Management of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Multiple-Day Highly or Moderately Emetogenic Chemotherapy: Role of Transdermal Granisetron

ABSTRACT

Granisetron transdermal delivery system (GTDS) is the first 5-HT₃ drug to be transdermally delivered and represents a convenient alternative to oral and intravenous antiemetics for the treatment of chemotherapy-induced nausea and vomiting. GTDS is effective and well tolerated in patients receiving multiple-day moderate-to-highly emetogenic chemotherapy. In this setting noninferiority studies showed similar efficacy when GTDS was compared with intravenous and oral granisetron and intravenous palonosetron. GTDS has shown good cardiovascular safety; however, special caution is needed in patients at risk for developing excessive QTc interval prolongation and arrhythmias. So far, GTDS has been investigated for intravenous prevention in comparison with granisetron and palonosetron; however, further prospects open the route to future clinical investigations.

KEYWORDS:

• 5-HT₃ receptor antagonists
• chemotherapy-induced nausea and vomiting
• transdermal granisetron

A significant number of multiple-day chemotherapy regimens are associated with a high incidence of chemotherapy-induced nausea and vomiting (CINV). The repeated administration of chemotherapeutic agents represents a significant risk factor for acute (occurring during the first 24 h after chemotherapy) and delayed (occurring at least 24 h after chemotherapy) emesis, which often overlap and are difficult to distinguish. Therefore, continuous protection during and after treatment is required. The American Society of Clinical Oncology (ASCO) guidelines suggest using antiemetics for each day of chemotherapy and for 2 days afterwards [1]. As delayed emesis is strongly dependent on control of CINV during the initial 24 h after chemotherapy, an optimal acute antiemetic prophylaxis is recommended. Long-acting antiemetics represent the gold standard of treatment, as they guarantee prolonged protection against CINV. Innovative formulations, such as transdermally delivered drugs, could represent an alternative to repeated oral administrations or intravenous infusions, because they are easy to use and improve patient compliance to treatment.

The choice of an appropriate antiemetic drug for prophylaxis is based on the emetogenic risk class of the administered chemotherapy. For moderately emetogenic chemotherapy (MEC), guidelines suggest a two-drug combination of a serotonin (5-hydroxytryptamine) subtype 3 (5-HT₃) receptor antagonist and dexamethasone, while after highly emetogenic chemotherapy (HEC) the suggested regimen is a three-drug combination of a 5-HT₃ receptor antagonist, dexamethasone and a NK1 receptor antagonist [1,2]. These three classes of drugs have substantially changed our ability to manage CINV. Nevertheless, about 25% of patients continue to experience CINV despite administration of optimal prophylaxis.

This narrative review analyzes the potential role of granisetron transdermal delivery system (GTDS) for management of CINV, particularly in the challenging setting of patients receiving multiple-day MEC or HEC.

Rationale for developing transdermal formulations

The first transdermal medication delivery system was introduced in the 1980s: a scopolamine skin patch, designed to be placed behind the ear 12 h before needed and which delivers drug for 3 days, evaluated for prevention/treatment of motion sickness in people making their first transition into orbital flight [3]. Nowadays, a number of drugs across different specialties are transdermally delivered in order to guarantee stable plasma dose, prolonged effects and improved compliance (e.g., buprenorphine, fentanyl, estradiol, testosterone, clonidine, nicotine and others). When drugs are administered via transdermal delivery systems, they enter by passive diffusion through skin into the bloodstream, by which they reach their site of action. Conversely, topical patches, such as 5% lidocaine plasters for localized neuropathic pain [4], act directly on their site of application. In this case, systemic absorption is neither necessary nor desired.

Transdermal delivery systems have a number of advantages, which include:

• Continuous medication delivery, constant rate of administration and prolonged action;

• Distant application from sites of action;

• By-pass of the gastrointestinal (GI) system and avoidance of first-pass hepatic metabolism;

• Ability of medications to directly enter systemic circulation;

• Higher patient compliance compared with other routes of administration (reduced number of daily/weekly administrations and reduced pill burden).

In the case of antiemetics, transdermal delivery systems offer a further advantage in that they can also be used in patients unable to take or tolerate parenteral or oral formulations. This may be particularly relevant in patients with nausea and emesis, as well as with swallowing difficulties or when the absorption of oral drugs is uncertain. Patients who undergo head, neck, or GI surgery or radiotherapy, or those with comorbid conditions such as xerostomia, may be unable to use oral medications. In this population, transdermal delivery systems represent the gold standard because medications are continuously delivered through the skin and bypass the GI tract, making for a more consistently absorbed delivery system [5].

Transdermal patches are traditionally made of three separate layers: a protective outer membrane, a drug compartment and a rate-controlling microporous membrane. Currently, most of these systems, named reservoir patches, have been switched to matrix-type patches, which are slimmer and smaller, because they are contained in one layer. Moreover, matrix patches have an additional safety benefit. With reservoir patches, when damage occurs to the rate-controlling membrane, there is a significant risk of drug overdose as medication can come out of the drug compartment in an uncontrolled fashion. Matrix patches prevent the risk of overdose by ensuring that the rate of medication release never rises above a safe level.

There are few limitations of this route of administration. First, only drugs with low molecular weight, high lipophilicity and relative high potency can be delivered by the transdermal route. Second, complete or partial loss of skin adhesion may occur in the case of immersion in water, excessive sweating or application in areas of hair growth. Third, patients may be sensitive to the adhesive material in the patch, most commonly leading to pruritus and erythema. Finally, although transdermal patches are set to deliver a consistent rate of medication over time, there are individual variations affecting the patch release rate, such as skin texture, thickness and pigmentation, age (there are age-related changes to skin makeup) and body temperature (as temperature increases the rate of drug release increases). Minimal variations may be related to the site of application; however, drugs are usually equally absorbed regardless of application site (i.e., arms, thighs, back or abdomen).

Pharmacological profile of GTDS

GTDS was the first transdermal antiemetic agent approved for the prevention of CINV, and is still the only transdermal antiemetic for CINV available on the market. It was approved in 2008 by the US FDA and in 2013 by the EMA.

Granisetron is a selective 5-HT₃ receptor antagonist. 5-HT₃ is one of the most important mediators of CINV. This category of antiemetics acts by binding 5-HT₃ receptors located peripherally on the vagal afferent nerve in the GI tract and centrally on the chemoreceptor trigger zone (CRTZ) [6]. The CRTZ is a group of neurons in the area of the medulla oblongata that receives inputs by peripheral (visceral afferents from the GI tract and vestibular region) and central areas (cerebral cortex and thalamus). It represents the vomiting center. GI distension and mucosal irritation are very potent stimuli for vomiting. They act through vagal afferents terminating in the area postrema of the nucleus tractus solitarius, whose neurons project to the CRTZ. The latter, not being protected by a true blood–brain barrier, is exposed to emetogenic chemical compounds carried by the blood, such as chemotherapy. Moreover, chemotherapeutic drugs are known to stimulate enterochromaffin cells in the GI tract to release serotonin, which enhances intestinal secretions, accelerates small bowel transit, stimulates antral contractions and vagal afferents, promoting nausea and vomiting [7].

Granisetron is strongly selective for 5-HT₃, with little or no affinity for other serotonin receptors. Similarly granisetron does not show any clinically significant interaction with adrenergic, dopaminergic, histaminergic and opioidergic receptors. Its affinity for 5-HT₃ receptors is 4000–40,000-fold higher than that for other receptors [6].

GTDS is a 52 cm² matrix-type transdermal patch, which contains 34.3 mg of granisetron and delivers 3.1 mg of granisetron per 24 h for up to 7 days. The patch must be applied to the outer upper arm 24–48 h before the first day of chemotherapy. GTDS can be either removed 24 h after the completion of chemotherapy or worn for up to 7 days [6].

In a Phase I study, the pharmacokinetics (PK) of GTDS were evaluated in 12 healthy volunteers after a single 6-day application of three different doses, and compared with oral granisetron [8]. In this cross-over study, subjects were randomized to: oral granisetron (2 mg) for 5 days; GTDS 52 cm² patch (34.3 mg granisetron); 33 cm² patch (21.8 mg granisetron); and 15 cm² patch (9.9 mg granisetron). We report here the PK data for the GTDS 52 cm² patch (because this is the approved patch on the market) in comparison with 2 mg oral granisetron (Table 1). For GTDS, the mean peak plasma concentration of granisetron (C_max) of 3.85 ng/ml was reached in 48 h (mean time to C_max = T_max range: 24–48 h). The average plasma concentration over the 6-day treatment period was 2.23 ng/ml. By comparison, when oral granisetron was administered for 5 days, C_max was reached in 2 h, ranging from 5.25 ng/ml (day 1) to 5.5 ng/ml (day 5), and the average plasma concentration was 2.6 ng/ml. The terminal elimination half-life (T_1/2) of GTDS was 35.9 h, compared with 6.4–7.9 h for oral granisetron. At day 5, the mean area under the curve (AUC_0–∞) was 420 ng/ml*h for GTDS and 98 ng/ml*h for oral granisetron. Plasma granisetron concentrations decreased slowly until patch removal at 144 h (1.6 ng/ml). According to these pharmacokinetic data, GTDS guarantees a slighter increase in plasma drug concentration compared with oral granisetron and a constant drug release, which should ensure a stable control against CINV.

A recently published paper reported four Phase I studies that evaluated whether PK parameters of GTDS can be affected by specific situations which may occur in clinical practice: different site of patch application; age, weight, BMI and triceps’ skinfold thickness; heat; and concurrent use of the patch and intravenous therapy and consecutive patch use [9]. The first study evaluated 12 healthy subjects’ PK data for GTDS. When a 15 cm² patch was applied on the abdomen, C_max = 1.9 ng/ml and T_max = 57 h. By comparison, when a 15 cm² patch was applied on the upper arm, C_max = 1.15 ng/ml and T_max = 48 h. The authors judged these findings comparable; therefore abdominal application of GTDS was considered an appropriate alternative when application on the upper arm is limited by clinical conditions, such as edema in patients who underwent axilla surgery for breast cancer. The second study (NCT00868764) found similar PK profiles among groups of different ages (≥65 years vs control group ≥18–45 years) and different BMI (underweight, normal and obese) [9]. Similarly, no significant correlations were found between PK parameters and triceps’ skinfold thickness, as a surrogate measure of subcutaneous fat. Therefore, the authors concluded that dose adjustments are not required for either elderly or extreme BMI patients. The third study (NCT01073696) evaluated the effect of heat, generated by an adhesive patch designed to provide targeted relief to minor muscular and joint aches and pains (Cura-Heat^® Back and Shoulder Pain air-activated heat pack [Kobayashi Healthcare Europe Ltd, London, UK]) [9]. Packs were applied over the patch for 4.5 h daily for 5 days, generating a temperature of approximately 42°C (107.6 F). Heat slightly increased granisetron C_max from 6.14 to 7.25 ng/ml and bioavailability from 574 to 606.6 ng/ml*h. These findings suggested that systemic exposure to granisetron was similar with and without heat application; therefore the application of external heat over a short period did not affect the PK profile of GTDS. In clinical practice this means that sunlight, warm water, electric blankets or local warming pain reliever should not significantly increase patient’s exposure to granisetron; however heat exposure is not recommended during GTDS use. Finally, the fourth study (NCT00873197) explored the effects of co-administration of GTDS with intravenous granisetron (0.01 mg/kg) [9]. Intravenous granisetron was administered in a single dose on the same day of GTDS application. After 7 days, the first patch was removed and a new patch was applied on the opposite arm, without any intravenous injection of granisetron. Co-administration of the intravenous dose resulted in a rapid distribution of the drug (T_max0–24 = 0.16 h) and rapid decline in plasma concentrations to 12 h post-dose. A new peak of plasma concentration at 48 h was related to GTDS application. Similarly, the second GTDS patch caused a second peak plasma concentration and a minimal granisetron accumulation. The authors concluded that consecutive GTDS patch application or co-administration of intravenous granisetron with the GTDS is feasible when clinically required [9].

Granisetron has a protein binding rate of 65% and a mean volume of distribution of 3 l/kg [10]. Granisetron clearance is predominantly hepatic [6]. Some metabolites may have 5-HT₃ receptor antagonist activity. Granisetron is metabolized partly by conjugation with glucuronide sulfate and partly by the isoenzymes CYP1A1 and CYP3A4 of the hepatic CYP450 [6]. Therefore, inducers or inhibitors of CYP1A1 and CYP3A4 could potentially alter the clearance rate of granisetron. Phenobarbital, for example, is an inducer of hepatic enzyme and increased granisetron clearance by 25% [6]. Similarly, ketoconazole inhibited the oxidation of granisetron; however, the clinical relevance of these modifications is still unknown [6]. A total of 12% of granisetron is excreted unchanged in urine. The rest is excreted as metabolites: 49% by the urine and 34% by the feces [6,11]. Mean plasma clearance (0.79 l/kg/h in healthy subjects) is not affected by age, gender or renal function. Therefore, dose adjustments are not required in patients with renal failure. However, in patients with hepatic impairment, clearance is approximately halved compared with control subjects [12].

Clinical evaluation of granisetron transdermal delivery system

GTDS for control of CINV following single-day MEC

In a Phase II clinical trial (Study 392MD/8/C), GTDS was compared with oral granisetron for the control of CINV in patients undergoing single-day MEC [13,14]. Two hundred and ten patients were randomized to receive a 52-cm² patch (granisetron 34.3 mg), followed by a placebo capsule, or a placebo patch, followed by oral granisetron 2 mg. The patch was applied 24 h before single-day chemotherapy for a total of 6 days, while the capsule was administered the next day, followed by chemotherapy one hour later. Patients were contacted by phone the day after for an interview, while a final clinical visit was conducted 4 days after chemotherapy. No statistically significant differences were observed in efficacy, defined as total control of CINV (no nausea or vomiting, no use of rescue medication or no study withdrawal), among the GTDS and oral granisetron groups. The percentage of patients obtaining total control of CINV was similar in the two treatment groups, in the delayed phase (primary end point), in the acute phase (0–24 h) and the overall period (0–120 h). CINV control in the delayed phase was reached in 32.2 vs 29.8% of treated patients, respectively, for GTDS and oral granisetron. In the acute phase, the percentages were higher (43.7 vs 52.4%, respectively) but without any significant difference between the two groups. Similarly, there was no statistically significant difference between the groups in terms of patients’ satisfaction with control over CINV. The response rates observed for acute and delayed CINV were lower than expected. One of reasons for this treatment failure could be the exclusion of dexamethasone. 2011 ASCO guidelines recommended use of a two-drug combination of palonosetron (day 1 only) and dexamethasone (days 1–3) in patients receiving MEC; when palonosetron is not available, it may be substituted with a first-generation 5-HT₃ serotonin receptor antagonist, preferably granisetron or ondansetron [1]. Several randomized studies, however, showed that a regimen of palonosetron and single-day dexamethasone is noninferior to palonosetron plus dexamethasone for 2 or 3 days in controlling CINV induced by MEC chemotherapy [15–17]. These findings are reflected in the recommendations of the MASCC/ESMO Antiemetic Guideline 2016 [18]: for the prevention of acute nausea and vomiting in MEC-treated patients, a 5-HT₃ receptor antagonist plus dexamethasone on day 1 is recommended, while the use of dexamethasone on days 2 and 3 can be considered in patients receiving MEC with well-known potential for delayed nausea and vomiting (such as oxaliplatin, anthracycline or cyclophosphamide).

GTDS was well tolerated in the Study 392MD/8/C.The percentage of patients who experienced treatment-emergent adverse events (TEAEs) was lower in the GTDS group compared with the oral granisetron group (4.5 vs 9.4%, respectively). Headache was the most commonly reported adverse event in both groups (3.4 and 4.7%, respectively) [13,14].

GTDS for control of CINV following multiple-day HEC or MEC

In a randomized, controlled, double-blind, parallel-group, Phase III study, patients starting their first cycle of multiday MEC or HEC (noncisplatin or cisplatin) received either a GTDS patch and placebo capsules (n = 318) or a placebo patch and active capsules (2 mg granisetron; n = 323) [19]. GTDS patches were applied to the upper arm 24–48 h before the start of chemotherapy, and left in place for 7 days, whereas capsules were administered 1 h before each day’s administration of chemotherapy. The primary end point was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. A total of 296 and 304 patients, respectively, completed the study in the GTDS and oral granisetron arms. GTDS demonstrated noninferiority compared with oral granisetron for complete CINV control (60 vs 65%, respectively, for GTDS and oral granisetron; difference -5%; 95% CI: -13–3%). GTDS maintained CINV control throughout the study, and was not inferior to oral granisetron on any day of the primary end point evaluation period. Patients’ global satisfaction with antiemetic therapy, assessed using a 10 cm visual analogue scale at the time of patch removal, was high with both treatments, without significant difference between the two groups: visual analogue scale score was 8.19 cm (±2.21) for GTDS-treated patients and 8.24 cm (±2.13) for oral granisetron patients (p = 0.887). The incidence of TEAEs was similar between the GTDS (41%) and oral granisetron (39%) groups. Most TEAEs were mild-to-moderate in severity, and were considered unrelated to treatment.

In a randomized, controlled, open-label, prospective study, Korean patients receiving multiday MEC (5-fluorouracil/leucovorin with irinotecan or oxaliplatin) received either a GTDS patch (n = 139), or control (intravenous and oral granisetron, n = 137) [20]. GTDS patches were applied to the upper arm 24–48 h before the start of chemotherapy and left in place for 4 days. In the control group, 3 mg of intravenous granisetron was administered on day 1 and 1 mg of oral granisetron was administered every 12 h on days 2 and 3. The primary end point was complete control of CINV (no vomiting/retching and no use of rescue medication) from chemotherapy initiation until 24 h after final administration. GTDS demonstrated noninferiority compared with the intravenous/oral group for complete CINV control (75 vs 74.6%, respectively, for GTDS and intravenous/oral granisetron; 95% CI: -10.73–11.55%). Both treatments were safe and well tolerated.

A subsequent retrospective analysis of the study by Boccia et al. was conducted to identify predictors of emetogenicity, and to determine rules for evaluating the emetogenicity of 3-day chemotherapeutic regimens [21]. The results of this analysis indicate that Hesketh scores, which were previously established to classify the emetogenicity of individual chemotherapeutic agents and combinations [22], are also applicable to multiday, multiagent regimens in patients receiving prophylactic antiemetics. In particular, the Hesketh score on day 1 was a strong predictor of the emetogenicity of multiday chemotherapeutic regimens, and the presence of an individual chemotherapeutic agent with the highest Hesketh score on day 1 was reported as the greatest variable predictor of emesis with multiagent regimens [21].

GTDS versus palonosetron for control of CINV following multiple-day MEC

In a randomized, controlled, open-label, crossover study, 196 Korean patients receiving multiday MEC were randomized to a GTDS/palonosetron (GP) or palonosetron/GTDS (PG) group [23]. The GP group received GTDS in the first chemotherapy cycle and intravenous palonosetron in the second chemotherapy cycle before receiving MEC in two consecutive cycles. The PG group received intravenous palonosetron in the first cycle and GTDS in the second cycle. GTDS patches were applied to the upper arm 24–48 h before the start of chemotherapy and left in place for 7 days. Intravenous palonosetron (0.25 mg/day) was administered 30 min before chemotherapy. The primary end point was complete control of CINV (no emesis episodes and no use of rescue medication) from chemotherapy initiation until 24 h after final administration. GTDS demonstrated noninferiority compared with palonosetron for complete CINV control during the acute phase (75.2 vs 79.8%, respectively, for GTDS and palonosetron; treatment difference -4.6%; 95% CI: -13.6–4.4%). There was no significant difference in CINV control during the acute phase after the end of the first and second chemotherapy cycle between the GP and the PG group. GTDS maintained CINV control throughout the study, and was not inferior to palonosetron on any day of the primary end point evaluation period. The impact of CINV on patients’ daily lives, assessed using Functional Living Index-Emesis, was lower with GTDS than palonosetron. The incidence of treatment-emergent, drug-related adverse events was similar between the GTDS and palonosetron groups (3.3% each).

The results of these randomized controlled trials suggest that GTDS could provide a promising new option for the control of CINV in patients receiving a multiday chemotherapy regimen.

GTDS for patients receiving concurrent radiation & chemotherapy

Data on the use of GTDS for treating concurrent radiation and chemotherapy-induced nausea and vomiting (RINV) are not available in the literature. However, a retrospective case-controlled study of cervical cancer patients receiving concurrent radiation and weekly chemotherapy with the HEC cisplatin (cisXRT) demonstrated a limited efficacy of GTDS for controlling CINV [24]. While cisXRT has been shown to be more effective than radiation alone in cervical cancer, it is associated with additional toxicities. Nausea and vomiting are some of the most significant adverse events, often causing treatment delays, reduced functional ability and impaired quality of life, resulting in malnutrition and electrolyte imbalances. Multiple studies have investigated acute toxicities associated with concurrent cisplatin-based chemotherapy and radiation therapy [25].

Unfortunately, the only available study on GTDS in patients treated with cisXRT [24] has a number of limitations, which reduce the validity of the obtained results. The major limitation of this retrospective study is its low power. Among 402 patients that received and completed cisXRT, a total of 285 patient medication records were reviewed for GTDS use, and 47 were identified. Identification was made difficult by the fact that GTDS is an outpatient prescription, therefore was not available on medical records. Only five patients met eligibility criteria to be included in the retrospective analysis. Patients were excluded due to being on other trials, or having previously received chemotherapy; or receiving additional chemotherapeutic agents with cisplatin; or having other malignancies. Patients were matched 3:1 (oral:patch). All five patients that received GTDS had at least three known risk factors for nausea, and four out of five had subjective improvement. However, rescue antiemetics were required for CINV in all five patients and treatment delays due to CINV were seen in two of the five patients.

The pelvis is a site of radiation at low emetic risk, therefore a single 5-HT₃ receptor antagonist could be used alone as either prevention or rescue [1]. However, cisplatin is considered the prototype of HEC, as it causes severe emesis in all treated patients, at all doses in clinical use. This is the reason why in this study the efficacy of GTDS was evaluated for its ability to prevent CINV rather than RINV.

Therefore, the above-mentioned study was too small and too limited to draw conclusions on a possible role of GTDS in RINV.

Tolerability profile of granisetron transdermal delivery system

The tolerability profile of GTDS seems to be very good in cancer patients undergoing single or multiday HEC or MEC. Tolerability of a medication is related not only to its pharmacological activity, but also to its pharmaceutical form. Therefore, in the case of GTDS, adverse events could be related specifically to either the active drug, granisetron, or the transdermal route of administration.

Considering the route of administration, there are two major issues for all transdermally delivered medications, which are adhesion and skin tolerance.

Concerning adhesion, in the clinical studies that evaluated the efficacy and safety of GTDS in CINV, a low rate (~1% of patients) of complete patch detachment was observed [13–14,20–21,23]. In the Phase III study by Boccia et al. 64% of patients had ≥90% adhesion compared with 78% in the placebo group. The remaining 36% of patients with at least 10% of the patch detachment could represent the weak point of the system [21]. Oily skin, perspiration and body hair are all factors that may impair patch adhesion, resulting in reduced drug delivery and inefficacy. Patches should be applied on clean, dry, hairless skin, avoiding oily soaps or skin moisturizers. However, it should be remembered that, even though the patches are waterproof, excessive sweating, as may occur in cancer patients because of opioid treatment or fever after chemotherapy, or immersion in water may cause partial or complete patch detachment.

Skin tolerance of the patch is good. Application site pruritus has been observed in a negligible percentage of patients (0.3%) [20–21,23].

In cancer patients who received HEC or MEC, GTDS was generally well tolerated [20–21,23]. The incidence of TEAEs was comparable between GTDS and oral granisetron (about 40%) [21]. Most of these events were not related to the study drug. Constipation was the most commonly reported adverse event and its incidence was higher in patients treated with GTDS (7%) than in those treated with oral granisetron (3%) [21], but lower for GTDS (2.7%) versus palonosetron (5%) [23]. Concomitant use of opioids in cancer patients may strongly interfere with this side effect. In the Phase III study by Boccia et al. [21], opioids were not included in the list of concomitant medications prohibited during the trial; however, there were no data available on their use. The only serious adverse event in patients receiving GTDS was a case of constipation, while, in the oral granisetron group, one case of toxic megacolon and three cases of QTc prolongation were reported. Constipation is also common to other 5-HT₃ receptor antagonists; however, it may represent a problem particularly when patients are receiving opioid therapy for cancer pain. Opioids act on mu-opioid receptors in the GI system and reduce peristalsis. Constipation is the most frequent adverse event in chronic opioid users, leading to the requirement for laxatives or reducing the analgesic dose and consequently pain relief [26]. Conversely, headache was more frequent in patients receiving oral granisetron (2.5%) than in those receiving GTDS (0.3%). All other drug-related adverse events were reported in 0–0.3% of the GTDS group and in 0–2.5% of the oral granisetron group.

Cardiovascular safety

5-HT₃ receptor antagonists, among other noncardiovascular drugs, are known to be associated with modifications of cardiac repolarization, by blocking hERG potassium channel (I_Kr) [27]. The recognition of the potential for QTc interval prolongation by noncardiovascular therapies has led to intense regulatory interest in the identification and characterization of repolarization effects of new and approved drugs [28]. All four members of the class (dolasetron, ondansetron, palonosetron and granisetron) may cause 50% I_Kr tail current inhibition, at different drug concentrations (IC₅₀), with different clinical safety margins for each drug administered at the recommended oral dose (Table 2) [29].

Concerns about potential QTc interval prolongation by 5-HT₃ receptor antagonists has led to regulatory label changes. Despite these concerns, only a few studies have addressed ECG changes in cancer patients treated with 5-HT₃ receptor antagonists for CINV. However, cancer patients may be particularly frail, because they are often older and have a higher incidence of comorbidities. Moreover, they are exposed to polytherapy; therefore they are more likely to be at risk of drug–drug interactions between chemotherapy and other QTc-prolonging drugs. In cancer patients with cardiovascular disease the choice of 5-HT₃ receptor antagonist may be crucial.

In December 2010, the FDA prohibited use of intravenous dolasetron for CINV due to substantial QTc interval prolongation, while its use for postoperative nausea and vomiting (PONV) was not discontinued because of the lower recommended dose [30]. Conversely, intravenous dolasetron for any indication was withdrawn from the Canadian market, due to its low safety profile, which is the lowest among the four 5-HT₃ receptor antagonists [31].

Ondansetron is the most potent I_Kr blocker among the four 5-HT₃ receptor antagonists, and its safety profile after oral doses of 8 mg is very low. According to a recent postmarketing analysis, 60 reports of arrhythmia occurrence have been reported, predominantly after intravenous administration. Most of these patients (67%) had a significant medical history or concomitant use of other QTc-prolonging medications, and one third occurred in cancer patients receiving chemotherapeutic agents [32]. In June 2012, the FDA prohibited use of intravenous ondansetron at doses above 16 mg due to marked QTc prolongation observed in the Thorough QTc Study and anecdotal reports of ondansetron-related arrhythmias [33]. The recommended oral dose is 24 mg administered as three 8 mg tablets over 30 min, and the recommended intravenous dose is 16 mg or less.

In August 2012, the EMA restricted the maximum single intravenous dose of ondansetron to 16 mg, by an infusion lasting at least 15 min, with particular caution in patients with clinical conditions that may increase the risk: alterations in electrolytes (hypokalemia and hypomagnesemia), congestive heart failure, bradyarrhythmias and use of other concomitant drugs affecting QTc interval. High-risk patients should be screened by routine ECG and electrolytes, particularly when receiving intravenous ondansetron [32].

Palonosetron has the best safety profile among the four 5-HT₃ receptor antagonists, because it has the highest IC₅₀ concentration and almost the lowest therapeutic plasma concentration. In cancer patients receiving chemotherapy, evaluation of ECG findings revealed that palonosetron caused a significant prolongation in PR distance, without any effect on QTc interval. Therefore it can be safely administered as an antiemetic in patients undergoing chemotherapy [34]. It may be considered safe in terms of QTc interval, even during general anesthesia with sevoflurane [35].

Granisetron also has a very high safety profile, however, in the USA, a safety warning has been added to the label for oral and intravenous administration, advising use with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this may lead to clinical sequelae [36]. In the study by Boccia et al. cardiovascular safety was assessed in 468 patients for whom full ECG data were available: no clinically significant ECG morphology changes were observed for either treatment, and no cases of QTc prolongation were recorded in the GTDS group [21]. A parallel four-arm study was conducted in healthy subjects, randomized to receive intravenous granisetron, GTDS, placebo or oral moxifloxacin, as active control [29]. Among a total of 240 subjects enrolled, neither intravenous granisetron nor GTDS were associated with statistically or clinically significant effects on QTc interval or other electrocardiographic variables. Despite GTDS achieving more prolonged therapeutic plasma concentrations of drug than intravenous granisetron, the longer exposure did not lead to significant or progressive QTc prolongation. These findings suggest that granisetron has a minimal effect, if any, on the QTc interval.

Discussion

Nausea and vomiting, because of the nature of their symptoms, are difficult to treat via the oral route of administration. Oral antiemetics may be not appropriate for patients who cannot swallow. However, on the other hand, intravenous infusions are not appropriate for management of symptoms at home and increase the risk of infections, particularly in oncological patients. Therefore, when CINV goes beyond the acute phase and becomes delayed, prolonged ‘noninvasive’ treatments are desirable, especially for multiple-day chemotherapy.

The transdermal route represents a suitable choice in terms of ease of use, duration of treatment and patient compliance. In recent years, interest in transdermal formulations has grown. Beyond GTDS, pharmaceutical research is seeking alternative methods of transdermal delivery for other antiemetics. A transdermal gel containing 2% ondansetron has been studied in vitro and tested in vivo in a rabbit model [37]. How to optimize transdermal penetration of other antiemetics is still under evaluation; the rate of drug ionization may be key to increasing the efficacy of transdermally delivered drugs [38].

Currently, the only available transdermally delivered antiemetic is GTDS. Clinical studies have shown its efficacy and overall good tolerability in the challenging set of patients undergoing multiple-day chemotherapy with MEC or HEC. This formulation may also have a role in the management of other forms of nausea and vomiting.

The PK profile of GTDS suggests a possible role in the management of anticipatory nausea and vomiting (ANV), which occurs in about 20% of treated patients before chemotherapy administration. This is a form of learned or conditioned response, as repeated exposure increases the risk; therefore, given its psychological basis, behavioral, rather than pharmacological approaches may be indicated [39]. Current guidelines for preventing ANV suggest use of the most active antiemetic regimens appropriate for the chemotherapy being administered for controlling acute and delayed CINV. If ANV occurs, behavioral therapy is suggested. New generation antiemetic treatments, which are more effective than their progenitors, have reduced the incidence of ANV. GTDS, which is administered 24–48 h before the beginning of chemotherapy could be investigated in this setting.

Another field to be explored is the efficacy of GTDS in preventing RINV. The only available study on combined radiation and chemotherapy is inconclusive because of the numerous limitations, including sample size and methodology [24].

Moreover, in the literature there are no direct comparisons between GTDS and other 5-HT₃ receptor antagonists, aside from oral granisetron. Nowadays, the gold standard 5-HT₃ receptor antagonist is long-acting palonosetron, which is recommended in the ASCO guidelines as first-line therapy for the prevention of CINV following single-day MEC regimens. Therefore, in the future, randomized controlled trials comparing GTDS and palonosetron are warranted to identify the correct position of GTDS in oncological protocols; the primary outcomes of such trials should be at least noninferiority and comparison of the tolerability profiles, and studies of repeated administration of GTDS may also be envisioned.

Finally, beyond CINV, GTDS could be useful in other conditions that are affected by nausea and vomiting. A recent trial showed the efficacy of GTDS in the management of patients with gastroparesis and nausea and vomiting refractory to conventional treatments [40]. Similarly, GTDS has been successfully used in women with nausea and vomiting associated with pregnancy who could not tolerate administration via the oral route. The reduction of nausea and vomiting was observed within one day, suggesting that the onset of action with the transdermal delivery was comparable with the intravenous infusion [41]. In chronic pain management, opioid titration is a critical step in patient compliance; unfortunately, even though tolerance reduces the incidence of opioid-induced nausea and vomiting over time, its incidence can be high and impair patients’ impression of the received treatment, leading to withdrawal for adverse events. A noninvasive, long-lasting antiemetic such as GTDS could represent a valid, well-accepted option for managing this side effect. Similarly, in the management of PONV, particularly in certain types of surgery where the incidence of PONV is higher or when these events are strongly feared for the first postoperative days (i.e., in stomach surgery), GTDS could be evaluated as alternative to currently used intravenous medications. Obviously these are only hypotheses of the authors, which need to be confirmed by well-structured clinical trials.

Conclusion

In conclusion, GTDS is currently the only transdermal antiemetic to be approved by the FDA and EMA for the treatment of CINV following multiple-day HEC or MEC. GTDS is an innovative and effective option, and is generally well tolerated in patients with cancer receiving chemotherapy; despite this, there are still a number of avenues to be explored regarding this formulation and such studies will further our understanding of the management of CINV.

Table 1. Pharmacokinetics of granisetron transdermal delivery system versus oral granisetron.

Pharmacokinetics	GTDS (52 cm^2 patch for 6 days)	Oral granisetron (2 mg for 5 days)
		Day 1	Day 5
Cmax (ng/ml)	3.85	5.25	5.5
Tmax (h)	48	1.5	2
Cavg (ng/ml)	2.23	2.14	2.6
T1/2 (h)	35.9	6.4	7.9
AUC 0–∞ (ng/ml*h)	420	65	98

AUC: Area under the curve concentration; C_avg: Average concentration; C_max: Maximum plasma concentration; GTDS: Granisetron transdermal delivery system; T_1/2: Half-life; T_max: Peak of maximal concentration.

Adapted with permission from [8].

Table 2. IC₅₀ for hERG cardiac K⁺ channel inhibition of 5-HT₃ receptor antagonists.

Drug	IC50 (mM)	PB (%)	Oral dose (mg)	Cmax (ng/ml)	Safety margin
Dolasetron	5.95	73	100	229	31
Ondansetron	0.81	73	8	38.1	35
Palonosetron	6.50	62	0.25	5.6	901
Granisetron	3.73	65	2	2	605

C_max: Maximum plasma concentration; IC₅₀: Concentration causing 50% inhibition of hERG tail current; K: Potassium; PB: Protein bound.

Adapted with permission from [29].

Executive Summary

• Multiple-day chemotherapy is associated with a high incidence of chemotherapy-induced nausea and vomiting (CINV).

• Granisetron transdermal delivery system (GTDS) is the first 5-HT₃ receptor antagonist to be transdermally delivered and represents a convenient alternative to oral and intravenous antiemetics for the treatment of CINV.

Rationale for developing transdermal formulations

• Transdermal formulations have a number of advantages, including:

  • Continuous medication delivery, constant rate of administration, prolonged action;

  • Distant application from sites of action;

  • By-pass of the GI tract and avoidance of first-pass hepatic metabolism;

  • Ability to directly enter systemic circulation;

  • High patient compliance due to reduced number of administrations and reduced pill burden;

  • Use in patients unable to take or tolerate parenteral or oral formulations.

Pharmacological profile of granisetron transdermal delivery system

• Granisetron is strongly selective for 5-HT₃, with little or no affinity for other serotonin receptors.

• C_max is reached in 48 h and T_1/2 is 36 h.

• Clearance is predominantly hepatic and is approximately halved in patients with hepatic impairment. Plasma clearance is not affected by age, gender or renal function.

Clinical evaluation of granisetron transdermal delivery system

• Following single-day MEC, no significant differences were observed in total control of CINV among patients receiving GTDS and oral granisetron.

• Following multiple-day MEC or highly emetogenic chemotherapy, GTDS was not inferior to intravenous and oral granisetron or intravenous palonosetron for total control of CINV.

Tolerability profile of granisetron transdermal delivery system

• The most commonly reported drug-related adverse event is constipation.

• While studies suggest minimal effect on the QTc interval, special caution is needed in patients at increased risk of developing excessive QTc interval prolongation and arrhythmias.

Conclusion

• GTDS is effective in the prevention of CINV in patients with cancer who are receiving multi-day MEC or HEC.

• GTDS is noninferior to intravenous and oral granisetron and intravenous palonosetron in this indication, and is generally well tolerated.

• GTDS provides a convenient option for the prevention of CINV, with the potential to improve patient compliance.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

English editing and technical checking of the manuscript before submission was provided by Carmen Innes, on behalf of Springer Healthcare Communications. This medical writing assistance was funded by Kyowa Kirin, Italy.