Zetron

Zetron uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Patient information
• Zetron reviews

1 INDICATIONS AND USAGE

Zetron^® (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.

Zetron is a serotonin -3 (5-HT3) receptor antagonist indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy for up to 5 consecutive days. (1)

2 DOSAGE AND ADMINISTRATION

The transdermal system should be applied to clean, dry, intact healthy skin on the upper outer arm. Zetron 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.

Apply a single transdermal system (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. (2)

2.1 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.

3 DOSAGE FORMS AND STRENGTHS

Zetron is a 52 cm² patch containing 34.3 mg of Zetron. The patch releases 3.1 mg of Zetron per 24 hours for up to 7 days.

Transdermal System: 52 cm² patch containing 34.3 mg of Zetron delivering 3.1 mg per 24 hours (3)

4 CONTRAINDICATIONS

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

Known hypersensitivity to Zetron or to any of the components of the patch (4)

5 WARNINGS AND PRECAUTIONS

• Zetron may mask a progressive ileus and/or gastric distention caused by the underlying condition.
• Serotonin syndrome has been reported with 5-HT3 receptor antagonists alone but particularly with concomitant use of serotonergic drugs. (5.2)
• Mild application site reactions have occurred; remove patch if severe reactions or a generalized skin reaction occur. (5.3)
• Avoid exposing the Zetron patch 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 by covering with clothing while wearing the patch and for 10 days after removing it. (5.5)

5.1 Gastrointestinal

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

5.2 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, 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 Zetron and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Zetron and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Zetron is used concomitantly with other serotonergic drugs. .

5.3 Skin Reactions

In clinical trials with Zetron, 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), the patch must be removed.

5.4 External Heat Sources

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

5.5 Exposure to Sunlight

Zetron 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 .

6 ADVERSE REACTIONS

The most common adverse reaction 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.

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 Zetron 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 Zetron, for 1 to 5 days.

Adverse reactions occurred in 8.7% (35/404) of patients receiving Zetron and 7.1% (29/406) of patients receiving oral Zetron. The most common adverse reaction was constipation that occurred in 5.4% of patients in the Zetron group and 3.0% of patients in the oral Zetron group.

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

5-HT₃ receptor antagonists, such as Zetron, 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 Zetron, 8 (2.7%) on oral Zetron, 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 Zetron 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 Zetron. 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

7 DRUG INTERACTIONS

Zetron 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, Zetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Zetron 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 Zetron.

Because Zetron 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 Zetron. 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 Zetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of Zetron 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 Zetron hydrochloride. The clinical significance of this change is not known.

Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-HT₃ receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin and noradrenaline reuptake inhibitors (SNRIs) .

No clinically relevant drug interactions have been reported in clinical studies with Zetron. (7)

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Use only if clearly needed.
• Nursing women: Caution should be exercised when administered to a nursing woman. (8.3)
• Pediatric use: Safety and effectiveness have not been established in pediatric patients. (8.4)
• Geriatric use: Clinical studies of Zetron did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger patients (8.5)

8.1 Pregnancy

Pregnancy Category B

Reproduction studies with Zetron 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 Zetron 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 Zetron 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 Zetron 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 Zetron based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to Zetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zetron should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers

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

8.4 Pediatric Use

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

8.5 Geriatric Use

Clinical studies of Zetron 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 Zetron in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous Zetron .

10 OVERDOSAGE

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

Overdosage of up to 38.5 mg of Zetron 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 Zetron.

11 DESCRIPTION

Zetron contains Zetron, which is a serotonin-3 (5-HT₃) 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 C₁₈H₂₄N₄O, while its chemical structure is:

Zetron is a white to off-white solid that is insoluble in water. Zetron is a thin, translucent, matrix-type transdermal patch that is rectangular-shaped with rounded corners, consisting of a backing, the drug matrix and a release liner.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Zetron is a selective 5-hydroxytryptamine₃ receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT_1, 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, Zetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single Zetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

12.2 Pharmacodynamics

The effect of Zetron 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 Zetron patch (n=60) or intravenous Zetron (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 Zetron was below 10 ms. This study suggests that Zetron 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 Zetron.

The effect on oro-cecal transit time following application of Zetron has not been studied. Zetron 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 Zetron hydrochloride slowed colonic transit in healthy subjects.

12.3 Pharmacokinetics

Absorption

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

Following a 7-day application of Zetron 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 C_max was 5.0 ng/mL (CV: 170%) and mean AUC_0-168hr was 527 ng-hr/mL (CV: 173%).

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

Following consecutive application of two Zetron patches, each for seven days, Zetron 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 Zetron 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 Zetron from Zetron 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 Zetron concentrations during the period of heat pad application. The elevated plasma concentration declined after removal of the heat pad. Mean C_max with intermittent heat exposure was 6% higher than without heat. Mean partial AUCs over 6 hours with 4 hour of heat application (AUC_0-6, AUC_24-30, and AUC_48-54) 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 Zetron patch.

Image

Distribution

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

Metabolism

Zetron 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.

Subpopulations

Gender

There is evidence to suggest that female subjects had higher Zetron concentrations than males following patch application. However, no statistically significant difference in clinical efficacy outcome was observed between genders.

Pediatrics

No studies have been performed to investigate the pharmacokinetics of Zetron in pediatrics.

Elderly

Following application of Zetron patch in healthy subjects, mean AUC_0-z, C_max, and C_avg 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 Zetron hydrochloride in elderly volunteers (mean age 71 years), lower clearance and longer half-life were observed compared to younger healthy volunteers.

Renal Impairment

Total clearance of Zetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of Zetron hydrochloride.

Hepatic Impairment

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance following a single 40 mcg/kg intravenous dose of Zetron hydrochloride was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of Zetron 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 Zetron exposure from Zetron 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 Zetron in male and female subjects with low BMI [<19.5 kg/m² (males), <18.5 kg/m² (females)] and high BMI (30.0 to 39.9 kg/m² inclusive) compared to a control group (BMI 20.0 to 24.9 kg/m² inclusive).

Race

The pharmacokinetic profile of Zetron from Zetron was assessed in healthy Japanese males. Following the application of a single 6-day Zetron 52 cm², in healthy male Japanese subjects, mean C_max, AUC_(0-144), and AUC_(0-∞) 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 t_max value was 48 hours.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 24-month carcinogenicity study, rats were treated orally with Zetron 1, 5 or 50 mg/kg/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 Zetron 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 Zetron, 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 Zetron, 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 Zetron, 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 Zetron, on a body surface area basis) in females.

In a 12-month oral toxicity study, treatment with Zetron 100 mg/kg/day (600 mg/m²/day, about 261 times the recommended human dose with Zetron, 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 Zetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive.

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

Zetron 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.

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

13.3 Phototoxicity

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

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

14 CLINICAL STUDIES

The effectiveness of Zetron in the prevention of chemotherapy-induced nausea and vomiting (CINV) was evaluated in a randomized, parallel group, double-blind, double-dummy study conducted in the U.S. and abroad. The study compared the efficacy, tolerability and safety of Zetron with that of 2 mg oral Zetron once daily in the prevention of nausea and vomiting in a total of 641 patients receiving multi-day chemotherapy.

The population randomized into the trial included 48% males and 52% females aged 16 to 86 years receiving moderately emetogenic (ME) or highly emetogenic (HE) multi-day chemotherapy. Seventy-eight (78%) of patients were White, 12% Asian, 10% Hispanic/Latino and 0% Black.

The Zetron patch was applied 24 to 48 hours before the first dose of chemotherapy, and kept in place for 7 days. Oral Zetron was administered daily for the duration of the chemotherapy regimen, 1 hour before each dose of chemotherapy. Efficacy was assessed from the first administration until 24 hours after the start of the last day's administration of the chemotherapy regimen.

The primary endpoint of the trial was the proportion of patients achieving no vomiting and/or retching, no more than mild nausea and no rescue medication from the first administration until 24 hours after the start of the last day's administration of multi-day chemotherapy. Using this definition, the effect of Zetron was established in 60.2% of patients in the Zetron arm and 64.8% of patients receiving oral Zetron (difference -4.89%; 95% confidence interval –12.91% to +3.13%).

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Zetron (Granisetron Transdermal System) is supplied as a 52 cm² patch containing 34.3 mg of Zetron. Each patch is printed on one side with the words "Granisetron 3.1 mg/24 hours". Each patch is packaged in a separate sealed foil-lined plastic pouch.

Zetron is available in packages of 1 (NDC 42747-726-01) patch.

Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F)..

Zetron should be stored in the original packaging.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling

17.1 Gastrointestinal

Because the use of Zetron 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.

17.2 Skin Reactions

Patients should be instructed to remove the patch if they have a severe skin reaction, or a generalized skin reaction.

When patients remove the patch, they should be instructed to peel it off gently.

17.3 Exposure to Sunlight

Zetron may be degraded by direct sunlight or exposure to sunlamps. In addition, an in vitro study using Chinese hamster ovary cells suggests that Zetron 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.

17.4 Serotonin Syndrome

Advise patients of the possibility of serotonin syndrome with concomitant use of Zetron 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.

17.5 External Heat Sources

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

Rx Only

Manufactured by:

3M Delivery Systems

St. Paul, MN 55107

Manufactured for:

Kyowa Kirin, Inc.

Bedminster, NJ 07921

Rev. 01/2017

Copyright © 2017, Kyowa Kirin, Inc. All rights reserved.

Zetron and Kyowa Kirin are trademarks owned by the Kyowa Kirin group of companies

Patient Information

Zetron^® [san-KOO-so]

(granisetron transdermal system)

Read the Patient Information that comes with Zetron before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. If you have any questions about Zetron, ask your healthcare provider.

What is Zetron?

Zetron is a prescription medicine used to prevent nausea and vomiting in people receiving some types of chemotherapy treatment. Zetron is a skin patch that slowly releases the medicine contained in the adhesive (glue), through clean and intact skin areas into your bloodstream while you wear the patch.

Who should not use Zetron?

Do not use Zetron if you are allergic to any of the ingredients in Zetron. See the end of this leaflet for a list of ingredients in Zetron.

What should I tell my healthcare provider before using Zetron?

Tell your healthcare provider about all your medical conditions, including if you:

• are allergic to medical adhesive tape, adhesive dressings or other skin patches
• have pain or swelling in your stomach area (abdomen).
• are pregnant. It is not known if Zetron will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant.
• are breast-feeding or plan to breast-feed. It is not known if Zetron passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Other medicines may affect how Zetron works. Zetron may also affect how other medicines work.

How should Zetron be used?

Use Zetron exactly as prescribed. See the detailed Patient Instructions for Applying Zetron at the end of this Patient Information leaflet.

What should I avoid while using Zetron?

Do not apply any heat source over or near the Zetron patch. For example,

• A heating pad or heat lamp should not be used where the patch is applied.
• You should avoid extended exposure to heat as it may increase your blood levels during the time of heat exposure.

Avoid sunlight. The medicine in Zetron (granisetron) may not work as well and/or may affect your skin if exposed to direct sunlight or the light from sunlamps or tanning beds. It is important to do the following:

• While you wear the patch, keep it covered with clothing if you will be in sunlight or near a sunlamp, including tanning beds.
• Keep the skin where Zetron was applied covered for another 10 days after the patch is taken off to protect from exposure to direct sunlight.

What are the possible side effects of Zetron?

Zetron can cause serious side effects:

• Using Zetron may make it harder to identify certain stomach and bowel problems that are from other causes. Tell your healthcare provider if you have any stomach area (abdominal) pain or swelling while using Zetron.
• Skin reactions. Skin reactions can happen just at the patch application site or outside the patch application site. Tell your healthcare provider if you get any redness, rashes, bumps, blisters or itching at the patch application site, and especially if they spread outside the place where the patch was or if they appear outside the patch application site. You may need to stop using Zetron.

Common side effects of Zetron are:

• constipation
• headache.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Zetron. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Zetron?

• Keep Zetron in the package it comes in.
• Store Zetron at 20-25°C (68-77°F).

Keep Zetron out of the reach of children.

General information about Zetron

Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use Zetron for a condition for which it is not prescribed. Do not give Zetron to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Zetron. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about Zetron that is written for health professionals.

For more information, go to www.sancuso.com or call 1-800-SANCUSO.

Patient Instructions for Applying Zetron

When do I apply the Zetron patch?

• Apply Zetron at least 1 day (24 hours) before your scheduled chemotherapy treatment.
• You may apply Zetron up to 2 days (48 hours) before your scheduled chemotherapy.
• Wear the patch all the time during your chemotherapy.
• Zetron may be worn for up to 7 days, depending on how long your chemotherapy treatment lasts (up to 5 days).
• Remove the patch at least 1 day (24 hours) after your chemotherapy is finished.
• Keep the patch covered, such as under clothing, while you are wearing it to avoid a skin reaction to sunlight or sunlamps. Keep the skin where Zetron was applied (application site) covered up for another 10 days after the patch is taken off to prevent a skin reaction. See "What should I avoid while using Zetron?"

Where do I apply the Zetron patch?

• Apply Zetron to a clean, dry, healthy area of skin on the outside part of your upper arm.
  

• The area you choose should not be oily, recently shaved or have any skin problems such as being damaged (cut or scraped) or irritated (redness or a rash).
• Do not apply Zetron to areas that have been treated with creams, oils, lotions, powders or other skin products that could keep the patch from sticking well to your skin.

How do I apply the Zetron patch?

The Zetron patch comes inside a pouch which is inside the carton.

• Do not remove the patch from the pouch until you are ready to use it.
• Do not cut the Zetron patch into pieces.
• Remove the pouch from the carton.
  

• Tear the pouch open using the slit provided, and remove the patch. Each pouch contains one Zetron patch stuck onto a rigid plastic film.
  

• The unprinted, sticky side of the patch is covered by a two-piece rigid plastic film. Bend the patch in the middle and remove one half of the rigid plastic film. Be careful not to stick the patch to itself and avoid touching the sticky side of the patch.
  

• While holding the remaining half of the rigid plastic film, apply the patch to your skin. Remove the second half of the rigid plastic film and press the whole patch firmly in place with your fingers and smooth down. Press firmly making sure it sticks well to the skin, especially around the edges.
  

• Wash your hands right away after applying the patch to remove any medicine that may have stuck to your fingers.
• Keep the patch in place for the whole time you are having chemotherapy. Remove the patch at least 1 day (24 hours) after your chemotherapy is finished. The patch can be worn for up to 7 days, depending on the number of days your chemotherapy treatment lasts.
• Do not re-use the patch after you remove it. See below for instructions on the right way to remove and throw away the patch.

What to do if the Zetron patch does not stick well?

If the patch does not stick well, you may use surgical bandages or medical adhesive tape to keep the patch in place. Place tape or bandages on the edges of the patch. Do not completely cover the patch with bandages or tape and do not wrap completely around your arm. If the patch comes more than half off or it becomes damaged see your healthcare provider.

Can I bathe or shower while wearing Zetron?

You can continue to shower and wash normally while wearing the Zetron patch. It is not known how other activities, for example swimming, strenuous exercise or using a sauna or whirlpool, may affect Zetron. Avoid these activities while wearing Zetron.

How do I remove and dispose of Zetron?

• When you remove the patch, peel it off gently.
• The used patch will still contain some of the medicine. After removing the used Zetron patch, fold it in half so that the sticky side sticks to itself. Throw away the Zetron patch in the garbage, out of the reach of children and pets. Do not re-use the patch.
• After removing the patch you may find some adhesive is left on your skin. Gently wash the area with soap and water to remove it. Do not use alcohol or other dissolving liquids, such as nail polish remover. These may cause skin irritation.
• Wash your hands after handling the patch.
• You may see mild redness on the skin where the patch is removed. This redness should go away within three days. If redness continues, tell your healthcare provider.

What are the ingredients in Zetron?

Active ingredient: Zetron.

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

Manufactured by:

3M Drug Delivery Systems, St. Paul, MN 55107

Manufactured for:

Kyowa Kirin, Inc., Bedminster, NJ 07921

Copyright © 2017 Kyowa Kirin, Inc. All rights reserved.

Zetron and Kyowa Kirin are trademarks owned by the Kyowa Kirin group of companies

Revised: 09/2017

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Zetron pharmaceutical active ingredients containing related brand and generic drugs:

• Granisetron

Zetron available forms, composition, doses:

• Injectable; Injection; Granisetron 1 mg / ml
• Tablets; Oral; Granisetron 1 mg

Zetron destination | category:

• Human:
• 5-HT3 Receptor Antagonists
• Antiemetics
• Supportive care therapy

Zetron Anatomical Therapeutic Chemical codes:

• A04AA02 - Granisetron

Zetron pharmaceutical companies:

• Zodak

References

1. Dailymed."SANCUSO (GRANISETRON) PATCH [KYOWA KIRIN, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."GRANISETRON: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "granisetron". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Zetron after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Zetron not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology