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Transdermal granisetron in CINV

Transdermal granisetron presents a novel drug delivery system for the prevention of chemotherapy-induced nausea and vomiting in patients where oral administration is not possible 
Lisa Yuen MRPharmS PgDip IP
Jacky Turner MMedSci MRPharmS
Department of Pharmacy,
Guy’s & St Thomas’ NHS Foundation Trust,
London, UK
Nausea and vomiting are common adverse events encountered by patients receiving chemotherapy. The emetogenicity of individual chemotherapeutic agents is considered the principal factor in determining whether chemotherapy-induced nausea and vomiting (CINV) will develop, and international organisations such as the Multinational Association of Supportive Care in Cancer (MASCC) and European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology (ASCO) have categorised the emetic potential of individual chemotherapy drugs into four levels of emetic risk according to the percentage of patients likely to experience CINV:
  • High emetic risk (>90%)
  • Moderate emetic risk (30–90%),
  • Low emetic risk (10–30%),
  • Minimal emetic risk (<10%).(1,2)
CINV can also be grouped into three types according to the onset: 
  • acute CINV occurs within 24 hours of receiving chemotherapy 
  • delayed CINV occurs at least 24 hours after receiving chemotherapy and 
  • anticipatory CINV, which occurs before chemotherapy administration and is a learned response, often when CINV has been poorly controlled in previous courses of chemotherapy.(3)
The goal is to prevent nausea and vomiting, and providing optimal emetic control in the acute phases avoids nausea and emesis developing in the delayed phase. Guidelines developed by MASCC/ESMO and ASCO recommend combinations of anti-emetics to prevent and control CINV according to the emetogenic potential of the chemotherapy being administered, the dose being given, the schedule of treatment and the onset of CINV.(1,2)
These therapeutic interventions are usually sufficient to control CINV in the majority of patients; however, there are inter-individual variables to be considered that increase the risk of CINV, such as female gender, history of motion sickness, age under 50 years, high tumour burden, brain metastases, electrolyte disturbances and concomitant drugs such as opioids used for pain management.(2,3)
Symptoms of uncontrolled CINV cause distress to patients. In addition, anxiety may develop about the potential for symptoms to recur on subsequent cycles, affecting quality of life. Severe cases of CINV may lead to dehydration, malnutrition, and electrolyte disturbances resulting in hospital admission, or may cause treatment delays or result in dose reductions that may affect clinical outcomes. 
The development and introduction of selective 5-hydroxytryptamine type-3 (5-HT3) receptor antagonists and neurokinin 1 (NK-1) receptor antagonists has reduced the incidence of CINV. 
Current guidelines recommend prophylaxis of CINV for:
  • Highly emetogenic chemotherapy (HEC) using a three-drug combination of a NK-1 receptor antagonist such as aprepitant, dexamethasone and a 5-HT3 receptor antagonist
  • Moderately emetogenic chemotherapy (MEC) using a two-drug combination of a 5-HT3 receptor antagonist and dexamethasone
  • Low-risk chemotherapy regimens using a corticosteroid such as dexamethasone, or metoclopramide,
  • Routine anti-emetics are not indicated for minimal emetic risk regimens.(1,2)
These therapeutic agents are available as oral or intravenous (IV) formulations; oral administration is the preferred option because it is less invasive, convenient for most patients and empowers patients to manage their treatment. There are situations where oral administration is not possible or uncomfortable, for example, in patients who develop severe and painful mucositis or xerostomia, patients who have dysphagia due to the location of the tumour, patients where absorption issues have been identified, and patients who develop an aversion to swallowing oral solid dosage forms in anticipatory CINV. IV administration may be considered in these patients; however, IV administration requires the need for venous access plus additional nursing resources, and is often inconvenient to the patient, particularly for those who may be needle-phobic. Therefore, a new formulation may be of benefit in this subgroup of patients.
Granisetron transdermal patch
Traditionally, 5-HT3 receptor antagonists are available in oral and IV formulations. A new formulation has now been developed as a transdermal patch. Sancuso® contains 34.3mg of the 5-HT3 receptor antagonist, granisetron, in a 52cm2 polymer matrix providing 3.1mg granisetron over 24 hours. It is licensed for the prevention of nausea and vomiting in adults who have swallowing difficulties, who are receiving MEC or HEC for three to five consecutive days,4 such as EP or BEP regimens in urological malignancies or a cisplatin/topotecan regimen in gynaecological cancer.
Clinical studies
In the ProStrakan-funded, randomised, double-blind, phase III study, patients were allocated at a 1:1 ratio to one of two treatment arms: 
1. Granisetron transdermal patch + placebo capsule,
2. Placebo transdermal patch + granisetron 2mg capsule. 
The patch was applied 24–48 hours before the first dose of MEC or HEC and remained in place for seven days in all patients. The capsule was administered one hour before MEC or HEC on each day the chemotherapy was administered. Emetogenicity of the chemotherapy regimens were based on the Hesketh score. NK-1 receptor antagonists were not permitted in the study; corticosteroids were permitted as prophylaxis at 
the investigators’ discretion in line with local practice.(5)
The primary efficacy endpoint was percentage of patients achieving complete control of CINV from first administration of chemotherapy to 24 hours after the last dose; the study showed the transdermal patch to be non-inferior to oral granisetron with 60.2% of patients receiving the transdermal patch and 64.8% receiving oral granisetron achieving complete control of CINV after receiving a single cycle of MEC or HEC.(5)
There is a delayed onset of action of granisetron from the transdermal patch, with a maximum plasma concentration reached 48 hours after application;(6) therefore the patch must be applied 24–48 hours prior to chemotherapy.(4,5) The patch should be applied to clean, dry, and healthy intact skin on the upper arm or abdomen and should be worn continuously until at least 24 hours after completion of chemotherapy, for a maximum of seven days.(4)
Available data showed that the pharmacokinetics of the granisetron transdermal patch are not affected by external heat or body fat.5 Upon removal of the patch, plasma concentrations decreased slowly over approximately 72 hours, which suggests a dermal reservoir of drug exists.(6,7)
The adverse events reported in the study for the transdermal patch reflected the adverse event profile of oral granisetron, the most common adverse event reported was constipation which was reported more frequently in patients receiving the patch than oral granisetron (6.6% versus 3.1%),(5) this difference may be due to the transdermal patch being applied for seven days compared to oral granisetron only being administered on the days of chemotherapy (three to five day duration). Skin reactions to the patch were reported as slight or moderate.(5)
The use of transdermal granisetron has been included as an option in the ASCO guidelines for patients receiving multi-day chemotherapy,(2) and has been accepted for use in NHS Scotland.(8)
There are advantages to a 5-HT3 receptor antagonist transdermal patch in patients with co-morbidities, such as dysphagia, mucositis or xerostomia, in terms of patient comfort, reducing tablet burden and avoiding first-pass metabolism. Other benefits are in patients who are needle-phobic and those with galactose intolerance, lactase deficiency or glucose–galactase malabsorption because each 2mg film-coated tablet of granisetron contains 138.76mg lactose monohydrate.(9)
Although transdermal granisetron is now available, there are limitations to its use in routine practice owing to its licence and dosing schedule. 
Due to the delayed onset of action, the transdermal patch must be applied 24–48 hours prior to the first day of chemotherapy, and careful planning, patient education and adherence is vital to successful prevention of CINV. This poses a potential problem if the patient forgets to apply the patch as directed; suboptimal levels of 5-HT3 receptor antagonist prior to the start of chemotherapy administration results in antiemetic failure and the patient will require an alternative or additional antiemetic agent, either orally or intravenously. 
The transdermal patch will only be suitable for patients unlikely to encounter delays in their chemotherapy schedule; patients on a one-visit pathway for their chemotherapy treatment who are subsequently delayed due to haematological toxicities will be exposed to low levels, but unnecessary drug therapy and therefore potential adverse effects due to the need to apply the patch needs 24–48 hours prior to chemotherapy. The patch will need to be removed, discarded and resupplied to the patient to be applied before the rescheduled treatment cycle, presenting an additional cost implication. A cost comparison is shown in Figure 1.
Sancuso® is only licensed for MEC or HEC over three to five consecutive days;(5) there is no trial experience for chemotherapy regimens less than three consecutive days, or for radiotherapy-induced emesis, nor is it suitable for chemotherapy regimens greater than five consecutive days.
Although the 5-HT3 receptor antagonist is available as a transdermal delivery system, consideration needs to be made for the other anti-emetic agents (NK-1 receptor antagonist in HEC, and corticosteroids in MEC and HEC) because these need to be administered either orally or intravenously.
The mean plasma half life of the IV and oral granisetron formulation is approximately nine hours,(9) whereas that for the transdermal patch is approximately 18 hours in cancer patients owing to slow absorption across the skin.(4) Patients using transdermal granisetron who experience significant side effects may be more difficult to manage due to delayed excretion of the drug.
CINV is a clinically important adverse event that can be managed with the appropriate use of anti-emetics; uncontrolled CINV may affect quality of life of patients, cause dose delays or dose reductions affecting clinical outcomes. Transdermal granisetron was shown to be non-inferior to oral granisetron for preventing CINV in a single trial but efficacy data are limited.(5) Trials are currently ongoing evaluating the efficacy and safety of Sancuso® in MEC and HEC.(10,11)
Further studies need to be conducted to improve our knowledge of transdermal granisetron, including patient satisfaction or preference compared with other oral (solid and liquid dose forms) or IV 5-HT3 receptor antagonists, and standardised anti-emetic combinations including dexamethasone and aprepitant, including assessment of quality of life data. The transdermal granisetron patch may be an useful option in selected patients with swallowing difficulties but limitations to the dosing schedule may restrict its use. 
  1. Roila F et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010;21(Suppl 5):v232–v243. 
  2. Basch E et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2011; 29: 4189-4198. 
  3. Committee for Medicinal Products for Human Use (CHMP). Guideline on non-clinical and clinical development of medical products for the prevention of nausea and vomiting associated with cancer chemotherapy. 14 Dec 2006. (accessed 6 March 2014).
  4. ProStrakan Ltd. Summary of Product Characteristics: Sancuso. 2012. (accessed 6 March 2014). 
  5. Boccia RV et al. Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. Support Care Cancer 2011;19:1609–17. 
  6. Howell J et al. Pharmacokinetics of a granisetron transdermal system for the treatment of chemotherapy induced nausea and vomiting. J Oncol Pharm Pract 2009;15:223–31.
  7. European Medicines Agency. Committee for Medicinal Products for Human Use: Sancuso assessment report. EMA/228344/2012.… (accessed 6 March 2014). 
  8. Scottish Medicines Consortium. Granisetron 3.1mg/24 hours transdermal patch (Sancuso). No: 895/13. 7. Oct 2013.… (accessed 6 March 2014). 
  9. Roche Products Ltd. Summary of Product Characteristics: Kytril, 2013. 
  10. US National Institutes of Health. Clinical trial record (NCT01662687): Phase 4 trial to evaluate the efficacy and safety of Sancuso patch in CINV (chemotherapy-induced nausea and vomiting) associated with the administration of MEC (moderately emetogenic chemotherapy). (accessed 6 March 2014). 
  11. US National Institutes of Health. Clinical trial record (NCT01659775): Phase 4 trial to evaluate the efficacy and safety of Sancuso patch in chemotherapy-induced nausea and vomiting associated with the administration of highly emetogenic chemotherapy (HEC). (accessed 6 March 2014).