Sancuso

Sancuso

granisetron

Manufacturer:

Kyowa Kirin

Distributor:

DCH Auriga - Healthcare
Full Prescribing Info
Contents
Granisetron.
Description
Sancuso is a 52 cm2 patch containing 34.3 mg of granisetron. The patch releases 3.1 mg of granisetron per 24 hours for up to 7 days.
Sancuso contains granisetron, which is an anti-nauseant and antiemetic agent. 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.
Granisetron is a white to off-white solid that is insoluble in water. Sancuso 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.
Excipients/Inactive Ingredients: Acrylate-vinylacetate copolymer, polyester, titanium dioxide, polyamide resin and polyethylene wax.
Action
Pharmacology: Mechanism of Action: 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.
Pharmacodynamics: The effect of granisetron on QTc prolongation was evaluated in a randomized, single-blind, positive (moxifloxacin 400 mg) - and placebo controlled parallel study in healthy subjects. A total of 240 subjects were administered Sancuso patch, intravenous granisetron (10 mcg/kg over 30 seconds). In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo adjusted, baseline corrected QTc based on Fridericia correction method (QTcF) for Sancuso was below 10 ms, the threshold for regulatory concern.
No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in studies using granisetron.
The effect on oro-cecal transit time following application of Sancuso has not been studied. Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in healthy subjects given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses of granisetron hydrochloride slowed colonic transit in healthy subjects.
Clinical Studies: The effectiveness of Sancuso in the prevention of chemotherapy-induced nausea and vomiting (CINV) was evaluated in a Phase 3 randomized, parallel group, double-blind, double-dummy study conducted in the U.S. and abroad. The study compared the efficacy, tolerability and safety of Sancuso with that of 2 mg oral granisetron 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 (ME) or highly emetogenic (HE) multi-day chemotherapy. Seventy-eight (78%) of patients were White, 12% Asian, 10% Hispanic/Latino and 0% Black.
The granisetron patch was applied 24 to 48 hours before the first dose of chemotherapy, and kept in place for 7 days. Oral granisetron was administered daily for the duration of the chemotherapy regimen, one 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 Sancuso was established in 60.2% of patients in the Sancuso arm and 64.8% of patients receiving oral granisetron (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.
Pharmacokinetics: 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%). (See Figure.)

Click on icon to see table/diagram/image

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.
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.
Subpopulations: Gender: There is evidence to suggest that female subjects had higher granisetron 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 Sancuso in pediatrics.
Elderly, and Renal or Hepatic Impairment: Although no studies have been performed to investigate the pharmacokinetics of Sancuso in elderly subjects, and in patients with renal or hepatic impairment, the following pharmacokinetic information is available for intravenous granisetron.
In the elderly, and in patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron were determined following a single 40 mcg/kg intravenous dose of granisetron hydrochloride.
Elderly: In elderly volunteers (mean age 71 years) pharmacokinetic parameters following a single 40 mcg/kg intravenous dose of granisetron hydrochloride, lower clearance and longer half-life were observed compared to younger healthy volunteers.
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 granisetron hydrochloride.
Hepatically-Impaired Patients: In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance following a single 40 mcg/kg intravenous dose of granisetron hydrochloride was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of granisetron and the good tolerance of doses well above the recommended dose, dose adjustment in patients with hepatic functional impairment is not necessary.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis and 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 astatistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m2/day, about 13 times the recommended human dose with Sancuso, on a body surface area basis) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, about 65 times the recommended human dose with Sancuso, on a body surface area basis). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m2/day, about 2.6 times the recommended human dose with Sancuso, on a body surface area basis) in males and 5 mg/kg/day (30 mg/m2/day, about 13 times the recommended human dose with Sancuso, on a body surface area basis) in females.
In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, about 261 times the recommended human dose with Sancuso, on a body surface area basis) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive.
Because of the tumor findings in rat studies, Sancuso should be prescribed only at the dose and for the indication recommended (see Indications, and Dosage & Administration).
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.
Indications/Uses
Sancuso (Granisetron Transdermal System) is indicated for the prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic chemotherapy regimens of up to 5 consecutive days duration.
Dosage/Direction for Use
The transdermal system (patch) should be applied to clean, dry, intact healthy skin on the upper outer arm. Sancuso should not be placed on skin that is red, irritated or damaged.
Each patch is packed in a pouch and should be applied directly after the pouch has been opened.
The patch should not be cut into pieces.
Adults: Apply a single patch to the upper outer arm a minimum of 24 hours before chemotherapy. The patch may be applied up to a maximum of 48 hours before chemotherapy as appropriate.
Remove the patch a minimum of 24 hours after completion of chemotherapy. The patch can be worn for up to 7 days depending on the duration of the chemotherapy regimen.
Overdosage
There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given.
Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or only the occurrence of a slight headache.
In clinical trials there were no reported cases of overdosage with Sancuso.
Contraindications
Sancuso is contraindicated in patients with known hypersensitivity to granisetron or to any of the components of the patch.
Special Precautions
Gastrointestinal: The use of granisetron in patients may mask a progressive ileus and/or gastric distention caused by the underlying condition.
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.
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 (see Pharmacology: Nonclinical Toxicology: Phototoxicity under Actions).
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. (See Interactions and Patient Counselling Information.)
Renal Failure or Hepatically-Impaired Patients: Although no studies have been performed to investigate the pharmacokinetics of Sancuso in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron (see Pharmacology: Pharmacokinetics under Actions).
Pediatric Use: Safety and effectiveness of Sancuso in pediatric patients under 18 years of age have not been established.
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.
Use In Pregnancy & Lactation
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.
Adverse Reactions
Clinical Trials Experience: The safety of Sancuso was evaluated in a total of 404 patients undergoing chemotherapy who participated in two double-blind, comparator studies with patch treatment durations of up to 7 days. The control groups included a total of 406 patients who received a daily dose of 2 mg oral granisetron, for 1 to 5 days.
Adverse reactions considered by the investigators as drug-related occurred in 8.7% (35/404) of patients receiving Sancuso and 7.1% (29/406) of patients receiving oral granisetron. The most common adverse reaction was constipation that occurred in 5.4% of patients in the Sancuso group and 3.0% of patients in the oral granisetron group.
The Table lists the treatment emergent adverse reactions that occurred in at least 3% of patients treated with Sancuso or oral granisetron. (See Table.)

Click on icon to see table/diagram/image

5-HT3 receptor antagonists, such as granisetron, may be associated with arrhythmias or ECG abnormalities. Three ECGs were performed on 588 randomized patients in the Phase 3 study: at baseline before treatment, the first day of chemotherapy, and 5 to 7 days after starting chemotherapy. QTcF prolongation greater than 450 milliseconds was seen in a total of 11 (1.9%) patients after receiving granisetron, 8 (2.7%) on oral granisetron and 3 (1.1%) on the patch. No new QTcF prolongation greater than 480 milliseconds was observed in any patient in this study. No arrhythmias were detected in this study.
Granisetron 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 practice.
Adverse events reported in clinical trials with other formulations of granisetron include the following: Gastrointestinal: abdominal pain, diarrhea, constipation, elevation of ALT and AST levels, nausea and vomiting.
Cardiovascular: Hypertension, hypotension, angina pectoris, atrial fibrillation and syncope have been observed rarely.
Central Nervous System: Dizziness, insomnia, headache, anxiety, somnolence and asthenia.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (e.g. anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
Other: Fever; events often associated with chemotherapy have also been reported: leucopenia, decreased appetite, anemia, alopecia, thrombocytopenia.
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, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer therapies. In agreement with these data, no clinically relevant drug interactions have been reported in clinical studies with Sancuso.
Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of granisetron. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known.
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) (see Precautions).
Storage
Store at 20°-25°C (68°-77°F); excursions permitted between 15°-30°C (59°-86°F). [Ssee USP Controlled Room Temperature].
Patient Counseling Information
17.1 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.
17.2 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.
17.3 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 (see Pharmacology: Nonclinical Toxicology: Phototoxicity).
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 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.
How to apply the Sancuso patch: The Sancuso patch comes inside a pouch which is inside the carton.
1. Do not remove the patch from the pouch until you are ready to use it.
2. Do not cut the Sancuso patch into pieces.
3. Remove the pouch from the carton.
4. Tear the pouch open using the slit provided, and remove the patch. Each pouch contains one Sancuso patch stuck onto a rigid plastic film, and a separate thin, clear protective liner.
5. Remove the thin, clear protective liner to expose the printed side of the patch. Throw away the liner. The protective liner is only included in the pouch to separate the patch from the inside of the pouch, and is not part of the patch.
6. 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.
7. 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.
8. Wash your hands right away after applying the patch to remove any medicine that may have stuck to your fingers.
9. 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.
10. Do not re-use the patch after you remove it. See as follows for instructions on the right way to remove and throw away the patch.
What to do if the Sancuso 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 Sancuso: You can continue to shower and wash normally while wearing the Sancuso patch. It is not known how other activities, for example swimming, strenuous exercise or using a sauna or whirlpool, may affect Sancuso. Avoid these activities while wearing Sancuso.
How do I remove and dispose of Sancuso: 1. When you remove the patch, peel it off gently.
2. The used patch will still contain some of the medicine. After removing the used Sancuso patch, fold it in half so that the sticky side sticks to itself. Throw away the Sancuso patch in the garbage, out of the reach of children and pets. Do not re-use the patch.
3. 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.
4. Wash your hands after handling the patch.
5. 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.
ATC Classification
A04AA02 - granisetron ; Belongs to the class of serotonin (5HT3) antagonists. Used for the prevention of nausea and vomiting.
Presentation/Packing
Transdermal patch 34.3 mg/52 cm2 x 1's.
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