SANCUSO- granisetron patch

United States - English - NLM (National Library of Medicine)

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Active ingredient:
granisetron (UNII: WZG3J2MCOL) (granisetron - UNII:WZG3J2MCOL)
Available from:
Kyowa Kirin, Inc.
INN (International Name):
GRANISETRON
Composition:
GRANISETRON 3.1 mg in 24 h
Administration route:
TRANSDERMAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Sancuso® is indicated for the prevention of nausea and vomiting in adults receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration. Sancuso is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the transdermal system [see Description (10)] . Risk Summary Available published data and postmarketing reports with granisetron use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a published ex vivo human placental perfusion model, no transplacental passage of granisetron was detected at a concentration (5 ng/mL) that mimics the plasma concentration achieved following transdermal application of Sancuso. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits administered granisetron hydrochloride during organogenesis at intravenous doses up to 24 times and 16 times, respective
Product summary:
Sancuso (granisetron transdermal system) is a 52 cm2 thin, translucent, rectangular-shaped transdermal system with rounded corners imprinted on one side with "Granisetron 3.1 mg/24 hours". The transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days. Each Sancuso transdermal system is packaged in a separate sealed foil-lined plastic pouch supplied in packages of 1 (NDC 42747-726-01) transdermal system. Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [see USP Controlled Room Temperature]. Sancuso should be stored in the original packaging.
Authorization status:
New Drug Application
Authorization number:
42747-726-01

SANCUSO- granisetron patch

Kyowa Kirin, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use SANCUSO safely and effectively. See full

prescribing information for SANCUSO.

SANCUSO (granisetron transdermal system)

Initial U.S. Approval: 2008

INDICATIONS AND USAGE

Sancuso is a serotonin-3 (5-HT ) receptor antagonist indicated for the prevention of nausea and vomiting in adults

receiving moderately and/or highly emetogenic chemotherapy for up to 5 consecutive days. (1)

DOSAGE AND ADMINISTRATION

The recommended dosage is a single transdermal system applied to the upper outer arm a minimum of 24 hours, up to a

maximum of 48 hours, before chemotherapy. The transdermal system should be worn at minimum, 24 hours after

chemotherapy is finished. The transdermal system can be worn for up to 7 days. (2)

DOSAGE FORMS AND STRENGTHS

Transdermal System: 3.1 mg per 24 hours. (3)

CONTRAINDICATIONS

Known hypersensitivity to granisetron or to any of the components of the transdermal system (4)

WARNINGS AND PRECAUTIONS

Granisetron may mask a progressive ileus and/or gastric distention; consider before use in patients with abdominal

surgery. Monitor for decreased bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

(5.1)

Serotonin syndrome has been reported with 5-HT receptor antagonists alone but particularly with concomitant use of

serotonergic drugs. If such symptoms occur, discontinue Sancuso and initiate supportive treatment. If concomitant use

of Sancuso with other serotonergic drugs is clinically warranted, patients should be aware of a potential increased risk of

serotonin syndrome. (5.2, 7.1)

Mild application site reactions have occurred; remove Sancuso transdermal system if severe reactions or a generalized

skin reaction occur. (5.3)

Avoid exposing Sancuso transdermal system and surrounding area to direct external heat sources, such as heating

pads (5.4).

Avoid direct exposure of application site to natural or artificial sunlight, including sunlamps, by covering with clothing

throughout the period of wear and for 10 days after removal. (5.5)

ADVERSE REACTIONS

The most common adverse reaction (≥ 3%) is constipation. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Kyowa Kirin, Inc. at 1-800-SANCUSO (1-800-726-

2876) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 4/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Progressive Ileus and Gastric Distention

5.2 Serotonin Syndrome

5.3 Skin Reactions

5.4 Increased Drug Exposure with Use of External Heat Sources

5.5 Phototoxicity with Ultraviolet Light Exposure

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

7.2 Concomitant Use Medications

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment or Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.3 Phototoxicity

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Sancuso

is indicated for the prevention of nausea and vomiting in adults receiving moderately and/or

highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.

2 DOSAGE AND ADMINISTRATION

The recommended dosage is a single transdermal system applied to the upper outer arm a minimum of

24 hours, up to a maximum of 48 hours, before chemotherapy. The transdermal system should be worn

at minimum, 24 hours after chemotherapy is finished. The transdermal system can be worn for up to 7

days.

Application and Removal Instructions

Each transdermal system releases 3.1 mg of granisetron per 24 hours for up to 7 days.

Each transdermal system is packed in a pouch and should be applied directly after the pouch has

been opened.

Only wear one transdermal system at any time.

Do not cut the transdermal system.

Open the pouch and apply the transdermal system to clean, dry, nearly hairless, intact healthy skin on

the upper outer arm.

Sections or subsections omitted from the full prescribing information are not listed.

Do not place Sancuso transdermal system on skin that is red, irritated, or damaged.

Do not apply a heat pad or heat lamp over or in vicinity of the transdermal system and avoid extended

exposure to heat [see Warnings and Precautions (5.4)].

Cover the application site of the transdermal system with clothing, if there is a risk of exposure to

direct natural or artificial sunlight throughout the period of wear and for 10 days following its

removal [see Warnings and Precautions (5.5)].

After the transdermal system is applied, wash hands thoroughly.

Remove the transdermal system by peeling off gently from the skin.

Upon removal, fold the transdermal system in half with the sticky side together, and discard in the

household trash in a manner that prevents accidental contact or ingestion by children, pets or others.

Sancuso contains granisetron. Do not use other granisetron-containing products with Sancuso.

3 DOSAGE FORMS AND STRENGTHS

Transdermal System: a 52 cm thin, translucent, rectangular-shaped transdermal system with rounded

corners imprinted on one side with "Granisetron 3.1 mg/24 hours". The transdermal system releases 3.1

mg of granisetron per 24 hours for up to 7 days.

4 CONTRAINDICATIONS

Sancuso is contraindicated in patients with known hypersensitivity to granisetron or to any of the

components of the transdermal system [see Description (10)].

5 WARNINGS AND PRECAUTIONS

5.1 Progressive Ileus and Gastric Distention

Sancuso may mask a progressive ileus and/or gastric distention. This should be particularly considered

before use of Sancuso in patients who have had recent abdominal surgery. Monitor for decreased

bowel activity, particularly in patients with risk factors for gastrointestinal obstruction.

5.2 Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT receptor antagonists. Most

reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin

reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine

oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). Some of the

reported cases were fatal. Serotonin syndrome occurring with overdose of another 5-HT receptor

antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-

HT receptor antagonist use occurred in a post- anesthesia care unit or an infusion center.

Symptoms associated with serotonin syndrome may include the following combination of signs and

symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic

instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia),

neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures,

with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be

monitored for the emergence of serotonin syndrome, especially with concomitant use of Sancuso and

other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Sancuso and initiate

supportive treatment. Patients should be informed of the increased risk of serotonin syndrome,

especially if Sancuso is used concomitantly with other serotonergic drugs. [see Drug Interactions (7)].

5.3 Skin Reactions

In clinical trials with Sancuso, application site reactions were reported that were generally mild in

intensity and did not lead to discontinuation of use. The incidence of reactions was comparable with

placebo.

If severe reactions, or a generalized skin reaction occur (e.g., allergic rash, including erythematous,

macular, papular rash or pruritus), remove the Sancuso transdermal system.

5.4 Increased Drug Exposure with Use of External Heat Sources

Prolonged exposure to heat results in increasing plasma concentrations of granisetron during the period

of heat exposure [see Clinical Pharmacology (12.3)]. Do not apply a heat pad or heat lamp over or in the

vicinity of the Sancuso transdermal system and avoid extended exposure to heat [see Dosage and

Administration (2)].

5.5 Phototoxicity with Ultraviolet Light Exposure

Granisetron may be affected by direct natural or artificial sunlight, including sunlamps. An in vitro study

using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity [see

Nonclinical Toxicology (13.3)]. To avoid a potential skin reaction, advise patients to cover the application

site of the transdermal system with clothing if there is a risk of exposure to direct natural or artificial

sunlight throughout the period of wear and for 10 days following its removal.

6 ADVERSE REACTIONS

The following are serious or otherwise clinically significant adverse reactions reported in other

sections of labeling:

Progressive ileus and gastric distention [see Warnings and Precautions (5.1)]

Serotonin syndrome [see Warnings and Precautions (5.2)]

Skin reactions [see Warnings and Precautions (5.3)]

Increased drug exposure with use of external heat sources [see Warnings and Precautions (5.4)]

Phototoxicity with ultraviolet light exposure [se Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in clinical practice.

The safety of Sancuso was evaluated in a total of 404 patients undergoing chemotherapy who

participated in two double-blind, comparator studies with transdermal system treatment durations of up

to 7 days. The control groups included a total of 406 patients who received a daily dose of 2 mg oral

granisetron, for 1 to 5 days.

Adverse reactions occurred in 9% (35/404) of patients receiving Sancuso and 7% (29/406) of patients

receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5% of

patients in the Sancuso group and 3% of patients in the oral granisetron group.

Table 1 lists the adverse reactions that occurred in at least 3% of patients treated with Sancuso or oral

granisetron.

Table 1: Incidence of Adverse Reactions in Double-Blind, Active

Comparator Controlled Studies in Cancer Patients Receiving

Chemotherapy (≥ 3% in either group)

Body System

Preferred Term

Sancus o

Trans dermal

Sys tem

N=404

(%)

Oral

granis etron

N=406

(%)

Gastrointestinal disorders

Constipation

Nervous system disorders

Headache

5-HT receptor antagonists, such as granisetron, may be associated with arrhythmias or ECG

abnormalities. Three ECGs were performed on 588 patients in a randomized, parallel group, double-

blind, double-dummy study: at baseline before treatment, the first day of chemotherapy, and 5 to 7 days

after starting chemotherapy. QTcF prolongation greater than 450 milliseconds was seen in a total of 11

(1.9%) patients after receiving granisetron, 8 (2.7%) on oral granisetron, and 3 (1.1%) on the transdermal

system. No new QTcF prolongation greater than 480 milliseconds was observed in any patient in this

study. No arrhythmias were detected in this study.

Adverse reactions reported in clinical trials with other formulations of granisetron include the

following:

Gastrointestinal: abdominal pain, diarrhea, constipation, elevation of ALT and AST levels, nausea and

vomiting

Cardiovascular: hypertension, hypotension, angina pectoris, atrial fibrillation and syncope have been

observed rarely

Central Nervous System: dizziness, insomnia, headache, anxiety, somnolence and asthenia

Hypersensitivity: rare cases of hypersensitivity reactions, sometimes severe (e.g. anaphylaxis, shortness

of breath, hypotension, urticaria) have been reported

Other: fever; events often associated with chemotherapy have also been reported: leucopenia,

decreased appetite, anemia, alopecia, thrombocytopenia.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Sancuso. Because

these reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

General Disorders and Administration Site Conditions: Application site reactions (pain, pruritus,

erythema, rash, irritation, vesicles, burn, discoloration, urticaria) [see Warnings and Precautions (5.3)];

transdermal system non-adhesion.

Cardiac Disorders: bradycardia, chest pain, palpitations, sick sinus syndrome

7 DRUG INTERACTIONS

7.1 Serotonergic Drugs

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms)

has been described following the concomitant use of 5-HT receptor antagonists and other

serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and

noradrenaline reuptake inhibitors (SNRIs). Monitor for the emergence of serotonin syndrome. If

symptoms occur, discontinue Sancuso and initiate supportive treatment [see Warnings and Precautions

(5.4)].

7.2 Concomitant Use Medications

There have been no definitive drug-drug interaction studies to examine pharmacokinetic or

pharmacodynamic interaction with other drugs. However, in humans, granisetron hydrochloride

injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-

ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection

also does not appear to interact with emetogenic cancer therapies. In agreement with these data, no

clinically relevant drug interactions have been reported in clinical studies with Sancuso.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available published data and postmarketing reports with granisetron use in pregnant women have not

identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal

outcomes. In a published ex vivo human placental perfusion model, no transplacental passage of

granisetron was detected at a concentration (5 ng/mL) that mimics the plasma concentration achieved

following transdermal application of Sancuso. In animal reproduction studies, no adverse developmental

effects were observed in pregnant rats and rabbits administered granisetron hydrochloride during

organogenesis at intravenous doses up to 24 times and 16 times, respectively, the maximum

recommended human dose delivered by the Sancuso transdermal system, based on body surface area (see

Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risks of major birth defects and miscarriage in

clinically recognized pregnancies are 2-4% and 15-20%, respectively.

In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and

rabbits administered granisetron hydrochloride at intravenous doses up to 24 times and 16 times,

respectively, the maximum recommended human dose delivered by the Sancuso transdermal system,

based on body surface area (see Data).

Data

Animal Data

Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at

intravenous doses up to 9 mg/kg/day (54 mg/m /day, about 24 times the recommended human dose

delivered by the Sancuso transdermal system, based on body surface area) and oral doses up to 125

mg/kg/day (750 mg/m /day, about 326 times the recommended human dose with Sancuso based on body

surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to

3 mg/kg/day (36 mg/m /day, about 16 times the human dose with Sancuso based on body surface area)

and at oral doses up to 32 mg/kg/day (384 mg/m /day, about 167 times the human dose with Sancuso

based on body surface area). These studies did not reveal any harm to the fetus due to granisetron.

8.2 Lactation

Risk Summary

There are no data on the presence of granisetron in human milk, the effects on the breastfed child, or the

effects on milk production. The developmental and health benefits of breastfeeding should be

considered along with the mother's clinical need for Sancuso and any potential adverse effects on the

breastfed child from Sancuso or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of Sancuso have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of Sancuso did not include sufficient numbers of subjects aged 65 and over to

determine whether they respond differently from younger subjects. Other reported clinical experience

has not identified differences in responses between the elderly and younger patients. In general,

cautious treatment selection for an elderly patient is prudent because of the greater frequency of

decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment or Hepatic Impairment

Although no studies have been performed to investigate the pharmacokinetics of Sancuso in patients

with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron

[see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended for renal or hepatic

impairment.

10 OVERDOSAGE

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic

treatment should be given.

11 DESCRIPTION

Sancuso contains granisetron, which is a serotonin-3 (5-HT ) receptor antagonist. Chemically it is 1-

methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a

molecular weight of 312.4. Its empirical formula is C

H N O, while its chemical structure is:

Granisetron

Granisetron is a white to off-white solid that is insoluble in water. The inactive ingredients are

acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax.

Sancuso is a 52 cm thin, translucent, matrix-type transdermal system that is rectangular- shaped with

rounded corners, consisting of a backing (polyester), the drug matrix (acrylate- vinylacetate copolymer)

and a release liner (siliconized polyester).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Granisetron is a selective 5-hydroxytryptamine (5-HT ) receptor antagonist with little or no affinity for

other serotonin receptors, including 5-HT , 5-HT

, 5-HT

, 5-HT ; for alpha -, alpha -, or beta-

adrenoreceptors; for dopamine-D ; or for histamine-H ; benzodiazepine; picrotoxin or opioid

receptors.

Serotonin receptors of the 5-HT type are located peripherally on vagal nerve terminals and centrally in

the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting,

1B/C

mucosal enterochromaffin cells release serotonin, which stimulates 5-HT receptors. This evokes

vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT

receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli

such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to

high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

12.2 Pharmacodynamics

The effect of granisetron on QTc prolongation was evaluated in a randomized, single-blind, positive

(moxifloxacin 400 mg) - and placebo controlled parallel study in healthy subjects. A total of 120

subjects were administered Sancuso transdermal system (n=60) or intravenous granisetron (10 mcg/kg

over 30 seconds; n=60). In a study with demonstrated ability to detect small effects, the upper bound of

the 90% confidence interval for the largest placebo adjusted, baseline corrected QTc based on

Fridericia correction method (QTcF) for Sancuso was below 10 ms. This study suggests that Sancuso

does not have significant effects on QT prolongation.

No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in studies

using granisetron.

The effect on oro-cecal transit time following application of Sancuso has not been studied. Granisetron

hydrochloride injection exhibited no effect on oro-cecal transit time in healthy subjects given a single

intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses of granisetron

hydrochloride slowed colonic transit in healthy subjects.

12.3 Pharmacokinetics

Absorption

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

Following a 7-day application of Sancuso transdermal system in 24 healthy subjects, high inter- subject

variability in systemic exposure was observed. Maximal concentration was reached at approximately 48

hours (range: 24-168 hours) following application. Mean C

was 5 ng/mL (CV: 170%) and mean

was 527 ng-hr/mL (CV: 173%).

Mean Plasma Concentration of Granisetron (mean ± SD)

Based on the measure of residual content of the transdermal system after removal, approximately 66%

0-168hr

(SD: ± 10.9) of granisetron is delivered following transdermal system application for 7 days.

Following consecutive application of two Sancuso transdermal systems, each for seven days,

granisetron plasma concentrations were maintained over the study period with evidence of minimal

accumulation. The mean plasma concentration at 24 hours after the second transdermal system

application was 1.5-fold higher due to residual granisetron from the first transdermal system. As the

plasma concentration increased after the second transdermal system application, the difference

decreased and the mean plasma concentration at 48 hours was 1.3-fold higher after application of the

second transdermal system compared to that after application of the first transdermal system.

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 (107.6°F) was applied over

the transdermal system for 4 hours each day over the 5 day period of wear. The application of the heat

pad was associated with an increase in plasma granisetron concentrations during the period of heat pad

application. The elevated plasma concentration declined after removal of the heat pad. Mean C

with

intermittent heat exposure was 6% higher than without heat. Mean partial AUCs over 6 hours with 4

hour of heat application (AUC

, AUC

, and AUC

) were 4.9, 1.4, and 1.1 fold higher,

respectively, with heat pad than without heat pad [see Dosage and Administration (2), Warnings and

Precautions (5.4)].

Distribution

Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red

blood cells.

Elimination

Metabolism

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation.

In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by

ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal

studies suggest that some of the metabolites may also have 5-HT receptor antagonist activity.

Excretion

Clearance is predominantly by hepatic metabolism. Based on a study with 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, 49% in the urine, and 34% in the feces.

Use in Specific Populations

Geriatric Patients

Following application of Sancuso transdermal system in healthy subjects, mean AUC

, and C

were 17%, 15%, and 16% higher, respectively in male and female elderly subjects (≥ 65 years)

compared to younger subjects (aged 18-45 years inclusive). These pharmacokinetic parameters were

largely overlapped between the two age groups with high variability (CV: >50%).

Following a single 40 mcg/kg intravenous dose of granisetron hydrochloride in elderly subjects (mean

age 71 years), lower clearance and longer half-life were observed compared to younger healthy

subjects.

Male and Female Patients

There is evidence to suggest that female subjects had higher granisetron concentrations than males

following transdermal system application. However, no statistically significant difference in clinical

efficacy outcome was observed between males and females.

Racial or Ethnic Groups

The pharmacokinetic profile of granisetron from Sancuso was assessed in healthy Japanese males.

24-30

48-54

Following the application of a single 6-day Sancuso 52 cm transdermal system, in healthy male

Japanese subjects, mean C

, AUC

, and AUC

values were 5.02 ng/mL (CV: 66%), 492

ng.hr/mL (CV: 72%), and 562 ng.hr/mL (CV: 60%), respectively, and a median tmax value was 48 hours.

Patients with Renal Impairment

Total clearance of granisetron was not affected in patients with severe renal failure who received a

single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Patients with Hepatic Impairment

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance following

a single 40 mcg/kg intravenous dose of granisetron hydrochloride was approximately halved compared

to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of

granisetron and the good tolerance of doses well above the recommended dose, dose adjustment in

patients with hepatic functional impairment is not necessary.

Body Mass Index

In a clinical study designed to assess granisetron exposure from Sancuso in subjects with differing

levels of body fat, using body mass index (BMI) as a surrogate measure for subcutaneous fat, no

significant differences were seen in the plasma pharmacokinetics of Sancuso in male and female

subjects with low BMI [<19.5 kg/m (males), <18.5 kg/m (females)] and high BMI (30.0 to 39.9 kg/m

inclusive) compared to a control group (BMI 20.0 to 24.9 kg/m inclusive).

Drug Interaction Studies

Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP1A1

and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and hence, the half-life

of granisetron. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the

metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride

in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron

hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with

ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with

phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron

hydrochloride. The clinical significance of this change is not known.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6,

30 or 300 mg/m /day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m /day) during

week 59 due to toxicity. For a 50 kg person of average height (1.46 m body surface area), these doses

represent about 2.6, 13, and 65 times the recommended clinical dose (3.1 mg/day, 2.3 mg/m /day,

delivered by the Sancuso transdermal system, on a body surface area basis). There was a statistically

significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5

mg/kg/day (30 mg/m /day, about 13 times the recommended human dose with Sancuso, on a body surface

area basis) and above, and in females treated with 25 mg/kg/day (150 mg/m /day, about 65 times the

recommended human dose with Sancuso, on a body surface area basis). No increase in liver tumors was

observed at a dose of 1 mg/kg/day (6 mg/m /day, about 2.6 times the recommended human dose with

Sancuso, on a body surface area basis) in males and 5 mg/kg/day (30 mg/m /day, about 13 times the

recommended human dose with Sancuso, on a body surface area basis) in females.

In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m /day, about 261

times the recommended human dose with Sancuso, on a body surface area basis) produced

hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A

24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in

(0-144)

(0-∞)

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