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DRUGS & SUPPLEMENTS
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Kevatril
How often in a day do you take medicine? How many times? |
Kevatril 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
1 INDICATIONS AND USAGE
Kevatril® (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.
Kevatril 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. Kevatril 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
Kevatril is a 52 cm2 patch containing 34.3 mg of Kevatril. The patch releases 3.1 mg of Kevatril per 24 hours for up to 7 days.
Transdermal System: 52 cm2 patch containing 34.3 mg of Kevatril delivering 3.1 mg per 24 hours (3)
4 CONTRAINDICATIONS
Kevatril is contraindicated in patients with known hypersensitivity to Kevatril or to any of the components of the patch.
Known hypersensitivity to Kevatril or to any of the components of the patch (4)
5 WARNINGS AND PRECAUTIONS
- Kevatril 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 Kevatril 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 Kevatril 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 Kevatril and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Kevatril and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Kevatril is used concomitantly with other serotonergic drugs. .
5.3 Skin Reactions
In clinical trials with Kevatril, 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 Kevatril patch. Patients should avoid prolonged exposure to heat as plasma concentration continues increasing during the period of heat exposure .
5.5 Exposure to Sunlight
Kevatril 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 Kevatril 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 Kevatril, for 1 to 5 days.
Adverse reactions occurred in 8.7% (35/404) of patients receiving Kevatril and 7.1% (29/406) of patients receiving oral Kevatril. The most common adverse reaction was constipation that occurred in 5.4% of patients in the Kevatril group and 3.0% of patients in the oral Kevatril group.
Table 1 lists the adverse reactions that occurred in at least 3% of patients treated with Kevatril or oral Kevatril.
| Body System Preferred Term | Kevatril TDS N=404 (%) | Oral Kevatril N=406 (%) |
|---|---|---|
| Gastrointestinal disorders | ||
| Constipation | 5.4 | 3.0 |
| Nervous system disorders | ||
| Headache | 0.7 | 3.0 |
5-HT3 receptor antagonists, such as Kevatril, 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 Kevatril, 8 (2.7%) on oral Kevatril, 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 Kevatril 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 Kevatril. 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
Kevatril 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, Kevatril hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Kevatril 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 Kevatril.
Because Kevatril 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 Kevatril. 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 Kevatril hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of Kevatril 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 Kevatril 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 Kevatril. (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 Kevatril 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 Kevatril 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 Kevatril 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 Kevatril 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 Kevatril 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 Kevatril based on body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to Kevatril. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Kevatril should be used during pregnancy only if clearly needed.
8.3 Nursing Mothers
It is not known whether Kevatril is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Kevatril is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of Kevatril have not been established in pediatric patients.
8.5 Geriatric Use
Clinical studies of Kevatril 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 Kevatril in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous Kevatril .
10 OVERDOSAGE
There is no specific antidote for Kevatril overdosage. In the case of overdosage, symptomatic treatment should be given.
Overdosage of up to 38.5 mg of Kevatril 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 Kevatril.
11 DESCRIPTION
Kevatril contains Kevatril, 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:
| Kevatril |
Kevatril is a white to off-white solid that is insoluble in water. Kevatril 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Kevatril is a selective 5-hydroxytryptamine3 receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1, 5-HT1A, 5-HT1B/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, Kevatril blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single Kevatril injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.
12.2 Pharmacodynamics
The effect of Kevatril 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 Kevatril patch (n=60) or intravenous Kevatril (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 Kevatril was below 10 ms. This study suggests that Kevatril 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 Kevatril.
The effect on oro-cecal transit time following application of Kevatril has not been studied. Kevatril 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 Kevatril hydrochloride slowed colonic transit in healthy subjects.
12.3 Pharmacokinetics
Absorption
Kevatril crosses intact skin into the systemic circulation by a passive diffusion process.
Following a 7-day application of Kevatril 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 Kevatril (mean ± SD) |
Based on the measure of residual content of the patch after removal, approximately 66% (SD: ± 10.9) of Kevatril is delivered following patch application for 7 days.
Following consecutive application of two Kevatril patches, each for seven days, Kevatril 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 Kevatril 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 Kevatril from Kevatril 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 Kevatril 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 Kevatril patch.
Image
Distribution
Plasma protein binding is approximately 65%. Kevatril distributes freely between plasma and red blood cells.
Metabolism
Kevatril 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 Kevatril 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 Kevatril in pediatrics.
Elderly
Following application of Kevatril patch in healthy subjects, mean AUC0-z, Cmax, and Cavg 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 Kevatril 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 Kevatril was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of Kevatril 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 Kevatril hydrochloride was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of Kevatril 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 Kevatril exposure from Kevatril 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 Kevatril 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 Kevatril from Kevatril was assessed in healthy Japanese males. Following the application of a single 6-day Kevatril 52 cm2, in healthy male Japanese subjects, mean Cmax, 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 tmax 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 Kevatril 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 Kevatril 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 Kevatril, 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 Kevatril, 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 Kevatril, 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 Kevatril, on a body surface area basis) in females.
In a 12-month oral toxicity study, treatment with Kevatril 100 mg/kg/day (600 mg/m2/day, about 261 times the recommended human dose with Kevatril, 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 Kevatril did not show a statistically significant increase in tumor incidence, but the study was not conclusive.
Because of the tumor findings in rat studies, Kevatril should be prescribed only at the dose and for the indication recommended .
Kevatril 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.
Kevatril at subcutaneous doses up to 6 mg/kg/day (36 mg/m2/day, about 16 times the recommended human dose of Kevatril, 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 Kevatril, 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, Kevatril increased the percentage of cells with chromosomal aberration following photoirradiation.
Kevatril was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested in vivo in guinea-pigs, Kevatril patches did not show any potential for photoirritation or photosensitivity. No phototoxicity studies have been performed in humans.
14 CLINICAL STUDIES
The effectiveness of Kevatril 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 Kevatril with that of 2 mg oral Kevatril 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 Kevatril patch was applied 24 to 48 hours before the first dose of chemotherapy, and kept in place for 7 days. Oral Kevatril 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 Kevatril was established in 60.2% of patients in the Kevatril arm and 64.8% of patients receiving oral Kevatril (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
Kevatril (Granisetron Transdermal System) is supplied as a 52 cm2 patch containing 34.3 mg of Kevatril. 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.
Kevatril 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)..
Kevatril 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 Kevatril 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
Kevatril may be degraded by direct sunlight or exposure to sunlamps. In addition, an in vitro study using Chinese hamster ovary cells suggests that Kevatril 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 Kevatril 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 Kevatril 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.
Kevatril and Kyowa Kirin are trademarks owned by the Kyowa Kirin group of companies
Patient Information
Kevatril® [san-KOO-so]
(granisetron transdermal system)
| IMPORTANT: For skin use only |
Read the Patient Information that comes with Kevatril 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 Kevatril, ask your healthcare provider.
What is Kevatril?
Kevatril is a prescription medicine used to prevent nausea and vomiting in people receiving some types of chemotherapy treatment. Kevatril 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.
| Important: Kevatril contains Kevatril, the same medicine in Kytril. Do not take Kytril at the same time you use Kevatril unless your healthcare provider tells you it is alright. |
Who should not use Kevatril?
Do not use Kevatril if you are allergic to any of the ingredients in Kevatril. See the end of this leaflet for a list of ingredients in Kevatril.
What should I tell my healthcare provider before using Kevatril?
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 Kevatril 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 Kevatril 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 Kevatril works. Kevatril may also affect how other medicines work.
How should Kevatril be used?
Use Kevatril exactly as prescribed. See the detailed Patient Instructions for Applying Kevatril at the end of this Patient Information leaflet.
What should I avoid while using Kevatril?
Do not apply any heat source over or near the Kevatril 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 Kevatril (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 Kevatril 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 Kevatril?
Kevatril can cause serious side effects:
- Using Kevatril 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 Kevatril.
- 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 Kevatril.
Common side effects of Kevatril 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 Kevatril. 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 Kevatril?
- Keep Kevatril in the package it comes in.
- Store Kevatril at 20-25°C (68-77°F).
Keep Kevatril out of the reach of children.
General information about Kevatril
Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use Kevatril for a condition for which it is not prescribed. Do not give Kevatril 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 Kevatril. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about Kevatril that is written for health professionals.
For more information, go to www.sancuso.com or call 1-800-SANCUSO.
Patient Instructions for Applying Kevatril
When do I apply the Kevatril patch?
- Apply Kevatril at least 1 day (24 hours) before your scheduled chemotherapy treatment.
- You may apply Kevatril up to 2 days (48 hours) before your scheduled chemotherapy.
- Wear the patch all the time during your chemotherapy.
- Kevatril 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 Kevatril 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 Kevatril?"
Where do I apply the Kevatril patch?
- Apply Kevatril 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 Kevatril 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 Kevatril patch?
The Kevatril 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 Kevatril 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 Kevatril 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 Kevatril 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 Kevatril?
You can continue to shower and wash normally while wearing the Kevatril patch. It is not known how other activities, for example swimming, strenuous exercise or using a sauna or whirlpool, may affect Kevatril. Avoid these activities while wearing Kevatril.
How do I remove and dispose of Kevatril?
- When you remove the patch, peel it off gently.
- The used patch will still contain some of the medicine. After removing the used Kevatril patch, fold it in half so that the sticky side sticks to itself. Throw away the Kevatril 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 Kevatril?
Active ingredient: Kevatril.
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.
Kevatril and Kyowa Kirin are trademarks owned by the Kyowa Kirin group of companies
Revised: 09/2017
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Kevatril pharmaceutical active ingredients containing related brand and generic drugs:
Kevatril available forms, composition, doses:
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.