Sancuso - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

SANCUSO 3.1 mg/24 hours transdermal patch

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 52 cm2 transdermal patch contains 34.3 mg of granisetron releasing 3.1 mg of granisetron per 24 hours.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Transdermal patch.

Thin, translucent, matrix-type, rectangular-shaped transdermal patch with rounded corners.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

SANCUSO transdermal patch is indicated in adults for the prevention of nausea and vomiting associated with moderately or highly emetogenic chemotherapy, for a planned duration of 3 to 5 consecutive days, where oral anti-emetic administration is complicated by factors making swallowing difficult (see section 5.1).

4.2 Posology and method of administration

Posology

Adults

Apply a single transdermal patch 24 to 48 hours before chemotherapy, as appropriate.

Due to a gradual increase in plasma levels of granisetron following application of the transdermal patch, a slower onset of efficacy compared to 2 mg oral granisetron may be observed at the start of chemotherapy; the patch should be applied 24–48 hours before chemotherapy.

The transdermal patch should be removed a minimum of 24 hours after completion of chemotherapy. The transdermal patch can be worn for up to 7 days depending on the duration of the chemotherapy regimen.

Following routine haematological monitoring, the transdermal patch should only be applied to patients whose chemotherapy treatment is unlikely to be delayed in order to reduce the possibility of unnecessary exposure to granisetron.

Use of concomitant corticosteroids

The Multinational Association of Supportive Care in Cancer (MASCC) guidelines recommend the administration of dexamethasone with 5HT3 antagonist prior to chemotherapy. In the pivotal SANCUSO study, the concomitant use of corticosteroids, e.g. dexamethasone, was permitted provided it was part of the chemotherapy regimen. Any increase in corticosteroid use during the study was reported as rescue treatment.

Special populations

Elderly

Dosing as for adults (see sections 4.4 and 5.2).

Renal or hepatic impairment

No dose adjustment is necessary. Dosing as for adults (see sections 4.4 and 5.2). Although no evidence of an increased incidence of adverse reactions have been observed in patients with renal or hepatic impairment receiving granisetron orally and intravenously, based on granisetron pharmacokinetics, a degree of caution must be exercised in this population.

Paediatric population

The safety and efficacy of SANCUSO in children aged 0 to 18 years have not yet been established. No data are available.

Method of administration

The transdermal patch should be applied to clean, dry, intact healthy skin on the outer part of the upper arm. If it is not possible to apply the transdermal patch to the arm, it can be applied to the abdomen.

The transdermal patch should not be placed on skin that is red, irritated or damaged.

Each transdermal patch is packed in a sachet and should be applied directly after the sachet has been opened. The release liner is removed prior to application.

The transdermal patch should not be cut into pieces.

In the event of a transdermal patch becoming completely or partially detached, the original transdermal patch should be reattached in the same position using medical tape (if necessary). If reattachment is not possible or the transdermal patch is damaged, a new transdermal patch should be applied in the same position as the original transdermal patch. If this is not possible, a new transdermal patch should be applied on the opposite arm. The newly applied transdermal patch should be removed in line with the timing recommended above.

4.3 Contraindications

Hypersensitivity to the active substance, to other 5-HT3 receptor antagonists or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Application site reactions

In clinical trials with SANCUSO, application site reactions were reported which were generally mild in intensity and did not lead to discontinuation of use. If severe reactions, or a generalised skin reaction occur (e.g. allergic rash, including erythematous, macular, papular rash or pruritus), the transdermal patch must be removed.

Gastrointestinal disorders

As granisetron may reduce lower bowel motility, patients with signs of sub-acute intestinal obstruction should be monitored following its administration.

Cardiac disorders

5-HT3 receptor 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 antiarrhythmics or beta-blockers. No clinically relevant effects have been observed in clinical studies with SANCUSO.

Exposure to sunlight

Granisetron may be affected by direct natural or artificial sunlight, see section 5.3 for further information. Patients must be advised to cover the transdermal patch application site, e.g. with clothing, if there is a risk of exposure to sunlight throughout the period of wear and for 10 days following its removal.

Showering or washing

Showering or washing normally can be continued while wearing SANCUSO. Activities such as swimming, strenuous exercise or using a sauna should be avoided.

External heat

External heat (for example hot water bottles or heat pads) should be avoided on the area of the transdermal patch.

Special populations

No dose adjustments are necessary for the elderly or patients with renal or hepatic impairment. Although no evidence of an increased incidence of adverse reactions have been observed in patients with renal or hepatic impairment receiving granisetron orally and intravenously, based on granisetron pharmacokinetics, a degree of caution must be exercised in this population.

Serotonin syndrome

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone, but mostly in combination with other serotonergic medicinal products (including selective serotonin reuptake inhibitors (SSRIs), and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.

4.5 Interaction with other medicinal products and other forms of interaction

For serotonergic medicinal products (e.g. SSRIs and SNRIs), there have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and other serotonergic medicinal products (including SSRIs and SNRIs).

Co-administration of intravenous 5-HT3 receptor antagonists with oral paracetamol in human subjects has been reported to result in a block in the analgesic effect via a pharmacodynamic mechanism.

As granisetron is metabolised by hepatic cytochrome P450 active substance-metabolising enzymes (CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the 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 (approximately 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.

In vitro studies using human microsomes indicate that granisetron neither stimulates nor inhibits the cytochrome P450 enzyme system.

In studies in healthy subjects, no evidence of any interaction has been indicated between granisetron and benzodiazepines (lorazepam), neuroleptics (haloperidol) or anti-ulcer medicinal products (cimetidine).

No clinically relevant interactions between SANCUSO and emetogenic cancer chemotherapies have been seen. Furthermore, no interaction has been observed between granisetron and emetogenic cancer therapies. In agreement with these data, no clinically relevant interactions have been reported in clinical studies with SANCUSO. In clinical interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of granisetron.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited amount of data (less than 300 pregnancy outcomes) from the use of granisetron in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of SANCUSO during pregnancy.

Breast-feeding

It is unknown whether granisetron or its metabolites are excreted in human milk. Breast-feeding should be discontinued during treatment with SANCUSO.

Fertility

There are no data on the effect of granisetron on human fertility. Fertility was unaffected following granisetron treatment in rats.

4.7 Effects on ability to drive and use machines

SANCUSO has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

The safety profile of SANCUSO is derived from controlled clinical trials and from post-marketing experience. The most commonly reported adverse reaction in clinical studies was constipation, occurring in approximately 8.7% of patients. The majority of adverse reactions were mild or moderate in severity.

Tabulated list of adverse reactions

Adverse reactions from clinical studies and spontaneous reports with SANCUSO are listed in the table below.

Within the system organ class, the adverse reactions are listed by frequency using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Adverse reactions are presented in order of decreasing seriousness within each frequency grouping.

Table 1: ______ Adverse reactions reported for SANCUSO

System Organ Class	Adverse reaction	Frequency
Immune system disorder	Hypersensitivity reactions	Not known
Metabolism and nutrition disorders	Decreased appetite	Uncommon
Nervous system disorders	Headache Dystonia	Uncommon Rare
	Dyskinesia	Rare
Ear and labyrinth disorders	Vertigo	Uncommon
Vascular disorders	Flushing	Uncommon
Gastrointestinal disorders	Constipation	Common
	Dry mouth, nausea, retching	Uncommon

Hepatobiliary disorders	Alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased	Uncommon
Skin and subcutaneous tissue disorders	Application site irritation Application site reactions (application site pain, application site pruritus, application site erythema, application site rash, application site irritation) *	Uncommon Not known
Musculoskeletal and connective tissue disorders	Arthralgia	Uncommon
General disorders and administration site conditions	Generalised oedema	Uncommon

*Spontaneous reports

Description of selected adverse reactions

Patients who are being treated with moderately or highly emetogenic chemotherapy may still experience vomiting despite treatment with antiemetic therapy, including SANCUSO.

Class effects

Class effects for granisetron seen with other formulations (oral and intravenous) include the following:

• – Hypersensitivity reactions, e.g. anaphylaxis, urticaria

• – Insomnia

• – Headache

• – Extrapyramidal reactions

• – Somnolence

• – Dizziness

• – QT prolongation

• – Constipation

• – Diarrhoea

• – Elevated hepatic transaminases

• – Rash

• – Asthenia

4.9 Overdose

There is no specific antidote for granisetron. In the event of overdose, the transdermal patch should be removed. Symptomatic treatment should be given.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5HT3) antagonists, ATC code: A04AA02.

Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5HT3 receptors). Pharmacological studies have demonstrated that granisetron is effective against nausea and vomiting as a result of cytostatic therapy. Radioligand binding studies have demonstrated that granisetron has negligible affinity for other receptor types, including 5HT1, 5HT2, 5HT4 and dopamine D2 binding sites.

A pivotal, randomised, double-blind, double-dummy, multinational Phase III study compared the efficacy, tolerability and safety of SANCUSO with that of 2 mg oral granisetron once daily in the prevention of nausea and vomiting in a total of 641 patients receiving multi-day chemotherapy. The study was designed to show non-inferiority of SANCUSO to oral granisetron.

The population randomised into the trial included 48% males and 52% females aged 16 to 86 years receiving moderately emetogenic (ME) or highly emetogenic (HE) multi-day chemotherapy. 78% of patients were white, with 12% Asian and 10% Hispanic/Latino.

The granisetron transdermal patch was applied 24 to 48 hours prior to the first dose of chemotherapy, and kept in place for 7 days. Oral granisetron was administered daily for the duration of the chemotherapy regimen, one hour prior to each dose of chemotherapy. Anti-emetic activity was assessed from the first administration until 24 hours after the start of the last day’s adminis­tration of the ME or HE chemotherapy regimen.

Non-inferiority of SANCUSO versus oral granisetron was confirmed, with complete control (CC) achieved in 60.2% of patients in the SANCUSO arm and 64.8% of patients receiving oral granisetron in the per protocol set (difference –4.89%; 95% confidence interval –12.91% to +3.13%; n=284 transdermal patch, n=298 oral). CC was defined as no vomiting and/or retching, no more than mild nausea and no rescue medicine from the first administration until 24 hours after the start of the last day’s adminis­tration of multi-day chemotherapy.

Due to the gradual increase in plasma levels of granisetron following application of the transdermal patch, initial plasma levels at the start of chemotherapy may be lower than 2 mg oral granisetron and a slower onset of efficacy may therefore be observed. Consequently, SANCUSO is indicated for use in patients where oral anti-emetic administration is complicated by factors making swallowing difficult.

Complete control by day is illustrated below.

In clinical trials with SANCUSO, there were no treatment-related effects on heart rate or blood pressure. Assessment of serial ECGs in patients showed no QT prolongation and no change in ECG morphology. The effect of SANCUSO on QTc interval was specifically evaluated in a blinded, randomised, parallel, placebo and positive (moxifloxacin) controlled thorough QTc trial with SANCUSO in 240 adult male and female subjects. No significant effect on QTc prolongation was observed for SANCUSO.

An assessment of transdermal patch adhesion in 621 patients receiving either active or placebo transdermal patches showed that less than 1% of transdermal patches became detached over the course of the 7 day period of transdermal patch application.

There is no clinical trial experience with SANCUSO and patients on chemotherapy for less than 3 consecutive days, or over multiple cycles of chemotherapy, or with high-dose chemotherapy prior to stem-cell transplantation.

5.2 Pharmacokinetic properties

Absorption

Granisetron crosses intact skin into the systemic circulation by a passive diffusion process. Following SANCUSO application, granisetron is absorbed slowly, with maximal concentrations reached between 24 and 48 hours.

Based on the measure of residual content of the transdermal patch after removal, approximately 65% of granisetron is delivered resulting in an average daily dose of 3.1 mg per day.

Concurrent administration of a single intravenous bolus of 0.01 mg/kg (maximum 1 mg) granisetron at the same time a SANCUSO transdermal patch was applied was investigated in healthy subjects. An initial peak in plasma concentrations of granisetron, attributable to the intravenous dose, was reached at 10 minutes post-administration. The known pharmacokinetic profile of the transdermal patch over the period of wear (7 days) was not affected.

Following consecutive application of two SANCUSO transdermal patches in healthy subjects, each for seven days, granisetron levels were maintained over the study period with evidence of minimal accumulation.

In a study designed to assess the effect of heat on the transdermal delivery of granisetron from SANCUSO in healthy subjects, a heat pad generating an average temperature of 42°C was applied over the transdermal patch for 4 hours each day over the 5 day period of wear. While application of the heat pad was associated with a minor and transient increase in the transdermal patch flux during the period of heat pad application, no overall increase in granisetron exposure was observed when compared to a control group.

In a pharmacokinetic study in healthy volunteers, where SANCUSO was applied for a period of 7 days, mean total exposure (AUC0-mfmity) was 416 ng h/ml (range 55 – 1192 ng h/ml), with a between subject variability of 89%. Mean Cmax was 3.9 ng/ml (range 0.7 – 9.5 ng/ml), with a between subject variability of 77%. This variability is similar to the known high variability in granisetron pharmacokinetics after oral or intravenous administration.

Distribution

Granisetron is distributed with a mean volume of distribution of approximately 3 l/kg. Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.

Biotransformation

No differences in the metabolic profiles of granisetron were observed between the oral and transdermal uses.

Granisetron is mainly metabolised to 7-hydroxygranisetron and 9’N-desmethylgrani­setron. In vitro studies using human liver microsomes indicate that CYP1A1 is the major enzyme responsible for the 7-hydroxylation of granisetron, whereas CYP3A4 contributes to 9’desmethylation.

Elimination

Granisetron is cleared primarily by hepatic metabolism. After intravenous dosing, the mean plasma clearance ranged from 33.4 to 75.7 l/h in healthy subjects and from 14.7 to 33.6 l/h in patients with wide inter-subject variability. The mean plasma half-life in healthy subjects is 4–6 hours and in patients is 9–12 hours. After transdermal patch application, the apparent granisetron plasma half-life in healthy subjects was prolonged to approximately 36 hours due to the slow absorption rate of granisetron through the skin.

In clinical studies conducted with SANCUSO, clearance in cancer patients was shown to be approximately half that of healthy subjects.

After intravenous injection, approximately 12% of the dose is excreted unchanged in the urine of healthy subjects in 48 hours. The remainder of the dose is excreted as metabolites, with 49% in the urine and 34% in the faeces.

Pharmacokinetics in special populations

The effects of gender on the pharmacokinetics of SANCUSO have not been specifically studied. No consistent gender effects on pharmacokinetics were observed in clinical studies with SANCUSO, with a large inter-individual variability reported in both sexes. Population PK modelling has confirmed the absence of a gender effect on the pharmacokinetics of SANCUSO.

Elderly

In a clinical study no differences were seen in the plasma pharmacokinetics of SANCUSO in male and female elderly subjects (> 65 years) compared with younger subjects (aged 18–45 years inclusive).

Renal or hepatic impairment

No clinical studies have been performed specifically to investigate the pharmacokinetics of SANCUSO in patients with renal or hepatic impairment. No clear relationship between renal function (as measured by creatinine clearance) and granisetron clearance was identified in population PK modelling. In patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron were determined following a single 40 Mg/kg intravenous dose of granisetron hydrochloride.

Hepatic impairment

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of granisetron and the good tolerance well above the recommended dose, dose adjustment in patients with functional hepatic impairment is not necessary.

Renal impairment

No correlation between creatinine clearance and total clearance was observed in cancer patients, indicating no influence of renal impairment on the pharmacokinetics of granisetron.

Body Mass Index (BMI)

In a clinical study designed to assess granisetron exposure from SANCUSO in subjects with differing levels of body fat, using BMI as a surrogate measure for body fat, no differences were seen in the plasma pharmacokinetics of SANCUSO in male and female subjects with a low BMI [<19.5 kg/m2 (males), <18.5 kg/m2 (females)] and a high BMI (30.0 to 39.9 kg/m2 inclusive) compared to a control group (BMI 20.0 to 24.9 kg/m2inclu­sive).

Paediatric population

There are limited data available in patients <18 years of age. No studies have been performed to investigate the pharmacokinetics of SANCUSO in paediatric patients <13 years of age.

5.3 Preclinical safety data

Preclinical data did not reveal any special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproductive toxicity and genotoxicity. Carcinogenicity studies showed no special hazard for humans when used at the recommended dose. However, when administered in higher doses and over a prolonged period of time, the risk of carcinogenicity cannot be ruled out but with the short application period recommended for the transdermal delivery system, a carcinogenic risk for humans is not expected.

SANCUSO transdermal patches did not show any potential for photoirritation or photosensitivity when tested in vivo in guinea-pigs. Granisetron was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cell line, granisetron increased the percentage of cells with chromosome damage following photoirradiation. Although, the clinical relevance of this finding is not completely clear, patients should be advised to cover the transdermal patch application site if there is a risk of exposure to sunlight throughout the period of wear and for 10 days following its removal (see section 4.4).

When tested for skin sensitising potential in guinea pigs, SANCUSO showed a low potential for irritancy.

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 could affect cardiac depolarisation and repolarisation and therefore PR, QRS, and QT intervals. These data help to clarify the mechanisms by which some of the ECG changes (particularly QT and QRS prolongation) associated with this class of substance can occur. However, no clinically relevant effects on ECG have been observed in clinical studies with SANCUSO, including a through QT study in 240 healthy subjects (section 5.1).

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Backing layer

Polyester

Matrix layer

Acrylate-vinylacetate copolymer

Release liner

Siliconised polyester

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from light.

6.5 Nature and contents of container

Each transdermal patch is packaged in a heat-sealed sachet composed of polyester-coated paper/alumini­um/LLDPE.

Each carton contains 1 transdermal patch.

6.6 Special precautions for disposal

The transdermal patch will still contain active substance following use. After removal, the used transdermal patch should be folded firmly in half, adhesive side inwards and then discarded out of the reach of children.

7. MARKETING AUTHORISATION HOLDER

Kyowa Kirin Holdings B.V.

Bloemlaan 2

2132NP Hoofddorp

The Netherlands

Tel: +31 (0) 237200822

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/12/766/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 20 April 2012

Date of latest renewal: 9 January 2017