Em Ex

Em Ex (granisetron hydrochloride) is indicated for the prevention of:

• Nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.
• Nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation.

Em Ex® (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.

Sancuso® (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.

Emetogenic Chemotherapy

The recommended adult dosage of oral Em Ex (granisetron hydrochloride) is 2 mg once daily or 1 mg twice daily. In the 2 mg once-daily regimen, two 1 mg tablets or 10 mL of Em Ex (granisetron) Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are given up to 1 hour before chemotherapy. In the 1 mg twice-daily regimen, the first 1 mg tablet or one teaspoonful (5 mL) of Em Ex (granisetron) Oral Solution is given up to 1 hour before chemotherapy, and the second tablet or second teaspoonful (5 mL) of Em Ex (granisetron) Oral Solution, 12 hours after the first. Either regimen is administered only on the day(s) chemotherapy is given. Continued treatment, while not on chemotherapy, has not been found to be useful.

Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients

No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Radiation (Either Total Body Irradiation or Fractionated Abdominal Radiation)

The recommended adult dosage of oral Em Ex (granisetron) is 2 mg once daily. Two 1 mg tablets or 10 mL of Em Ex (granisetron) Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are taken within 1 hour of radiation.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

No dosage adjustment is recommended.

The transdermal system (patch) should be applied to clean, dry, intact healthy skin on the upper outer arm. Em Ex should not be placed on skin that is red, irritated or damaged.

Each patch is packed in a pouch and should be applied directly after the pouch has been opened.

The patch should not be cut into pieces.

Adults

Apply a single patch to the upper outer arm a minimum of 24 hours before chemotherapy. The patch may be applied up to a maximum of 48 hours before chemotherapy as appropriate. Remove the patch a minimum of 24 hours after completion of chemotherapy. The patch can be worn for up to 7 days depending on the duration of the chemotherapy regimen.

The transdermal system (patch) should be applied to clean, dry, intact healthy skin on the upper outer arm. Sancuso should not be placed on skin that is red, irritated or damaged.

Each patch is packed in a pouch and should be applied directly after the pouch has been opened.

The patch should not be cut into pieces.

Adults

Apply a single patch to the upper outer arm a minimum of 24 hours before chemotherapy. The patch may be applied up to a maximum of 48 hours before chemotherapy as appropriate. Remove the patch a minimum of 24 hours after completion of chemotherapy. The patch can be worn for up to 7 days depending on the duration of the chemotherapy regimen.

Em Ex (granisetron) is contraindicated in patients with known hypersensitivity to the drug or any of its components.

Em Ex is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the patch.

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

WARNINGS

No information provided.

PRECAUTIONS

Em Ex (granisetron) is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Em Ex (granisetron) in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.

An adequate QT assessment has not been conducted, but QT prolongation has been reported with Em Ex (granisetron). Therefore, Em Ex (granisetron) should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the QT interval are particularly at risk.

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/m²/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m²/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m² body surface area), these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m², oral) 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/m²/day, 20 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m²/day, 101 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m²/day, 4 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m²/day, 20 times the recommended human dose based on body surface area) in females. In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m²/day, 405 times the recommended human dose based on body surface area) 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 tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, Em Ex (granisetron hydrochloride) should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).

Granisetron was not mutagenic in in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at oral doses up to 100 mg/kg/day (600 mg/m²/day, 405 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy

Teratogenic Effects

Pregnancy Category B.

Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m²/day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m²/day, 255 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Em Ex (granisetron) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

During clinical trials, 325 patients 65 years of age or older received Em Ex (granisetron) Tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Gastrointestinal

The use of granisetron in patients may mask a progressive ileus and/or gastric distention caused by the underlying condition.

Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 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-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 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 Em Ex and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Em Ex and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Em Ex is used concomitantly with other serotonergic drugs..

Skin Reactions

In clinical trials with Em Ex, application site reactions were reported which 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), the patch must be removed.

External Heat Sources

A heat pad should not be applied over or in vicinity of Em Ex patch. Patients should avoid prolonged exposure to heat as plasma concentration continues increasing during the period of heat exposure.

Exposure To Sunlight

Granisetron may be affected by direct natural or artificial sunlight. Patients must be advised to cover the 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 because of a potential skin reaction.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)

Gastrointestinal

Because the use of granisetron may mask a progressive ileus and/or gastric distention caused by the underlying condition, patients should be instructed to tell their physician if they have pain or swelling in their abdomen.

Skin Reactions

Patients should be instructed to remove the patch if they have a severe skin reaction, or a generalized skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or pruritus). When patients remove the patch, they should be instructed to peel it off gently.

Exposure To Sunlight

Granisetron may be degraded by direct sunlight or exposure to sunlamps. In addition, an in vitro study using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity.

Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight or sunlamps throughout the period of wear and for 10 days following its removal.

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome with concomitant use of Em Ex and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms, with or without gastrointestinal symptoms.

External Heat Sources

Patients should be advised not to apply a heat pad over or near the Em Ex patch. Patients should avoid prolonged exposure to heat as plasma concentration continues increasing during the period of heat exposure.

Nonclinical Toxicology

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/m²/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m²/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m² body surface area), these doses represent about 2.6, 13 and 65 times the recommended clinical dose (3.1 mg/day, 2.3 mg/m²/day, delivered by the Em Ex patch, 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/m²/day, about 13 times the recommended human dose with Em Ex, on a body surface area basis) and above, and in females treated with 25 mg/kg/day (150 mg/m²/day, about 65 times the recommended human dose with Em Ex, on a body surface area basis). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m²/day, about 2.6 times the recommended human dose with Em Ex, on a body surface area basis) in males and 5 mg/kg/day (30 mg/m²/day, about 13 times the recommended human dose with Em Ex, on a body surface area basis) in females.

In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m²/day, about 261 times the recommended human dose with Em Ex, 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 tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, Em Ex should be prescribed only at the dose and for the indication recommended.

Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m²/day, about 16 times the recommended human dose of Em Ex, on a body surface area basis), and oral doses up to 100 mg/kg/day (600 mg/m²/day, about 261 times the recommended human dose of Em Ex, on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.

Phototoxicity

When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cell line, at 200 and 300 mcg/ml, granisetron increased the percentage of cells with chromosomal aberration following photoirradiation.

Granisetron was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested in vivo in guinea-pigs, Em Ex patches did not show any potential for photoirritation or photosensitivity. No phototoxicity studies have been performed in humans.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m²/day, about 24 times the recommended human dose delivered by the Em Ex patch, based on body surface area) and oral doses up to 125 mg/kg/day (750 mg/m²/day, about 326 times the recommended human dose with Em Ex based on body surface area). Reproduction studies have been performed in pregnant rabbits at intravenous doses up to 3 mg/kg/day (36 mg/m²/day, about 16 times the human dose with Em Ex based on body surface area) and at oral doses up to 32 mg/kg/day (384 mg/m²/day, about 167 times the human dose with Em Ex based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Em Ex should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Em Ex is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Clinical studies of Em Ex 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.

Renal Impairment Or Hepatic Impairment

Although no studies have been performed to investigate the pharmacokinetics of Em Ex in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Gastrointestinal

The use of granisetron in patients may mask a progressive ileus and/or gastric distention caused by the underlying condition.

Serotonin Syndrome

The development of serotonin syndrome has been reported with 5-HT3 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-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 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..

Skin 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. 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), the patch must be removed.

External Heat Sources

A heat pad should not be applied over or in vicinity of Sancuso patch. Patients should avoid prolonged exposure to heat as plasma concentration continues increasing during the period of heat exposure.

Exposure To Sunlight

Granisetron may be affected by direct natural or artificial sunlight. Patients must be advised to cover the 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 because of a potential skin reaction.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION)

Gastrointestinal

Because the use of granisetron may mask a progressive ileus and/or gastric distention caused by the underlying condition, patients should be instructed to tell their physician if they have pain or swelling in their abdomen.

Skin Reactions

Patients should be instructed to remove the patch if they have a severe skin reaction, or a generalized skin reaction (e.g. allergic rash, including erythematous, macular, papular rash or pruritus). When patients remove the patch, they should be instructed to peel it off gently.

Exposure To Sunlight

Granisetron may be degraded by direct sunlight or exposure to sunlamps. In addition, an in vitro study using Chinese hamster ovary cells suggests that granisetron has the potential for photogenotoxicity.

Patients must be advised to cover the patch application site, e.g. with clothing, if there is a risk of exposure to sunlight or sunlamps throughout the period of wear and for 10 days following its removal.

Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome with concomitant use of Sancuso and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms, with or without gastrointestinal symptoms.

External Heat Sources

Patients should be advised not to apply a heat pad over or near the Sancuso patch. Patients should avoid prolonged exposure to heat as plasma concentration continues increasing during the period of heat exposure.

Nonclinical Toxicology

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/m²/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m²/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m² body surface area), these doses represent about 2.6, 13 and 65 times the recommended clinical dose (3.1 mg/day, 2.3 mg/m²/day, delivered by the Sancuso patch, 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/m²/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/m²/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/m²/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/m²/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/m²/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 tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, Sancuso should be prescribed only at the dose and for the indication recommended.

Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m²/day, about 16 times the recommended human dose of Sancuso, on a body surface area basis), and oral doses up to 100 mg/kg/day (600 mg/m²/day, about 261 times the recommended human dose of Sancuso, on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.

Phototoxicity

When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cell line, at 200 and 300 mcg/ml, granisetron increased the percentage of cells with chromosomal aberration following photoirradiation.

Granisetron was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested in vivo in guinea-pigs, Sancuso patches did not show any potential for photoirritation or photosensitivity. No phototoxicity studies have been performed in humans.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Reproduction studies with granisetron hydrochloride have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m²/day, about 24 times the recommended human dose delivered by the Sancuso patch, based on body surface area) and oral doses up to 125 mg/kg/day (750 mg/m²/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/m²/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/m²/day, about 167 times the human dose with Sancuso based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Sancuso should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sancuso is administered to a nursing woman.

Pediatric Use

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

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.

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.

QT prolongation has been reported with Em Ex (see PRECAUTIONS and DRUG INTERACTIONS).

Chemotherapy-Induced Nausea and Vomiting

Over 3700 patients have received Em Ex (granisetron) Tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens.

In patients receiving Em Ex (granisetron) Tablets 1 mg bid for 1, 7 or 14 days, or 2 mg daily for 1 day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed in Table 4.

Table 4 Principal Adverse Events in Clinical Trials¹

Other adverse events reported in clinical trials were:

Gastrointestinal: In single-day dosing studies in which adverse events were collected for 7 days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24hour efficacy assessment period.

Hepatic: In comparative trials, elevation of AST and ALT ( > 2 times the upper limit of normal) following the administration of Em Ex (granisetron) Tablets occurred in 5% and 6% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2%; ALT: 9%).

Cardiovascular: Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and syncope have been observed rarely.

Central Nervous System: Dizziness (5%), insomnia (5%), anxiety (2%), somnolence (1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms has been reported in a patient treated with Em Ex (granisetron) Tablets.

Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.

Other: Fever (5%). Events often associated with chemotherapy also have been reported: leukopenia (9%), decreased appetite (6%), anemia (4%), alopecia (3%), thrombocytopenia (2%).

Over 5000 patients have received injectable Em Ex (granisetron) in clinical trials.

Table 5 gives the comparative frequencies of the five commonly reported adverse events ( ≥ 3%) in patients receiving Em Ex (granisetron) Injection, 40 mcg/kg, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following Em Ex (granisetron) Injection administration.

Table 5 : Principal Adverse Events in Clinical Trials — Single-Day Chemotherapy

In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to Em Ex (granisetron) , except for headache, which was clearly more frequent than in comparison groups.

Radiation-Induced Nausea and Vomiting

In controlled clinical trials, the adverse events reported by patients receiving Em Ex (granisetron) Tablets and concurrent radiation were similar to those reported by patients receiving Em Ex (granisetron) Tablets prior to chemotherapy. The most frequently reported adverse events were diarrhea, asthenia, and constipation. Headache, however, was less prevalent in this patient population.

Postmarketing Experience

QT prolongation has been reported with Em Ex (see PRECAUTIONS and DRUG INTERACTIONS).

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 Em Ex was evaluated in a total of 404 patients undergoing chemotherapy who participated in two double-blind, comparator studies with patch 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 8.7% (35/404) of patients receiving Em Ex and 7.1% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5.4% of patients in the Em Ex group and 3.0% of patients in the oral granisetron group.

Table 1 lists the adverse reactions that occurred in at least 3% of patients treated with Em Ex or oral granisetron.

Table 1: Incidence of Adverse Reactions in Double-Blind, Active Comparator Controlled Studies in Cancer Patients Receiving Chemotherapy (Events ≥ 3% in either group)

5-HT3 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 patch. 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Em Ex. 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); patch non-adhesion)

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

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 patch 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 8.7% (35/404) of patients receiving Sancuso and 7.1% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5.4% of patients in the Sancuso group and 3.0% 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 (Events ≥ 3% in either group)

5-HT3 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 patch. 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.

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); patch non-adhesion)

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

There is no specific treatment for granisetron hydrochloride overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache.

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given.

Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or only the occurrence of a slight headache.

In clinical trials there were no reported cases of overdosage with Em Ex.

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given.

Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or only the occurrence of a slight headache.

In clinical trials there were no reported cases of overdosage with Sancuso.

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 Em Ex patch (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 Em Ex was below 10 ms. This study suggests that Em Ex 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 Em Ex 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.

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 patch (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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Radiation (Either Total Body Irradiation or Fractionated Abdominal Radiation)

The recommended adult dosage of oral Em Ex (granisetron) is 2 mg once daily. Two 1 mg tablets or 10 mL of Em Ex (granisetron) Oral Solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are taken within 1 hour of radiation.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in the Elderly

No dosage adjustment is recommended.

HOW SUPPLIED

Tablets

White, triangular, biconvex, film-coated tablets; tablets are debossed K1 on one face.

1 mg Unit of Use 2's: NDC 0004-0241-33

1 mg Single Unit Package 20's: NDC 0004-0241-26 (intended for institutional use only)

Storage

Store between 15° and 30°C (59° and 86°F). Keep container closed tightly. Protect from light.

Oral Solution

Clear, orange-colored, orange-flavored, 2 mg/10 mL, in 30 mL amber glass bottles with child-resistant closures: NDC 0004-0237-09

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Keep bottle closed tightly and stored in an upright position. Protect from light.

Distributed by: Roche Laboratories Inc., 340 Kingsland Street, Nutley, New Jersey 07110-1199. Revised: September 2009.

SIDE EFFECTS

QT prolongation has been reported with Em Ex (see PRECAUTIONS and DRUG INTERACTIONS).

Chemotherapy-Induced Nausea and Vomiting

Over 3700 patients have received Em Ex (granisetron) Tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens.

In patients receiving Em Ex (granisetron) Tablets 1 mg bid for 1, 7 or 14 days, or 2 mg daily for 1 day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed in Table 4.

Table 4 Principal Adverse Events in Clinical Trials¹

Other adverse events reported in clinical trials were:

Gastrointestinal: In single-day dosing studies in which adverse events were collected for 7 days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24hour efficacy assessment period.

Hepatic: In comparative trials, elevation of AST and ALT ( > 2 times the upper limit of normal) following the administration of Em Ex (granisetron) Tablets occurred in 5% and 6% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2%; ALT: 9%).

Cardiovascular: Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and syncope have been observed rarely.

Central Nervous System: Dizziness (5%), insomnia (5%), anxiety (2%), somnolence (1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms has been reported in a patient treated with Em Ex (granisetron) Tablets.

Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.

Other: Fever (5%). Events often associated with chemotherapy also have been reported: leukopenia (9%), decreased appetite (6%), anemia (4%), alopecia (3%), thrombocytopenia (2%).

Over 5000 patients have received injectable Em Ex (granisetron) in clinical trials.

Table 5 gives the comparative frequencies of the five commonly reported adverse events ( ≥ 3%) in patients receiving Em Ex (granisetron) Injection, 40 mcg/kg, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following Em Ex (granisetron) Injection administration.

Table 5 : Principal Adverse Events in Clinical Trials — Single-Day Chemotherapy

In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to Em Ex (granisetron) , except for headache, which was clearly more frequent than in comparison groups.

Radiation-Induced Nausea and Vomiting

In controlled clinical trials, the adverse events reported by patients receiving Em Ex (granisetron) Tablets and concurrent radiation were similar to those reported by patients receiving Em Ex (granisetron) Tablets prior to chemotherapy. The most frequently reported adverse events were diarrhea, asthenia, and constipation. Headache, however, was less prevalent in this patient population.

Postmarketing Experience

QT prolongation has been reported with Em Ex (see PRECAUTIONS and DRUG INTERACTIONS).

DRUG INTERACTIONS

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, Em Ex (granisetron) Injection has been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with antiemetic treatments. Em Ex (granisetron) Injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. 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 Em Ex (granisetron) in vitro.

In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of Em Ex (granisetron). 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 Em Ex (granisetron). The clinical significance of this change is not known.

QT prolongation has been reported with Em Ex (granisetron). Use of Em Ex (granisetron) in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may result in clinical consequences.

WARNINGS

No information provided.

PRECAUTIONS

Em Ex (granisetron) is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Em Ex (granisetron) in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distention.

An adequate QT assessment has not been conducted, but QT prolongation has been reported with Em Ex (granisetron). Therefore, Em Ex (granisetron) should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. Patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the QT interval are particularly at risk.

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/m²/day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m²/day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m² body surface area), these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m², oral) 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/m²/day, 20 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m²/day, 101 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m²/day, 4 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m²/day, 20 times the recommended human dose based on body surface area) in females. In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m²/day, 405 times the recommended human dose based on body surface area) 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 tumor incidence, but the study was not conclusive.

Because of the tumor findings in rat studies, Em Ex (granisetron hydrochloride) should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).

Granisetron was not mutagenic in in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test.

Granisetron at oral doses up to 100 mg/kg/day (600 mg/m²/day, 405 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy

Teratogenic Effects

Pregnancy Category B.

Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m²/day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m²/day, 255 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Em Ex (granisetron) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

During clinical trials, 325 patients 65 years of age or older received Em Ex (granisetron) Tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age.

OVERDOSE

There is no specific treatment for granisetron hydrochloride overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache.

CONTRAINDICATIONS

Em Ex (granisetron) is contraindicated in patients with known hypersensitivity to the drug or any of its components.

CLINICAL PHARMACOLOGY

Granisetron is a selective 5-hydroxytryptamine₃ (5-HT₃) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT₁; 5-HT_1A; 5-HT_1B/C; 5-HT₂; for alpha₁-, alpha₂-, or beta-adrenoreceptors; for dopamine-D₂; or for histamine-H₁; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT₃ type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT₃ receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT₃ 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.

In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies.

Following single and multiple oral doses, Em Ex (granisetron) Tablets slowed colonic transit in normal volunteers. However, Em Ex (granisetron) had no effect on oro-cecal transit time in normal volunteers when given as a single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg.

Pharmacokinetics

In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of Em Ex (granisetron) Tablets produced mean pharmacokinetic data shown in Table 1.

Table 1 : Pharmacokinetic Parameters (Median [range]) Following Em Ex Tablets (granisetron hydrochloride)

A 2 mg dose of Em Ex (granisetron) Oral Solution is bioequivalent to the corresponding dose of Em Ex (granisetron) Tablets (1 mg x 2) and may be used interchangeably.

Absorption

When Em Ex (granisetron) Tablets were administered with food, AUC was decreased by 5% and Cmax increased by 30% in non-fasted healthy volunteers who received a single dose of 10 mg.

Distribution

Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.

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-HT₃ receptor antagonist activity.

Elimination

Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 11% of the orally administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces.

Subpopulations

Gender

The effects of gender on the pharmacokinetics of Em Ex (granisetron) Tablets have not been studied. However, after intravenous infusion of Em Ex (granisetron) , no difference in mean AUC was found between males and females, although males had a higher Cmax generally.

In elderly and pediatric patients and in patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron was determined following administration of intravenous Em Ex (granisetron).

Elderly

The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of Em Ex (granisetron) Injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly.

Renal Failure Patients

Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of Em Ex (granisetron) Injection.

Hepatically Impaired Patients

A pharmacokinetic study with intravenous Em Ex (granisetron) in patients with hepatic impairment due to neoplastic liver involvement showed that total clearance was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters noted in patients, dosage adjustment in patients with hepatic functional impairment is not necessary.

Pediatric Patients

A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg intravenous dose of Em Ex (granisetron) Injection, showed that volume of distribution and total clearance increased with age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life. When volume of distribution and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are similar in pediatric and adult cancer patients.

Clinical Trials

Chemotherapy-Induced Nausea and Vomiting

Em Ex (granisetron) Tablets prevent nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, as shown by 24-hour efficacy data from studies using both moderately- and highly-emetogenic chemotherapy.

Moderately Emetogenic Chemotherapy

The first trial compared Em Ex (granisetron) Tablets doses of 0.25 mg to 2 mg twice a day, in 930 cancer patients receiving, principally, cyclophosphamide, carboplatin, and cisplatin (20 mg/m² to 50 mg/m²). Efficacy was based on complete response (ie, no vomiting, no moderate or severe nausea, no rescue medication), no vomiting, and no nausea. Table 2 summarizes the results of this study.

Table 2 : Prevention of Nausea and Vomiting 24 Hours Post­Chemotherapy¹

Results from a second double-blind, randomized trial evaluating Em Ex (granisetron) Tablets 2 mg once a day and Em Ex (granisetron) Tablets 1 mg twice a day were compared to prochlorperazine 10 mg twice a day derived from a historical control. At 24 hours, there was no statistically significant difference in efficacy between the two Em Ex (granisetron) Tablet regimens. Both regimens were statistically superior to the prochlorperazine control regimen (see Table 3).

Table 3 : Prevention of Nausea and Vomiting 24 Hours Post­Chemotherapy¹

Results from a Em Ex (granisetron) Tablets 2 mg daily alone treatment arm in a third double-blind, randomized trial, were compared to prochlorperazine (PCPZ), 10 mg bid, derived from a historical control. The 24-hour results for Em Ex (granisetron) Tablets 2 mg daily were statistically superior to PCPZ for all efficacy parameters: complete response (58%), no vomiting (79%), no nausea (51%), total control (49%). The PCPZ rates are shown in Table 3.

Cisplatin-Based Chemotherapy

The first double-blind trial compared Em Ex (granisetron) Tablets 1 mg bid, relative to placebo (historical control), in 119 cancer patients receiving high-dose cisplatin (mean dose 80 mg/m²). At 24 hours, Em Ex (granisetron) Tablets 1 mg bid was significantly (P < 0.001) superior to placebo (historical control) in all efficacy parameters: complete response (52%), no vomiting (56%) and no nausea (45%). The placebo rates were 7%, 14%, and 7%, respectively, for the three efficacy parameters.

Results from a Em Ex (granisetron) Tablets 2 mg once a day alone treatment arm in a second double-blind, randomized trial, were compared to both Em Ex (granisetron) Tablets 1 mg twice a day and placebo historical controls. The 24-hour results for Em Ex (granisetron) Tablets 2 mg once a day were: complete response (44%), no vomiting (58%), no nausea (46%), total control (40%). The efficacy of Em Ex (granisetron) Tablets 2 mg once a day was comparable to Em Ex (granisetron) Tablets 1 mg twice a day and statistically superior to placebo. The placebo rates were 7%, 14%, 7%, and 7%, respectively, for the four parameters.

No controlled study comparing granisetron injection with the oral formulation to prevent chemotherapy-induced nausea and vomiting has been performed.

Radiation-Induced Nausea and Vomiting

Total Body Irradiation

In a double-blind randomized study, 18 patients receiving Em Ex (granisetron) Tablets, 2 mg daily, experienced significantly greater antiemetic protection compared to patients in a historical negative control group who received conventional (non-5-HT₃ antagonist) antiemetics. Total body irradiation consisted of 11 fractions of 120 cGy administered over 4 days, with three fractions on each of the first 3 days, and two fractions on the fourth day. Em Ex (granisetron) Tablets were given one hour before the first radiation fraction of each day.

Twenty-two percent (22%) of patients treated with Em Ex (granisetron) Tablets did not experience vomiting or receive rescue antiemetics over the entire 4-day dosing period, compared to 0% of patients in the historical negative control group (P < 0.01).

In addition, patients who received Em Ex (granisetron) Tablets also experienced significantly fewer emetic episodes during the first day of radiation and over the 4-day treatment period, compared to patients in the historical negative control group. The median time to the first emetic episode was 36 hours for patients who received Em Ex (granisetron) Tablets.

Fractionated Abdominal Radiation

The efficacy of Em Ex (granisetron) Tablets, 2 mg daily, was evaluated in a double-blind, placebo-controlled randomized trial of 260 patients. Em Ex (granisetron) Tablets were given 1 hour before radiation, composed of up to 20 daily fractions of 180 to 300 cGy each. The exceptions were patients with seminoma or those receiving whole abdomen irradiation who initially received 150 cGy per fraction. Radiation was administered to the upper abdomen with a field size of at least 100 cm².

The proportion of patients without emesis and those without nausea for Em Ex (granisetron) Tablets, compared to placebo, was statistically significant (P < 0.0001) at 24 hours after radiation, irrespective of the radiation dose. Em Ex (granisetron) was superior to placebo in patients receiving up to 10 daily fractions of radiation, but was not superior to placebo in patients receiving 20 fractions.

Patients treated with Em Ex (granisetron) Tablets (n=134) had a significantly longer time to the first episode of vomiting (35 days vs. 9 days, P < 0.001) relative to those patients who received placebo (n=126), and a significantly longer time to the first episode of nausea (11 days vs. 1 day, P < 0.001). Em Ex (granisetron) provided significantly greater protection from nausea and vomiting than placebo.

Absorption

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

Following a 7-day application of Em Ex 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 patch application. Mean Cmax was 5.0 ng/mL (CV: 170%) and mean AUC0-168hr was 527 ng-hr/mL (CV:173%).

Mean Plasma Concentration of Granisetron (mean ± SD)

Based on the measure of residual content of the patch after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following patch application for 7 days.

Following consecutive application of two Em Ex patches, each for seven days, granisetron levels were maintained over the study period with evidence of minimal accumulation. The mean plasma concentration at 24 hours after the second patch application was 1.5-fold higher due to residual granisetron from the first patch. As the plasma concentration increased after the second patch application, the difference decreased and the mean plasma concentration at 48 hours was 1.3-fold higher after the second patch compared to that after the first patch.

In a study designed to assess the effect of heat on the transdermal delivery of granisetron from Em Ex in healthy subjects, a heat pad generating an average temperature of 42°C (107.6°F) was applied over the patch 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 Cmax with intermittent heat exposure was 6% higher than without heat. Mean partial AUCs over 6 hours with 4 hour of heat application (AUC0-6, AUC24-30, and AUC48-54) were 4.9, 1.4, and 1.1 folds higher, respectively, with heat pad than without heat pad. A heat pad should not be applied over or in the near vicinity of the Em Ex patch.

Distribution

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

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-HT3 receptor antagonist activity.

Elimination

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.

Absorption

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

Following a 7-day application of Sancuso 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 patch application. Mean Cmax was 5.0 ng/mL (CV: 170%) and mean AUC0-168hr was 527 ng-hr/mL (CV:173%).

Mean Plasma Concentration of Granisetron (mean ± SD)

Based on the measure of residual content of the patch after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following patch application for 7 days.

Following consecutive application of two Sancuso patches, each for seven days, granisetron levels were maintained over the study period with evidence of minimal accumulation. The mean plasma concentration at 24 hours after the second patch application was 1.5-fold higher due to residual granisetron from the first patch. As the plasma concentration increased after the second patch application, the difference decreased and the mean plasma concentration at 48 hours was 1.3-fold higher after the second patch compared to that after the first patch.

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 patch 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 Cmax with intermittent heat exposure was 6% higher than without heat. Mean partial AUCs over 6 hours with 4 hour of heat application (AUC0-6, AUC24-30, and AUC48-54) were 4.9, 1.4, and 1.1 folds higher, respectively, with heat pad than without heat pad. A heat pad should not be applied over or in the near vicinity of the Sancuso patch.

Distribution

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

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-HT3 receptor antagonist activity.

Elimination

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.