-coloured solution. The content allows withdrawal of 1ml. Concentrate for solution for infusion or injection.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Granisetron is indicated for the prevention or treatment of nausea and vomiting induced by cytostatic therapy and for the prevention and treatment of post-operative nausea and vomiting.

4.2 Posology and method of administration

For intravenous administration only. Cytostatic therapy Children and adolescents aged 2-16 years Prevention: A single dose of 40μg/kg bodyweight (up to 3mg) should be administered as an intravenous infusion, diluted in 10 to 30ml infusion fluid and administered over five minutes. Administration should be completed prior to the start of cytostatic therapy. Treatment: The same dose of Granisetron as above should be used for treatment as prevention. One additional dose of 40μg/kg bodyweight (up to 3mg) may be administered within a 24-hour period if required. This additional dose should be administered at least 10 minutes apart from the initial infusion. Renally impaired No special requirements apply. Hepatically impaired No special requirements apply. Post-operative nausea and vomiting Adults For prevention in adults, a single dose of 1mg of Granisetron should be diluted to 5ml and administered as a slow intravenous injection (over 30 seconds). Administration should be completed prior to induction of anaesthesia. For the treatment of established post-operative nausea and vomiting in adults, a single dose of 1mg of Granisetron should be diluted to 5ml and administered by slow intravenous injection (over 30 seconds). Maximum dose and duration of treatment Two doses (2mg) in one day. Children There is no experience in the use of Granisetron in the prevention and treatment of post-operative nausea and vomiting in children. Granisetron is not therefore recommended for the treatment of post-operative nausea and vomiting in this age group. Elderly As for adults.


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Renally impaired As for adults. Hepatically impaired As for adults.

4.3 Contraindications

Known hypersensitivity to Granisetron, or any of the excipients, or to any other serotonin (5-HT3) antagonists (e.g. ondansetron).

4.4 Special warnings and precautions for use

As Granisetron may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following administration of Granisetron. No special precautions are required for elderly patients or renally and/or hepatically impaired patients. Although to date no signs of an increased incidence of undesirable effects have been observed in hepatically impaired patients, owing to the kinetics a degree of caution should be exercised in using Granisetron within this category. Serotonin (5-HT3) antagonists, such as granisetron, may be associated with arrhythmias or ECG abnormalities. This potentially may have clinical significance in patients with pre-existing arrhythmias or cardiac conduction disorders or patients who are being treated with antiarrhythmic agents or beta-blockers.

4.5 Interaction with other medicinal products and other forms of interaction Animal studies indicate that granisetron neither stimulates nor inhibits the cytochrome P450 enzyme system. Because granisetron is metabolized by hepatic cytochrome P450 enzymes, inducers or inhibitors of these enzymes may change clearance and, hence, the half-life of granisetron. In human subjects, hepatic enzyme induction by phenobarbital has led to an increase in total plasma clearance (approx. 25%) following intravenous administration of granisetron. In vitro studies have shown that ketoconazole may inhibit the metabolism of granisetron via the cytochrome P450 3A isoenzyme family. The clinical significance of this is unknown. To date no signs of interaction have been observed between granisetron and medicinal products that are often prescribed in anti-emetic therapy, such as benzodiazepines, neuroleptics and agents for peptic indications. Furthermore, no interaction has been observed between granisetron and emetogenic cytostatic therapies.

4.6 Pregnancy and lactation There is no clinical data in human pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3). Therefore Granisetron should not be administered to pregnant women unless there are compelling clinical reasons. There are no data on the excretion of Granisetron in breast milk. Breast feeding should therefore be discontinued during therapy.

4.7 Effects on ability to drive and use machines

Granisetron has no influence on the ability to drive and use machines. 4.8 Undesirable effects

Granisetron has been generally well tolerated in human studies. As reported with other drugs of this class, headache and constipation have been the most frequently noted adverse events


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but the majority have been mild or moderate in nature. Rare cases of hypersensitivity reaction, occasionally severe (e.g. anaphylaxis) have been reported. Other allergic reactions including minor skin rashes have also been reported. In clinical trials, transient increases in hepatic transaminases, generally within the normal range, have been seen.

Cardiac disorders Rare (≥1/10,000 to <1/1,000)

Arrhythmias, chest pain

Nervous system disorders Very common (≥1/10) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), not known (cannot be estimated from the available data)

Headache Extrapyramidal disorders (dystonias and dyskinesias) Coma

Gastrointestinal disorders Very common (≥1/10) Common (≥1/100 to <1/10)

Nausea, constipation Reduced appetite, diarrhoea, vomiting, abdominal pain

Skin and subcutaneous tissue disorders Very rare (<1/10,000), not known (cannot be estimated from the available data)

Rash

General disorders and administration site conditions Common (≥1/100 to <1/10) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), not known (cannot be estimated from the available data)

Asthenia, pain, fever Hypersensitivity reaction, anaphylaxis Fainting, dizziness, insomnia, agitation

Hepatobiliary disorders Rare (≥1/10,000 to <1/1,000)

Abnormal hepatic function, increased transaminases

Psychiatric disorders Very rare (<1/10,000), not known (cannot be estimated from the available data)

Anorexia

4.9 Overdose

There is no specific antidote for Granisetron. In the case of overdosage, symptomatic treatment should be given. One patient has received 30mg of Granisetron intravenously. The patient reported a slight headache but no other sequelae were observed.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Serotonin (5-HT3) antagonists, ATC code: A04AA02 Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT3) receptors. Radioligand binding studies have demonstrated that Granisetron has negligible affinity for other receptor types including 5-HT and dopamine D2 binding sites. Granisetron is effective intravenously, either prophylactically or by intervention, in abolishing the retching and vomiting evoked by administration of cytotoxic drugs or by whole body X-irradiation. Granisetron is effective, intravenously, in the prevention and treatment of post-operative nausea and vomiting.


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5.2 Pharmacokinetic properties General characteristics Distribution Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 L/kg; plasma protein binding is approximately 65%. Biotransformation Biotransformation pathways involve N-demethylation and aromatic ring oxidation followed by conjugation. Elimination Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged Granisetron averages 12% of dose whilst that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients is approximately nine hours, with a wide inter-subject variability. Characteristics in patients The plasma concentration of Granisetron is not clearly correlated with anti-emetic efficacy. Clinical benefit may be conferred even when Granisetron is not detectable in plasma. In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects. In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects. In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary.

5.3 Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies repeated dose toxicity, carcinogenicity, reproductive toxicity and genotoxicity. A study in cloned human cardiac ion channels has shown that granisetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. Granisetron has been shown to block both sodium and potassium channels, which potentially affects both depolarization and repolarisation through prolongation of PR, QRS, and QT intervals. This data helps to clarify the molecular mechanisms by which some of the ECG changes (particularly QT and QRS prolongation) associated with this class of agents occur. However, there is no modification of the cardiac frequency, blood pressure or the ECG trace.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Sodium Chloride Hydrochloric Acid Sodium Hydroxide Water for Injections

6.2 Incompatibilities

As a general precaution, Granisetron should not be mixed in solution with other drugs. Prophylactic administration of Granisetron should be completed prior to the start of cytostatic therapy.

6.3 Shelf life

Granisetron ampoules have a shelf-life of 3 years. Once opened, and after dilution with a recommended diluent, the ampoules have a shelf-life 24 hours.

6.4 Special precautions for storage

Keep the ampoules in the outer carton in order to protect from light. Do not freeze.


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6.5 Nature and contents of container Granisetron is supplied in clear glass ampoules in packs of five, with an outer carton.

6.6 Special precautions for disposal

Preparing the infusion Children: To prepare the dose of 40 µg/kg, the appropriate volume is withdrawn and diluted with infusion fluid to a total volume of 10 to 30ml. Any one of the following solutions may be used: 0.9% w/v Sodium Chloride Injection BP; 0.18% w/v Sodium Chloride and 4% w/v Glucose Injection BP; 5% w/v Glucose Injection BP; Hartmann's Solution for Injection BP; Sodium Lactate Injection BP; or 10% Mannitol Injection BP. No other diluents should be used. Ideally, intravenous infusions of Granisetron should be prepared at the time of administration. After dilution (see above), or when the container is opened for the first time, the shelf-life is 24 hours when stored at ambient temperature in normal indoor illumination protected from direct sunlight. It must not be used after 24 hours. If to be stored after preparation, Granisetron infusions must be prepared under appropriate aseptic conditions. Adults: to prepare a dose of 1mg, 1ml should be withdrawn from the ampoule and diluted to 5ml with 0.9% w/v Sodium Chloride Injection BP. No other diluent should be used.

7 MARKETING AUTHORISATION HOLDER

Caduceus Pharma Limited 6th Floor, 94 Wigmore Street, London W1U 3RF UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 24668/0035 PL 24668/0038

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 27/04/2009 10 DATE OF REVISION OF THE TEXT

27/04/2009


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1 NAME OF THE MEDICINAL PRODUCT Granisetron 3mg/1ml concentrate for solution for infusion or injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 3 ml contains 3.0 mg of granisetron (as the hydrochloride)

For full list of excipients, see section 6.1. 3 PHARMACEUTICAL FORM

A glass ampoule containing a sterile, clear, colourless or slightly straw-coloured solution. The content allows withdrawal of 3ml. Concentrate for solution for infusion or injection.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Granisetron is indicated for the prevention or treatment of nausea and vomiting induced by cytostatic therapy.

4.2 Posology and method of administration

For intravenous administration only. Adults 3mg Granisetron, which should be administered either in 15ml infusion fluid as an intravenous bolus over not less than 30 seconds or diluted in 20 to 50ml infusion fluid and administered over five minutes. Prevention: In clinical trials, the majority of patients have required only a single dose of Granisetron to control nausea and vomiting over 24 hours. Up to two additional doses of 3mg Granisetron may be administered within a 24-hour period. There is clinical experience in patients receiving daily administration for up to five consecutive days in one course of therapy. Prophylactic administration of Granisetron should be completed prior to the start of cytostatic therapy. Treatment: The same dose of Granisetron should be used for treatment as prevention. Additional doses should be administered at least 10 minutes apart. Maximum daily dosage Up to three doses of 3mg Granisetron may be administered within a 24-hour period. The maximum dose of Granisetron to be administered over 24 hours should not exceed 9mg. Concomitant use of dexamethasone The efficacy of Granisetron may be enhanced by the addition of dexamethasone. Children and adolescents aged 2-16 years Prevention: A single dose of 40μg/kg bodyweight (up to 3mg) should be administered as an intravenous infusion, diluted in 10 to 30ml infusion fluid and administered over five minutes. Administration should be completed prior to the start of cytostatic therapy. Treatment: The same dose of Granisetron as above should be used for treatment as prevention. One additional dose of 40μg/kg bodyweight (up to 3mg) may be administered within a 24-hour period if required. This additional dose should be administered at least 10 minutes apart from the initial infusion. Elderly No special requirements apply to elderly patients. Patients with renal or hepatic impairment No special requirements apply to those patients with renal or hepatic impairment


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4.3 Contraindications Known hypersensitivity to Granisetron, or any of the excipients, or to any other serotonin (5-HT3) antagonists (e.g. ondansetron).

4.4 Special warnings and precautions for use

As Granisetron may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following administration of Granisetron. No special precautions are required for elderly patients or renally and/or hepatically impaired patients. Although to date no signs of an increased incidence of undesirable effects have been observed in hepatically impaired patients, owing to the kinetics a degree of caution should be exercised in using Granisetron within this category. Serotonin (5-HT3) antagonists, such as granisetron, may be associated with arrhythmias or ECG abnormalities. This potentially may have clinical significance in patients with pre-existing arrhythmias or cardiac conduction disorders or patients who are being treated with antiarrhythmic agents or beta-blockers.

4.5 Interaction with other medicinal products and other forms of interaction Animal studies indicate that granisetron neither stimulates nor inhibits the cytochrome P450 enzyme system. Because granisetron is metabolized by hepatic cytochrome P450 enzymes, inducers or inhibitors of these enzymes may change clearance and, hence, the half-life of granisetron. In human subjects, hepatic enzyme induction by phenobarbital has led to an increase in total plasma clearance (approx. 25%) following intravenous administration of granisetron. In vitro studies have shown that ketoconazole may inhibit the metabolism of granisetron via the cytochrome P450 3A isoenzyme family. The clinical significance of this is unknown. To date no signs of interaction have been observed between granisetron and medicinal products that are often prescribed in anti-emetic therapy, such as benzodiazepines, neuroleptics and agents for peptic indications. Furthermore, no interaction has been observed between granisetron and emetogenic cytostatic therapies.

4.6 Pregnancy and lactation There is no clinical data in human pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3). Therefore Granisetron should not be administered to pregnant women unless there are compelling clinical reasons. There are no data on the excretion of Granisetron in breast milk. Breast feeding should therefore be discontinued during therapy.

4.7 Effects on ability to drive and use machines

Granisetron has no influence on the ability to drive and use machines. 4.8 Undesirable effects

Granisetron has been generally well tolerated in human studies. As reported with other drugs of this class, headache and constipation have been the most frequently noted adverse events but the majority have been mild or moderate in nature. Rare cases of hypersensitivity reaction, occasionally severe (e.g. anaphylaxis) have been reported. Other allergic reactions including minor skin rashes have also been reported. In clinical trials, transient increases in hepatic transaminases, generally within the normal range, have been seen.


20

Cardiac disorders Rare (≥1/10,000 to <1/1,000)

Arrhythmias, chest pain

Nervous system disorders Very common (≥1/10) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), not known (cannot be estimated from the available data)

Headache Extrapyramidal disorders (dystonias and dyskinesias) Coma

Gastrointestinal disorders Very common (≥1/10) Common (≥1/100 to <1/10)

Nausea, constipation Reduced appetite, diarrhoea, vomiting, abdominal pain

Skin and subcutaneous tissue disorders Very rare (<1/10,000), not known (cannot be estimated from the available data)

Rash

General disorders and administration site conditions Common (≥1/100 to <1/10) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), not known (cannot be estimated from the available data)

Asthenia, pain, fever Hypersensitivity reaction, anaphylaxis Fainting, dizziness, insomnia, agitation

Hepatobiliary disorders Rare (≥1/10,000 to <1/1,000)

Abnormal hepatic function, increased transaminases

Psychiatric disorders Very rare (<1/10,000), not known (cannot be estimated from the available data)

Anorexia

4.9 Overdose

There is no specific antidote for Granisetron. In the case of overdosage, symptomatic treatment should be given. One patient has received 30mg of Granisetron intravenously. The patient reported a slight headache but no other sequelae were observed.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Serotonin (5-HT3) antagonists, ATC code: A04AA02 Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5-HT3) receptors. Radioligand binding studies have demonstrated that Granisetron has negligible affinity for other receptor types including 5-HT and dopamine D2 binding sites. Granisetron is effective intravenously, either prophylactically or by intervention, in abolishing the retching and vomiting evoked by administration of cytotoxic drugs or by whole body X-irradiation. Granisetron is effective, intravenously, in the prevention and treatment of post-operative nausea and vomiting.

5.2 Pharmacokinetic properties

General characteristics Distribution Granisetron is extensively distributed, with a mean volume of distribution of approximately 3 L/kg; plasma protein binding is approximately 65%. Biotransformation Biotransformation pathways involve N-demethylation and aromatic ring oxidation followed by conjugation.


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Elimination Clearance is predominantly by hepatic metabolism. Urinary excretion of unchanged Granisetron averages 12% of dose whilst that of metabolites amounts to about 47% of dose. The remainder is excreted in faeces as metabolites. Mean plasma half-life in patients is approximately nine hours, with a wide inter-subject variability. Characteristics in patients The plasma concentration of Granisetron is not clearly correlated with anti-emetic efficacy. Clinical benefit may be conferred even when Granisetron is not detectable in plasma. In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects. In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects. In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Despite these changes, no dosage adjustment is necessary.

5.3 Preclinical safety data

Preclinical data revealed no special hazard for humans based on conventional studies repeated dose toxicity, carcinogenicity, reproductive toxicity and genotoxicity. A study in cloned human cardiac ion channels has shown that granisetron has the potential to affect cardiac repolarisation via blockade of HERG potassium channels. Granisetron has been shown to block both sodium and potassium channels, which potentially affects both depolarization and repolarisation through prolongation of PR, QRS, and QT intervals. This data helps to clarify the molecular mechanisms by which some of the ECG changes (particularly QT and QRS prolongation) associated with this class of agents occur. However, there is no modification of the cardiac frequency, blood pressure or the ECG trace.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Sodium Chloride Hydrochloric Acid Sodium Hydroxide Water for Injections

6.2 Incompatibilities

As a general precaution, Granisetron should not be mixed in solution with other drugs. Prophylactic administration of Granisetron should be completed prior to the start of cytostatic therapy.

6.3 Shelf life

Granisetron ampoules have a shelf-life of 3 years. Once opened, and after dilution with a recommended diluent, the ampoules have a shelf-life of 24 hours.

6.4 Special precautions for storage

Keep the ampoules in the outer carton in order to protect from light. Do not freeze.

6.5 Nature and contents of container Granisetron is supplied in clear glass ampoules in packs of five, with an outer carton.

6.6 Special precautions for disposal

Adults: To prepare a dose of 3mg, 3ml is withdrawn from the ampoule and diluted either to 15ml with 0.9% w/v Sodium Chloride Injection BP (for bolus administration) or in infusion fluid to a total volume of 20 to 50ml in any of the following solutions: 0.9% w/v Sodium Chloride Injection BP; 0.18% w/v Sodium Chloride and 4% w/v Glucose Injection BP; 5%


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w/v Glucose Injection BP; Hartmann's Solution for Injection BP; Sodium Lactate Injection BP; or 10% Mannitol Injection BP (for infusion). No other diluents should be used. Children: To prepare the dose of 40μg/kg the appropriate volume (up to 3ml) is withdrawn from the ampoule and diluted with infusion fluid (as for adults) to a total volume of 10 to 30ml. Ideally, intravenous infusions of Granisetron should be prepared at the time of administration. After dilution (see above), or when the container is opened for the first time, the shelf-life is 24 hours when stored at ambient temperature in normal indoor illumination protected from direct sunlight. It must not be used after 24 hours. If to be stored after preparation, Granisetron infusions must be prepared under appropriate aseptic conditions. As a general precaution, Granisetron should not be mixed in solution with other drugs.

7 MARKETING AUTHORISATION HOLDER

Caduceus Pharma Limited 6th Floor, 94 Wigmore Street, London W1U 3RF UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 24668/0036 PL 24668/0039

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 27/04/2009 10 DATE OF REVISION OF THE TEXT

27/04/2009


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UKPAR Granisetron 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection PL 24668/0035-6, 0038-9

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UKPAR Granisetron 1mg/1ml and 3mg/3ml Concentrate for Solution for Infusion or Injection PL 24668/0035-6, 0038-9

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granisetron 1mg 1ml and 3mg 3ml conc for sol for inf or ... · granisetron 3mg/3ml concentrate for...

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