Componenti:
Metodo di azione:
Opzione di trattamento:
Revisione medica di Kovalenko Svetlana Olegovna, Pharmacy Ultimo aggiornamento in data 01.04.2022
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Primi 20 medicinali con gli stessi componenti:
Kyotil (granisetron hydrochloride) è indicato per la prevenzione di :
- Nausea e vomito associati a cicli iniziali e ripetuti di terapia del cancro emetogenico, incluso cisplatino ad alte dosi.
- Nausea e vomito associati a radiazioni, compresa l'irradiazione totale del corpo e le radiazioni addominali frazionate.
Kyotil® (Granisetron Transdermal System) è indicato per la prevenzione della nausea e del vomito in pazienti che ricevono regimi chemioterapici moderatamente e / o altamente emetogenici della durata massima di 5 giorni consecutivi.
Sancuso® (Granisetron Transdermal System) è indicato per la prevenzione della nausea e del vomito in pazienti che ricevono regimi chemioterapici moderatamente e / o altamente emetogenici della durata massima di 5 giorni consecutivi.
Chemioterapia emetogenica
Il dosaggio raccomandato per adulto di Kyotil orale (granisetron cloridrato) è di 2 mg una volta al giorno o 1 mg due volte al giorno. Nel regime una volta al giorno di 2 mg, due compresse da 1 mg o 10 ml di soluzione orale di Kyotil (granisetron) (2 cucchiaini da tè, equivalenti a 2 mg di granisetron) vengono somministrate fino a 1 ora prima della chemioterapia. Nel regime di 1 mg due volte al giorno, la prima compressa da 1 mg o una cucchiaino (5 ml) di soluzione orale di Kyotil (granisetron) viene somministrata fino a 1 ora prima della chemioterapia e la seconda compressa o la seconda cucchiaino (5 ml) di Kyotil (granisetron) Soluzione orale, 12 ore dopo la prima. Entrambi i regimi vengono somministrati solo il giorno o i giorni in cui viene somministrata la chemioterapia. Il trattamento continuato, sebbene non in chemioterapia, non è risultato utile.
Uso nei pazienti anziani, con insufficienza renale o con compromissione epatica
Non è raccomandato alcun aggiustamento del dosaggio (vedere FARMACOLOGIA CLINICA: Farmacocinetica).
Uso pediatrico
La sicurezza e l'efficacia nei pazienti pediatrici non sono state stabilite.
Radiazione (irradiazione totale del corpo o radiazione addominale frazionata)
Il dosaggio raccomandato per adulti di Kyotil orale (granisetron) è di 2 mg una volta al giorno. Due compresse da 1 mg o 10 ml di soluzione orale di Kyotil (granisetron) (2 cucchiaini da tè, equivalenti a 2 mg di granisetron) vengono assunte entro 1 ora dalla radiazione.
Uso pediatrico
La sicurezza e l'efficacia nei pazienti pediatrici non sono state stabilite.
Usa negli anziani
Non è raccomandato alcun aggiustamento del dosaggio.
Il sistema transdermico (batch) deve essere applicato su una pelle sana, asciutta e intatta nella parte superiore del braccio esterno. Kyotil non deve essere posizionato su una pelle rossa, irritata o danneggiata.
Ogni patch è confezionata in una custodia e deve essere applicata direttamente dopo l'apertura della custodia.
La patch non deve essere tagliata a pezzi.
Adulti
Applicare una singola patch sulla parte superiore del braccio esterno almeno 24 ore prima della chemioterapia. Il cerotto può essere applicato fino a un massimo di 48 ore prima della chemioterapia, a seconda dei casi. Rimuovere il cerotto almeno 24 ore dopo il completamento della chemioterapia. Il cerotto può essere indossato per un massimo di 7 giorni a seconda della durata del regime di chemioterapia.
Il sistema transdermico (batch) deve essere applicato su una pelle sana, asciutta e intatta nella parte superiore del braccio esterno. Sancuso non deve essere posizionato su una pelle rossa, irritata o danneggiata.
Ogni patch è confezionata in una custodia e deve essere applicata direttamente dopo l'apertura della custodia.
La patch non deve essere tagliata a pezzi.
Adulti
Applicare una singola patch sulla parte superiore del braccio esterno almeno 24 ore prima della chemioterapia. Il cerotto può essere applicato fino a un massimo di 48 ore prima della chemioterapia, a seconda dei casi. Rimuovere il cerotto almeno 24 ore dopo il completamento della chemioterapia. Il cerotto può essere indossato per un massimo di 7 giorni a seconda della durata del regime di chemioterapia.
Kyotil (granisetron) è controindicato nei pazienti con nota ipersensibilità al farmaco o ad uno qualsiasi dei suoi componenti.
Kyotil è controindicato nei pazienti con nota ipersensibilità al granisetron o ad uno qualsiasi dei componenti del cerotto.
Sancuso è controindicato nei pazienti con nota ipersensibilità al granisetron o ad uno qualsiasi dei componenti del cerotto.
WARNINGS
No information provided.
PRECAUTIONS
Kyotil (granisetron) is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Kyotil (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 Kyotil (granisetron). Therefore, Kyotil (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, Kyotil (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 Kyotil (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 Kyotil (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 Kyotil and other serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Kyotil and initiate supportive treatment. Patients should be informed of the increased risk of serotonin syndrome, especially if Kyotil is used concomitantly with other serotonergic drugs..
Skin Reactions
In clinical trials with Kyotil, 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 Kyotil 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 Kyotil 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 Kyotil 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 Kyotil 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 Kyotil, 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 Kyotil, 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 Kyotil, 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 Kyotil, 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 Kyotil, 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, Kyotil 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 Kyotil, 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 Kyotil, 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, Kyotil 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 Kyotil 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 Kyotil 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 Kyotil 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 Kyotil 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, Kyotil 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 Kyotil is administered to a nursing woman.
Pediatric Use
Safety and effectiveness of Kyotil have not been established in pediatric patients.
Geriatric Use
Clinical studies of Kyotil 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 Kyotil 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.
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.
Il prolungamento dell'intervallo QT è stato riportato con Kyotil (vedi PRECAUZIONI e INTERAZIONI DI FARMACI).
Nausea e vomito indotti dalla chemioterapia
Oltre 3700 pazienti hanno ricevuto compresse di Kyotil (granisetron) in studi clinici con terapie per il cancro emetogenico costituite principalmente da regimi di ciclofosfamide o cisplatino.
Nei pazienti che ricevono Kyotil (granisetron) le compresse da 1 mg fanno un'offerta per 1, 7 o 14 giorni o 2 mg al giorno per 1 giorno, sono elencate le esperienze avverse riportate in oltre il 5% dei pazienti con incidenze comparative e placebo Tabella 4.
Tabella 4 Principali eventi avversi negli studi clinici1
Percentuale di pazienti con evento | ||||
Kyotil (granisetron) 1 Compresse 1 mg due volte al giorno (N = 978) | Kyotil (granisetron) 1 Compresse 2 mg una volta al giorno (N = 1450) | Comparatore2 (N = 599) | Placebo (N = 185) | |
Mal di testa3 | 21% | 20% | 13% | 12% |
Costipazione | 18% | 14% | 16% | 8% |
Astenia | 14% | 18% | 10% | 4% |
Diarrea | 8% | 9% | 10% | 4% |
Dolore addominale | 6% | 4% | 6% | 3% |
Dispepsia | 4% | 6% | 5% | 4% |
1 Gli eventi avversi sono stati registrati per 7 giorni quando le compresse di Kyotil (granisetron) sono state somministrate in un solo giorno e per un massimo di 28 giorni quando le compresse di Kyotil (granisetron) sono state somministrate per 7 o 14 giorni. 2 Metoclopramide / desametasone; fenotiazine / desametasone; solo desametasone; proclorperazina. |
Altri eventi avversi riportati negli studi clinici sono stati:
Gastrointestinale: Negli studi di dosaggio di un giorno in cui sono stati raccolti eventi avversi per 7 giorni, la nausea (20%) e il vomito (12%) sono stati registrati come eventi avversi dopo il periodo di valutazione dell'efficacia di 24 ore.
Epatico: Negli studi comparativi, l'elevazione di AST e ALT (> 2 volte il limite superiore della norma) a seguito della somministrazione di Kyotil (granisetron) Le compresse si sono verificate rispettivamente nel 5% e nel 6% dei pazienti. Queste frequenze non erano significativamente diverse da quelle osservate con i comparatori (AST: 2%; ALT: 9%).
Cardiovascolare: Ipertensione (1%); ipotensione, angina pectoris, fibrillazione atriale e sincope sono state osservate raramente.
Sistema nervoso centrale: Capogiri (5%), insonnia (5%), ansia (2%), sonnolenza (1%). Un caso compatibile con, ma non diagnostico, i sintomi extrapiramidali è stato riportato in un paziente trattato con compresse di Kyotil (granisetron).
Ipersensibilità: Sono stati segnalati rari casi di reazioni di ipersensibilità, a volte gravi (ad es. Anafilassi, mancanza di respiro, ipotensione, orticaria).
Altro: Febbre (5%). Sono stati anche segnalati eventi spesso associati alla chemioterapia: leucopenia (9%), riduzione dell'appetito (6%), anemia (4%), alopecia (3%), trombocitopenia (2%).
Oltre 5000 pazienti hanno ricevuto Kyotil iniettabile (granisetron) negli studi clinici.
Tabella 5 fornisce le frequenze comparative dei cinque eventi avversi comunemente riportati (≥ 3%) nei pazienti che ricevono iniezione di Kyotil (granisetron), 40 mcg / kg, in studi di chemioterapia di un giorno. Questi pazienti hanno ricevuto chemioterapia, principalmente cisplatino e fluidi per via endovenosa durante il periodo di 24 ore successivo alla somministrazione di iniezione di Kyotil (granisetron).
Tabella 5: principali eventi avversi negli studi clinici - Chemioterapia per un giorno
Percentuale di pazienti con evento | ||
Iniezione di Kyotil (granisetron)1 40 mcg / kg (N = 1268) | Comparatore2 (N = 422) | |
Mal di testa | 14% | 6% |
Astenia | 5% | 6% |
Sonnolenza | 4% | 15% |
Diarrea | 4% | 6% |
Costipazione | 3% | 3% |
1 Gli eventi avversi sono stati generalmente registrati per 7 giorni dopo la somministrazione di iniezione di Kyoto (granisetron). 2 Metoclopramide / desametasone e fenotiazine / desametasone |
In assenza di un gruppo placebo, vi è incertezza su quanti di questi eventi debbano essere attribuiti a Kyotil (granisetron), ad eccezione del mal di testa, che era chiaramente più frequente rispetto ai gruppi di confronto.
Nausea e vomito indotti dalle radiazioni
Negli studi clinici controllati, gli eventi avversi riportati dai pazienti che hanno ricevuto compresse di Kyotil (granisetron) e radiazioni concomitanti erano simili a quelli riportati dai pazienti che hanno ricevuto compresse di Kyotil (granisetron) prima della chemioterapia. Gli eventi avversi più frequentemente riportati sono stati diarrea, astenia e costipazione. Il mal di testa, tuttavia, era meno diffuso in questa popolazione di pazienti.
Esperienza post-marketing
Il prolungamento dell'intervallo QT è stato riportato con Kyotil (vedi PRECAUZIONI e INTERAZIONI DI FARMACI).
Esperienza di studi clinici
Poiché gli studi clinici sono condotti in condizioni molto diverse, i tassi di reazione avversa osservati negli studi clinici di un farmaco non possono essere confrontati direttamente con i tassi negli studi clinici di un altro farmaco e potrebbero non riflettere i tassi osservati nella pratica clinica.
La sicurezza di Kyotil è stata valutata in un totale di 404 pazienti sottoposti a chemioterapia che hanno partecipato a due studi di confronto in doppio cieco con durata del trattamento del cerotto fino a 7 giorni. I gruppi di controllo includevano un totale di 406 pazienti che hanno ricevuto una dose giornaliera di 2 mg di granisetron orale, per 1-5 giorni.
Le reazioni avverse si sono verificate nell'8,7% (35/404) dei pazienti trattati con Kyotil e nel 7,1% (29/406) dei pazienti trattati con granisetron orale. La reazione avversa più comune è stata la costipazione verificatasi nel 5,4% dei pazienti nel gruppo Kyotil e nel 3,0% dei pazienti nel gruppo granisetron orale.
La tabella 1 elenca le reazioni avverse verificatesi in almeno il 3% dei pazienti trattati con Kyotil o granisetron orale.
Tabella 1: Incidenza di reazioni avverse in studi controllati su doppio cieco e comparatore attivo in pazienti con cancro che ricevono chemioterapia (eventi ≥ 3% in entrambi i gruppi)
Termine preferito dal sistema corporeo | Kyotil TDS N = 404 (%) | Granisetron orale N = 406 (%) |
Disturbi gastrointestinali | ||
Costipazione | 5.4 | 3.0 |
Disturbi del sistema nervoso | ||
Mal di testa | 0.7 | 3.0 |
Gli antagonisti del recettore 5-HT3, come il granisetron, possono essere associati ad aritmie o anomalie ECG. Sono stati eseguiti tre ECG su 588 pazienti in uno studio randomizzato, in parallelo, in doppio cieco, in doppio manichino: al basale prima del trattamento, il primo giorno di chemioterapia e 5-7 giorni dopo l'inizio della chemioterapia. È stato osservato un prolungamento del QTcF superiore a 450 millisecondi in un totale di 11 (1,9%) pazienti dopo aver ricevuto granisetron, 8 (2,7%) su granisetron orale e 3 (1,1%) sul cerotto. In questo studio non è stato osservato alcun nuovo prolungamento del QTcF superiore a 480 millisecondi in nessun paziente. In questo studio non sono state rilevate aritmie.
Le reazioni avverse riportate negli studi clinici con altre formulazioni di granisetron includono quanto segue:
Gastrointestinale : dolore addominale, diarrea, costipazione, aumento dei livelli di ALT e AST, nausea e vomito
Cardiovascolare: Ipertensione, ipotensione, angina pectoris, fibrillazione atriale e sincope sono state osservate raramente
Sistema nervoso centrale : vertigini, insonnia, mal di testa, ansia, sonnolenza e astenia
Ipersensibilità: rari casi di reazioni di ipersensibilità, a volte gravi (ad es. sono stati segnalati anafilassi, mancanza di respiro, ipotensione, orticaria)
Altro: febbre; sono stati segnalati anche eventi spesso associati alla chemioterapia: leucopenia, riduzione dell'appetito, anemia, alopecia, trombocitopenia.
Esperienza post-marketing
Le seguenti reazioni avverse sono state identificate durante l'uso post-approvazione di Kyotil. Poiché queste reazioni sono riportate volontariamente da una popolazione di dimensioni incerte, non è sempre possibile stimare in modo affidabile la loro frequenza o stabilire una relazione causale con l'esposizione al farmaco.
Patologie sistemiche e condizioni relative al sito di amministrazione : Reazioni al sito di applicazione (dolore, prurito, eritema, eruzione cutanea, irritazione, vescicole, ustioni, scolorimento, orticaria); cerotto non aderente)
Disturbi cardiaci : bradicardia, dolore toracico, palpitazioni, sindrome del seno malato
Esperienza di studi clinici
Poiché gli studi clinici sono condotti in condizioni molto diverse, i tassi di reazione avversa osservati negli studi clinici di un farmaco non possono essere confrontati direttamente con i tassi negli studi clinici di un altro farmaco e potrebbero non riflettere i tassi osservati nella pratica clinica.
La sicurezza di Sancuso è stata valutata in un totale di 404 pazienti sottoposti a chemioterapia che hanno partecipato a due studi in doppio cieco e comparatore con durate del trattamento del cerotto fino a 7 giorni. I gruppi di controllo includevano un totale di 406 pazienti che hanno ricevuto una dose giornaliera di 2 mg di granisetron orale, per 1-5 giorni.
Le reazioni avverse si sono verificate nell'8,7% (35/404) dei pazienti trattati con Sancuso e nel 7,1% (29/406) dei pazienti trattati con granisetron orale. La reazione avversa più comune è stata la costipazione verificatasi nel 5,4% dei pazienti nel gruppo Sancuso e nel 3,0% dei pazienti nel gruppo granisetron orale.
La tabella 1 elenca le reazioni avverse verificatesi in almeno il 3% dei pazienti trattati con Sancuso o granisetron orale.
Tabella 1: Incidenza di reazioni avverse in studi controllati su doppio cieco e comparatore attivo in pazienti con cancro che ricevono chemioterapia (eventi ≥ 3% in entrambi i gruppi)
Termine preferito dal sistema corporeo | Sancuso TDS N = 404 (%) | Granisetron orale N = 406 (%) |
Disturbi gastrointestinali | ||
Costipazione | 5.4 | 3.0 |
Disturbi del sistema nervoso | ||
Mal di testa | 0.7 | 3.0 |
Gli antagonisti del recettore 5-HT3, come il granisetron, possono essere associati ad aritmie o anomalie ECG. Sono stati eseguiti tre ECG su 588 pazienti in uno studio randomizzato, in parallelo, in doppio cieco, in doppio manichino: al basale prima del trattamento, il primo giorno di chemioterapia e 5-7 giorni dopo l'inizio della chemioterapia. È stato osservato un prolungamento del QTcF superiore a 450 millisecondi in un totale di 11 (1,9%) pazienti dopo aver ricevuto granisetron, 8 (2,7%) su granisetron orale e 3 (1,1%) sul cerotto. In questo studio non è stato osservato alcun nuovo prolungamento del QTcF superiore a 480 millisecondi in nessun paziente. In questo studio non sono state rilevate aritmie.
Le reazioni avverse riportate negli studi clinici con altre formulazioni di granisetron includono quanto segue:
Gastrointestinale : dolore addominale, diarrea, costipazione, aumento dei livelli di ALT e AST, nausea e vomito
Cardiovascolare: Ipertensione, ipotensione, angina pectoris, fibrillazione atriale e sincope sono state osservate raramente
Sistema nervoso centrale : vertigini, insonnia, mal di testa, ansia, sonnolenza e astenia
Ipersensibilità: rari casi di reazioni di ipersensibilità, a volte gravi (ad es. sono stati segnalati anafilassi, mancanza di respiro, ipotensione, orticaria)
Altro: febbre; sono stati segnalati anche eventi spesso associati alla chemioterapia: leucopenia, riduzione dell'appetito, anemia, alopecia, trombocitopenia.
Esperienza post-marketing
Le seguenti reazioni avverse sono state identificate durante l'uso post-approvazione di Sancuso. Poiché queste reazioni sono riportate volontariamente da una popolazione di dimensioni incerte, non è sempre possibile stimare in modo affidabile la loro frequenza o stabilire una relazione causale con l'esposizione al farmaco.
Patologie sistemiche e condizioni relative al sito di amministrazione : Reazioni al sito di applicazione (dolore, prurito, eritema, eruzione cutanea, irritazione, vescicole, ustioni, scolorimento, orticaria); cerotto non aderente)
Disturbi cardiaci : bradicardia, dolore toracico, palpitazioni, sindrome del seno malato
Non esiste un trattamento specifico per il sovradosaggio di granisetron cloridrato. In caso di sovradosaggio, deve essere somministrato un trattamento sintomatico. È stato riportato un sovradosaggio fino a 38,5 mg di iniezione di granisetron cloridrato senza sintomi o solo l'insorgenza di un leggero mal di testa.
Non esiste un antidoto specifico per il sovradosaggio di granisetron. In caso di sovradosaggio, deve essere somministrato un trattamento sintomatico.
È stato riportato un sovradosaggio fino a 38,5 mg di granisetron cloridrato, come singola iniezione endovenosa, senza sintomi o solo il verificarsi di un leggero mal di testa.
Negli studi clinici non sono stati segnalati casi di sovradosaggio con Kyotil.
Non esiste un antidoto specifico per il sovradosaggio di granisetron. In caso di sovradosaggio, deve essere somministrato un trattamento sintomatico.
È stato riportato un sovradosaggio fino a 38,5 mg di granisetron cloridrato, come singola iniezione endovenosa, senza sintomi o solo il verificarsi di un leggero mal di testa.
Negli studi clinici non sono stati segnalati casi di sovradosaggio con Sancuso.
L'effetto del granisetron sul prolungamento dell'intervallo QTc è stato valutato in uno studio parallelo randomizzato, in singolo cieco, positivo (moxifloxacina 400 mg) e controllato con placebo su soggetti sani. A 120 soggetti sono stati somministrati cerotto Kyotil (n = 60) o granisetron per via endovenosa (10 mcg / kg per 30 secondi; n = 60). In uno studio con capacità dimostrata di rilevare piccoli effetti, il limite superiore dell'intervallo di confidenza al 90% per il QTc corretto per il placebo più grande, corretto al basale in base al metodo di correzione Fridericia (QTcF) per Kyotil era inferiore a 10 ms. Questo studio suggerisce che Kyotil non ha effetti significativi sul prolungamento dell'intervallo QT.
Nessuna evidenza di un effetto sulla prolattina plasmatica o sulle concentrazioni di aldosterone è stata trovata in studi su granisetron.
L'effetto sul tempo di transito oro-cecale a seguito dell'applicazione di Kyotil non è stato studiato. L'iniezione di granisetron cloridrato non ha mostrato alcun effetto sul tempo di transito oro-cecale in soggetti sani trattati con una singola infusione endovenosa di 50 mcg / kg o 200 mcg / kg. Dosi orali singole e multiple di granisetron cloridrato hanno rallentato il transito del colon in soggetti sani.
L'effetto del granisetron sul prolungamento dell'intervallo QTc è stato valutato in uno studio parallelo randomizzato, in singolo cieco, positivo (moxifloxacina 400 mg) e controllato con placebo su soggetti sani. A un totale di 120 soggetti è stato somministrato il cerotto Sancuso (n = 60) o il granisetron per via endovenosa (10 mcg / kg per 30 secondi; n = 60). In uno studio con capacità dimostrata di rilevare piccoli effetti, il limite superiore dell'intervallo di confidenza al 90% per il QTc corretto per il placebo più grande, corretto al basale in base al metodo di correzione Fridericia (QTcF) per Sancuso era inferiore a 10 ms. Questo studio suggerisce che Sancuso non ha effetti significativi sul prolungamento dell'intervallo QT.
Nessuna evidenza di un effetto sulla prolattina plasmatica o sulle concentrazioni di aldosterone è stata trovata in studi su granisetron.
L'effetto sul tempo di transito oro-cecale a seguito dell'applicazione di Sancuso non è stato studiato. L'iniezione di granisetron cloridrato non ha mostrato alcun effetto sul tempo di transito oro-cecale in soggetti sani trattati con una singola infusione endovenosa di 50 mcg / kg o 200 mcg / kg. Dosi orali singole e multiple di granisetron cloridrato hanno rallentato il transito del colon in soggetti sani.
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 Kyotil (granisetron) is 2 mg once daily. Two 1 mg tablets or 10 mL of Kyotil (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 & Drug InteractionsSIDE EFFECTS
QT prolongation has been reported with Kyotil (see PRECAUTIONS and DRUG INTERACTIONS).
Chemotherapy-Induced Nausea and Vomiting
Over 3700 patients have received Kyotil (granisetron) Tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens.
In patients receiving Kyotil (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
Percent of Patients With Event | ||||
Kyotil (granisetron) 1 Tablets 1 mg twice a day (n=978) | Kyotil (granisetron) 1 Tablets 2 mg once a day (n=1450) | Comparator2 (n=599) | Placebo (n=185) | |
Headache3 | 21% | 20% | 13% | 12% |
Constipation | 18% | 14% | 16% | 8% |
Asthenia | 14% | 18% | 10% | 4% |
Diarrhea | 8% | 9% | 10% | 4% |
Abdominal pain | 6% | 4% | 6% | 3% |
Dyspepsia | 4% | 6% | 5% | 4% |
1 Adverse events were recorded for 7 days when Kyotil (granisetron) Tablets were given on a single day and for up to 28 days when Kyotil (granisetron) Tablets were administered for 7 or 14 days. 2 Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine. |
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 Kyotil (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 Kyotil (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 Kyotil (granisetron) in clinical trials.
Table 5 gives the comparative frequencies of the five commonly reported adverse events ( ≥ 3%) in patients receiving Kyotil (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 Kyotil (granisetron) Injection administration.
Table 5 : Principal Adverse Events in Clinical Trials — Single-Day Chemotherapy
Percent of Patients with Event | ||
Kyotil (granisetron) Injection1 40 mcg/kg (n=1268) | Comparator2 (n=422) | |
Headache | 14% | 6% |
Asthenia | 5% | 6% |
Somnolence | 4% | 15% |
Diarrhea | 4% | 6% |
Constipation | 3% | 3% |
1 Adverse events were generally recorded over 7 days post-Kyotil (granisetron) Injection administration. 2 Metoclopramide/dexamethasone and phenothiazines/dexamethasone |
In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to Kyotil (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 Kyotil (granisetron) Tablets and concurrent radiation were similar to those reported by patients receiving Kyotil (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 Kyotil (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, Kyotil (granisetron) Injection has been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with antiemetic treatments. Kyotil (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 Kyotil (granisetron) in vitro.
In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of Kyotil (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 Kyotil (granisetron). The clinical significance of this change is not known.
QT prolongation has been reported with Kyotil (granisetron). Use of Kyotil (granisetron) in patients concurrently treated with drugs known to prolong the QT interval and/or are arrhythmogenic, this may result in clinical consequences.
Warnings & PrecautionsWARNINGS
No information provided.
PRECAUTIONS
Kyotil (granisetron) is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Kyotil (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 Kyotil (granisetron). Therefore, Kyotil (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, Kyotil (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 Kyotil (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 Kyotil (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.
Overdosage & ContraindicationsOVERDOSE
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
Kyotil (granisetron) is contraindicated in patients with known hypersensitivity to the drug or any of its components.
Clinical PharmacologyCLINICAL PHARMACOLOGY
Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) 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, 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, Kyotil (granisetron) Tablets slowed colonic transit in normal volunteers. However, Kyotil (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 Kyotil (granisetron) Tablets produced mean pharmacokinetic data shown in Table 1.
Table 1 : Pharmacokinetic Parameters (Median [range]) Following Kyotil Tablets (granisetron hydrochloride)
Peak Plasma Concentration (ng/mL) | Terminal Phase Plasma Half-Life (h) | Volume of Distribution (L/kg) | Total Clearance (L/h/kg) | |
Cancer Patients 1 mg bid, 7 days (n=27) | 5.99 [0.63 to 30.9] | N.D.1 | N.D. | 0.52 [0.09 to 7.37] |
Volunteers single 1 mg dose (n=39) | 3.63 [0.27 to 9.14] | 6.23 [0.96 to 19.9] | 3.94 [1.89 to 39.4] | 0.41 [0.11 to 24.6] |
1 Not determined after oral administration; following a single intravenous dose of 40 mcg/kg, terminal phase half-life was determined to be 8.95 hours. N.D. Not determined. |
A 2 mg dose of Kyotil (granisetron) Oral Solution is bioequivalent to the corresponding dose of Kyotil (granisetron) Tablets (1 mg x 2) and may be used interchangeably.
Absorption
When Kyotil (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 Kyotil (granisetron) Tablets have not been studied. However, after intravenous infusion of Kyotil (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 Kyotil (granisetron).
Elderly
The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of Kyotil (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 Kyotil (granisetron) Injection.
Hepatically Impaired Patients
A pharmacokinetic study with intravenous Kyotil (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 Kyotil (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
Kyotil (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 Kyotil (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 PostÂChemotherapy1
Percentages of Patients Kyotil Tablet Dose | ||||
Efficacy Measures | 0.25 mg twice a day (n=229) % | 0.5 mg twice a day (n=235) % | 1 mg twice a day (n=233) % | 2 mg twice a day (n=233) % |
Complete Response2 | 61 | 70* | 81*† | 72* |
No Vomiting | 66 | 77* | 88* | 79* |
No Nausea | 48 | 57 | 63* | 54 |
1 Chemotherapy included oral and injectable cyclophosphamide, carboplatin, cisplatin (20 mg/m² to 50 mg/m²), dacarbazine, doxorubicin, epirubicin. 2 No vomiting, no moderate or severe nausea, no rescue medication. *Statistically significant (P < 0.01) vs. 0.25 mg bid. †Statistically significant (P < 0.01) vs. 0.5 mg bid. |
Results from a second double-blind, randomized trial evaluating Kyotil (granisetron) Tablets 2 mg once a day and Kyotil (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 Kyotil (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 PostÂChemotherapy1
Efficacy Measures | Percentages of Patients | ||
Kyotil (granisetron) Tablets 1 mg twice a day (n = 354) % | Kyotil (granisetron) Tablets 2 mg once a day (n = 343) % | Prochlorperazine2 10 mg twice daily (n=111) % | |
Complete Response3 | 69* | 64* | 41 |
No Vomiting | 82* | 77* | 48 |
No Nausea | 51* | 53* | 35 |
Total Control4 | 51* | 50* | 33 |
1 Moderately emetogenic chemotherapeutic agents included cisplatin (20 mg/m² to 50 mg/m²), oral and intravenous cyclophosphamide, carboplatin, dacarbazine, doxorubicin. 2 Historical control from a previous double-blind Kyotil (granisetron) trial. 3 No vomiting, no moderate or severe nausea, no rescue medication. 4 No vomiting, no nausea, no rescue medication. *Statistically significant (P < 0.05) vs. prochlorperazine historical control. |
Cisplatin-Based Chemotherapy
The first double-blind trial compared Kyotil (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, Kyotil (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 Kyotil (granisetron) Tablets 2 mg once a day alone treatment arm in a second double-blind, randomized trial, were compared to both Kyotil (granisetron) Tablets 1 mg twice a day and placebo historical controls. The 24-hour results for Kyotil (granisetron) Tablets 2 mg once a day were: complete response (44%), no vomiting (58%), no nausea (46%), total control (40%). The efficacy of Kyotil (granisetron) Tablets 2 mg once a day was comparable to Kyotil (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 Kyotil (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. Kyotil (granisetron) Tablets were given one hour before the first radiation fraction of each day.
Twenty-two percent (22%) of patients treated with Kyotil (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 Kyotil (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 Kyotil (granisetron) Tablets.
Fractionated Abdominal Radiation
The efficacy of Kyotil (granisetron) Tablets, 2 mg daily, was evaluated in a double-blind, placebo-controlled randomized trial of 260 patients. Kyotil (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 Kyotil (granisetron) Tablets, compared to placebo, was statistically significant (P < 0.0001) at 24 hours after radiation, irrespective of the radiation dose. Kyotil (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 Kyotil (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). Kyotil (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 Kyotil 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 Kyotil 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 Kyotil 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 Kyotil 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.
However, we will provide data for each active ingredient