SANCUSO 3.1mg / 24h transdermal patch medication leaflet

SANCUSO 3.1 mg/24 hours transdermal patch

Each 52 cm2 transdermal patch contains 34.3 mg of granisetron releasing 3.1 mg of granisetron per24 hours.

For the full list of excipients, see section 6.1.

Transdermal patch.

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

SANCUSO transdermal patch is indicated in adults for the prevention of nausea and vomitingassociated with moderately or highly emetogenic chemotherapy, for a planned duration of3 to 5 consecutive days, where oral anti-emetic administration is complicated by factors makingswallowing difficult (see section 5.1).

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 transdermalpatch, a slower onset of efficacy compared to 2 mg oral granisetron may be observed at the start ofchemotherapy; 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 chemotherapyregimen.

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

Use of concomitant corticosteroids

The Multinational Association of Supportive Care in Cancer (MASCC) guidelines recommend theadministration of dexamethasone with 5HT3 antagonist prior to chemotherapy. In the pivotal

SANCUSO study, the concomitant use of corticosteroids, e.g. dexamethasone, was permitted providedit was part of the chemotherapy regimen. Any increase in corticosteroid use during the study wasreported as rescue treatment.

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

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

The safety and efficacy of SANCUSO in children aged 0 to 18 years have not yet been established. Nodata are available.

The transdermal patch should be applied to clean, dry, intact healthy skin on the outer part of the upperarm. 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 beenopened. 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 transdermalpatch should be reattached in the same position using medical tape (if necessary). If reattachment is notpossible or the transdermal patch is damaged, a new transdermal patch should be applied in the sameposition as the original transdermal patch. If this is not possible, a new transdermal patch should beapplied on the opposite arm. The newly applied transdermal patch should be removed in line with thetiming recommended above.

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

Application site reactions

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

Granisetron may mask a progressive ileus and/or gastric distension caused by an underlying condition.

Patients with signs of sub-acute intestinal obstruction should be monitored following itsadministration, as granisetron may reduce lower bowel motility.

Cardiac disorders5-HT3 receptor antagonists, such as granisetron, may be associated with arrhythmias or ECGabnormalities. This may potentially have clinical significance in patients with pre-existing arrhythmiasor cardiac conduction disorders and/or treated with antiarrhythmics or beta blockers. No clinicallyrelevant 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 furtherinformation. Patients must cover the transdermal patch application site, e.g. with clothing, if there is arisk 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 asswimming, 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 thetransdermal patch.

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 patientswith renal or hepatic impairment receiving granisetron orally and intravenously, based on granisetronpharmacokinetics, 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, butmostly in combination with other serotonergic medicinal products (including selective serotoninreuptake inhibitors (SSRIs), and serotonin noradrenaline reuptake inhibitors (SNRIs). There have alsobeen reports of possible drug-drug interactions between buprenorphine/Opioids and serotonergicmedicinal products leading to serotonin syndrome. Appropriate observation of patients for serotoninsyndrome-like symptoms is advised.

Skin Reactions

In clinical studies with granisetron transdermal patch, application site reactions generally mild inintensity were reported and did not lead to discontinuation of use. If severe reactions, or a generalisedskin reaction occur (e.g. allergic rash, including erythematous, macular, papular rash or pruritus), thetransdermal patch must be removed.

Potential for drug abuse and dependence

Granisetron has no known potential for abuse and dependence.

For serotonergic medicinal products (e.g. SSRIs and SNRIs, buprenorphine, opiods or otherserotonergic medicinal products), there have been reports of serotonin syndrome followingconcomitant 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 subjectshas 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 plasmaclearance (approximately 25%) following intravenous administration of granisetron.

In vitro studies have shown that ketoconazole may inhibit the metabolism of granisetron via thecytochrome P450 3A isoenzyme family. The clinical significance of this is unknown.

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

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

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

Interaction studies have only been performed in adults.

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

SANCUSO during pregnancy.

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

There are no data on the effect of granisetron on human fertility.

The effect of SANCUSO on the ability to drive or operate machinery has not been studied.

The safety profile of SANCUSO is derived from controlled clinical trials and from post-marketingexperience. 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 moderatein severity.

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

Within the system organ class, the adverse reactions are listed by frequency using the followingconvention: 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 availabledata).

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 Decreased appetite Uncommondisorders

Nervous system disorders Headache Uncommon

Dystonia Rare

Dyskinesia Rare

Serotonin syndrome Unknown

Ear and labyrinth disorders Vertigo Uncommon

Vascular disorders Flushing Uncommon

Gastrointestinal disorders Constipation Common

Dry mouth, nausea, retching Uncommon

Hepatobiliary disorders Alanine aminotransferase Uncommonincreased, aspartateaminotransferase increased,gamma-glutamyltransferaseincreased

Musculoskeletal and connective Arthralgia Uncommontissue disorders

General disorders and Generalised oedema Uncommonadministration site conditions Application site irritation* Uncommon

Application site reactions** Unknown

* Application site irritation includes: Application site pruritus and Skin irritation (Spontaneous reports)

**Application site reactions includes: Application site erythema, Application site rash, Application site pain,

Application site hypersensitivity, Application site vesicles, Application site burn, Application site urticaria and

Application site discolouration.

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

Serotonin Syndrome

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone, butmostly in combination with other serotonergic medicinal products (including Selective Serotonin

Reuptake Inhibitors (SSRIs) and Serotonin Noradrenaline (norepinephrine) Reuptake Inhibitors(SNRIs)). There have also been reports of possible drug-drug interactions betweenbuprenorphine/Opioids and serotonergic medicinal products leading to serotonin syndrome (seesection 4.5). Appropriate observation of patients for serotonin syndrome-like symptoms is advised.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5HT3receptors). Pharmacological studies have demonstrated that granisetron is effective against nausea andvomiting as a result of cytostatic therapy. Radioligand binding studies have demonstrated thatgranisetron 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 theefficacy, tolerability and safety of SANCUSO with that of 2 mg oral granisetron once daily in theprevention of nausea and vomiting in a total of 641 patients receiving multi-day chemotherapy. Thestudy 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 yearsreceiving moderately emetogenic (ME) or highly emetogenic (HE) multi-day chemotherapy. 78% ofpatients 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 thechemotherapy regimen, one hour prior to each dose of chemotherapy. Anti-emetic activity wasassessed from the first administration until 24 hours after the start of the last day’s administration ofthe 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 granisetronin the per protocol set (difference -4.89%; 95% confidence interval -12.91% to +3.13%; n=284transdermal patch, n=298 oral). CC was defined as no vomiting and/or retching, no more than mildnausea and no rescue medicine from the first administration until 24 hours after the start of the lastday’s administration of multi-day chemotherapy.

Due to the gradual increase in plasma levels of granisetron following application of the transdermalpatch, initial plasma levels at the start of chemotherapy may be lower than 2 mg oral granisetron and aslower onset of efficacy may therefore be observed. Consequently, SANCUSO is indicated for use inpatients 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 bloodpressure. Assessment of serial ECGs in patients showed no QT prolongation and no change in ECGmorphology. 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 wasobserved for SANCUSO.

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

There is no clinical trial experience with SANCUSO and patients on chemotherapy for less than3 consecutive days, or over multiple cycles of chemotherapy, or with -high dose chemotherapy priorto -stem cell transplantation.

Granisetron crosses intact skin into the systemic circulation by a passive diffusion process. Following

SANCUSO application, granisetron is absorbed slowly, with maximal concentrations reached between24 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 atthe same time a SANCUSO transdermal patch was applied was investigated in healthy subjects. Aninitial peak in plasma concentrations of granisetron, attributable to the intravenous dose, was reached at10 minutes post-administration. The known pharmacokinetic profile of the transdermal patch over theperiod of wear (7 days) was not affected.

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

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 overthe transdermal patch for 4 hours each day over the 5 day period of wear. While application of the heatpad was associated with a minor and transient increase in the transdermal patch flux during the periodof heat pad application, no overall increase in granisetron exposure was observed when compared to acontrol group.

In a pharmacokinetic study in healthy volunteers, where SANCUSO was applied for a period of7 days, mean total exposure (AUC0-infinity) was 416 ng h/ml (range 55 - 1192 ng h/ml), with a betweensubject variability of 89%. Mean Cmax was 3.9 ng/ml (range 0.7 - 9.5 ng/ml), with a between subjectvariability of 77%. This variability is similar to the known high variability in granisetronpharmacokinetics after oral or intravenous administration.

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

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

Granisetron is mainly metabolised to 7-hydroxygranisetron and 9’N-desmethylgranisetron. In vitrostudies using human liver microsomes indicate that CYP1A1 is the major enzyme responsible for the7-hydroxylation of granisetron, whereas CYP3A4 contributes to 9’desmethylation.

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

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

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

The effects of gender on the pharmacokinetics of SANCUSO have not been specifically studied. Noconsistent gender effects on pharmacokinetics were observed in clinical studies with SANCUSO, witha large inter-individual variability reported in both sexes. Population PK modelling has confirmed theabsence of a gender effect on the pharmacokinetics of SANCUSO.

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

No clinical studies have been performed specifically to investigate the pharmacokinetics of SANCUSOin patients with renal or hepatic impairment. No clear relationship between renal function (as measuredby creatinine clearance) and granisetron clearance was identified in population PK modelling. Inpatients with renal failure or hepatic impairment, the pharmacokinetics of granisetron were determinedfollowing a single 40 µg/kg intravenous dose of granisetron hydrochloride.

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

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 differinglevels of body fat, using BMI as a surrogate measure for body fat, no differences were seen in theplasma 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 controlgroup (BMI 20.0 to 24.9 kg/m2inclusive).

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

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

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

These studies did not reveal any evidence of impaired fertility or harm to the foetus due to granisetron.

Fertility was unaffected following granisetron treatment in rats.

SANCUSO transdermal patches did not show any potential for photoirritation or photosensitivity whentested in vivo in guinea-pigs. Granisetron was not phototoxic when tested in vitro in a mouse fibroblastcell line. When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cellline, granisetron increased the percentage of cells with chromosome damage followingphotoirradiation. Although, the clinical relevance of this finding is not completely clear, patientsshould be advised to cover the transdermal patch application site if there is a risk of exposure tosunlight 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 forirritancy.

A study in cloned human cardiac ion channels has shown that granisetron has the potential to affectcardiac repolarisation via blockade of hERG potassium channels. Granisetron has been shown to blockboth sodium and potassium channels, which could affect cardiac depolarisation and repolarisation andtherefore 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 canoccur. 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).

Backing layer

Polyester

Matrix layer

Acrylate-vinylacetate copolymer

Release liner

Siliconised polyester

Not applicable.

3 years

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

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

Each carton contains 1 transdermal patch.

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

Grünenthal GmbH

Zieglerstraße 652078 Aachen

Germany

EU/1/12/766/001

Date of first authorisation: 20 April 2012

Date of latest renewal: 9 January 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu