Cancer Management and Research Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Use and cardiovascular safety of transdermal and other granisetron preparations in cancer management 1 Jay W Mason Abstract: 5-HT3 antagonists have been available as oral and intravenous preparations for Thomas E Moon2 decades. The availability more recently of transdermal granisetron and the anticipated availability of a subcutaneous granisetron preparation have provided helpful alternatives to patients, and 1School of Medicine, University of Utah, Salt Lake City, UT, these preparations have been shown to have less potential to prolong QT than other drugs in 2Tarizona eHealth Services, Inc, the class. Emeryville, CA, USA Keywords: chemotherapy-induced nausea, vomiting, granisetron, QT prolongation Introduction Problem of chemotherapy-induced nausea and vomiting For personal use only. Chemotherapy-induced nausea and vomiting (CINV) occurs in 10%–90% of patients, depending on the emetic risk of the chemotherapeutic agent.1,2 There is a consider- able cost involved, not only for the expense of hospitalization and the direct treatment of CINV, but also because of the loss of workdays and the consequences of delayed 3–7 chemotherapy administration. There is consistent evidence that 5-HT3 antagonist antiemetic therapy has improved this problem without increasing the cost.3–7 Unmet needs in CINV treatment Delayed nausea and vomiting occurring hours or days after chemotherapy, either as a result of reduced plasma concentrations of prophylactic antiemetics administered at the time of chemotherapy, or inefficacy of ongoing oral antiemetic medications, is a Cancer Management and Research downloaded from https://www.dovepress.com/ by 137.108.70.14 on 22-Jan-2020 significant management problem.3,8 Palonosetron, due to its long half-life, provided a potential solution to this problem,9 yet despite its introduction, the problem continues to adversely affect the quality of life of chemotherapy recipients.10 An important objec- tive of the granisetron transdermal (TD) delivery system is maintenance of effective plasma concentration of granisetron during and for several days after administration of chemotherapy. Oral and intravenous (IV) administration of granisetron and other antiemetics is problematic in some patients. Because the oral route is complicated by variable bioavail- ability and by noncompliance, while the IV route may be too inconvenient, painful or Correspondence: Jay W Mason expensive for some patients, other modes of administration have been sought.11 Mason Cardiac Safety Consulting, 105 Londonderry Court, Reno, NV, 89511, USA Purpose of this report Tel +1 775 8499910 The purpose of this report is to review and assess the contribution of TD granisetron Fax +1 775 8499910 Email [email protected] to the control of acute and delayed CINV, and to delineate its place in the management submit your manuscript | www.dovepress.com Cancer Management and Research 2013:5 179–185 179 Dovepress © 2013 Mason and Moon, publisher and licensee Dove Medical Press Ltd. This is an Open Access article http://dx.doi.org/10.2147/CMAR.S34352 which permits unrestricted noncommercial use, provided the original work is properly cited. Powered by TCPDF (www.tcpdf.org) 1 / 1 Mason and Moon Dovepress of CINV. Because of the recent safety concerns related to QT (Cmax) is similar among young, elderly, and normal volunteers prolongation by 5-HT3 antagonists, leading to multiple label and patients, terminal elimination is considerably slower in changes12 and a product recall,13 the potential for arrhythmo- patients with cancer, and nearly as slow in elderly normals genesis through TD granisetron is discussed at length. compared to young normals (Table 1). Oral dosing with granisetron 2 mg qd (once a day) in Methods normal volunteers resulted in a mean Cmax of 5.5 nanogram/ 16 This report is based on a review of the medical literature, milliliter (ng/mL) and t1/2 of 7.9 hours on day 5, while a dose available US Food and Drug Administration (FDA) com- of 1 mg bid (twice a day) in patients with cancer resulted 16 munications and product labels, and a P&T Product Pro- in a Cmax of 5.9 ng/mL, according to the package insert. 14 filer provided by ProStrakan (Bridgewater, NJ, USA). In t1/2 in patients is not reported in the package insert or in the addition, pharmacokinetic and cardiac safety data regarding published literature. APF530, a sustained release subcutaneous (SC) preparation of granisetron, was provided by AP Pharma, Inc (Redwood Transdermal granisetron City, CA, USA). Product description The granisetron TD patch uses a drug-in-adhesive matrix Preparations, pharmacology, and diffusion method to deliver a predictable dose of granis- pharmacokinetics of granisetron etron for up to 7 days. The patch is a 52 cm2 rectangle that Currently available preparations contains 34.3 mg of granisetron, and delivers it at a rate of of granisetron 3.1 mg per 24 hours. Transdermal drug delivery is possible because the skin can absorb small, lipophilic molecules Granisetron is available as an oral tablet (1 mg or 2 mg), and by diffusion. The size of the transdermal patch, specific an IV infusion (1 mg in 1 mL and 3 mg in 3 mL ampules), characteristics of the matrix material in which the drug is both marketed under the brand name Kytril (Roche, Basel, For personal use only. suspended, properties of the drug itself, and the status of Switzerland) and as a generic compound. Granisetron in a TD the skin to which the patch is applied determine the rate patch (34.3 mg) was approved in 2008 and marketed under the and extent of drug delivery. While transdermal delivery is brand name Sancuso (ProStrakan, Inc). A sustained-release generally slow, requiring several hours or days to achieve SC injection (APF530, AP Pharma, Inc) may become avail- steady state, the plasma concentrations achieved are pre- able before or soon after publication of this report, as the US dictable and are not subject to rapid change, maximizing FDA has responded to a new drug application submission for the potential for efficacy without toxicities that result from this preparation, and approval during 2013 was established excessive plasma concentration. by the sponsor as its objective. Pharmacokinetics of transdermal Pharmacology of granisetron Granisetron and other selective 5-HT antagonists block granisetron 3 In a Phase 1 crossover study of twelve normal volunteers, Cancer Management and Research downloaded from https://www.dovepress.com/ by 137.108.70.14 on 22-Jan-2020 receptors in afferent vagal nerve termini in the gut and in the Howell et al17 compared the pharmacokinetics of the 52 cm2 chemoreceptor trigger zone (CTZ). Vagal receptors in the gut, patch to that of oral granisetron 2 mg daily (Figure 1). when stimulated by serotonin release by the intestinal mucosa Several differences are evident. The time at which maximum as a result of chemotherapy, send a signal to the vomiting center and the CTZ that induces nausea and vomiting. Direct Table 1 Pharmacokinetics of granisetron stimulation of the CTZ by chemotherapeutic agents may also Health status Age, years Mean C Mean t induce emesis. Granisetron prohibits the emesis reflex by max 1/2 IV granisetron* blocking these receptors. Normal volunteers 21–42 64.3 ng/mL 4.91 hours 65–81 57.0 ng/mL 7.69 hours Patients with cancer 63.8 ng/mL 8.95 hours Pharmacokinetics of IV Oral granisetron and oral granisetron Normal volunteers† 5.5 ng/mL 7.9 hours As indicated in the package insert,15 the elimination half-life Patients with cancer‡ 5.9 ng/mL – Notes: *40 µg/kg; †2 mg qd; ‡1 mg bid. (t1/2) of IV granisetron (40 µg per kg) depends on both age Abbreviations: t1/2, elimination half-life; IV, intravenous; qd, once a day; bid, twice a and health status. While the maximum plasma concentration day; ng/mL, nanogram/milliliter; Cmax, maximum plasma concentration. 180 submit your manuscript | www.dovepress.com Cancer Management and Research 2013:5 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Safety of granisetron preparations in cancer management 6 Patch 52 cm2 receiving a single dose (Straken Pharmaceutical Ltd, 2007) Mean concentration 5 patch 52 cm2:2.2 ng/ml of chemotherapy and repeated doses19 of chemotherapy over 2 mg oral 4 Mean concentration 3 to 5 days, in controlling both acute (first 24 hours) and oral:2.6 ng/ml 3 late (24–120 hours) CINV. In the single-day chemotherapy 2 18 1 study, 210 patients were randomized in a 1:1 ratio to receive Granisetron (ng/mL) 0 either oral granisetron or the TD patch, both administered 024287296 120 144 168 192 216 240 Time (hours) once. Total control of CINV (no nausea and no use of rescue medication) was achieved in 52.4% of patients in the former Figure 1 Plasma concentrations of granisetron resulting from repeated oral dosing (2 mg daily) and the Sancuso 52 cm2 TD patch17 in normal volunteers. and 43.7% in the latter group (not statistically or clinically Note: The patch was removed at the end of day 6 (144 hours). significantly different). Abbreviations: TD, transdermal; ng/mL, nanogram/milliliter. In the multiple-day study,19 in which 323 patients were randomized to receive daily oral granisetron given when plasma concentration was achieved (Tmax) was 1.5 hours to chemotherapy was administered, and 318 to receive the 2 hours during oral dosing, and approximately the same Cmax TD patch applied once 24 hours before chemotherapy and was achieved each day. Tmax for the patch was 48 hours, and removed on day 7, complete control of CINV (no more than Cmax varied substantially from day to day. While Cmax was mild nausea) was reported by 64.8% in the former group, greater after oral dosing compared to patch administration, and 60.2% in the latter (not significantly different) during the mean plasma concentration through 5 days was similar.