5-Hydroxytryptamine3 receptor antagonists and cardiac side effects.

Review

5-Hydroxytryptamine3 receptor antagonists and cardiac side effects 1.

Introduction

2.

Development of antiemetics

3.

What are the differences

Louise Brygger & Jørn Herrstedt† on behalf of the Academy of Geriatric Cancer Research (AgeCare) †

Odense University Hospital, Odense, Denmark

between serotonin antagonists?

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Newcastle on 09/12/14 For personal use only.

4.

Assessment of cardiovascular adverse events induced by antiemetics

5.

Cardiovascular AEs induced by older antiemetics

6.

Cardiovascular AEs induced by 5-HT3-receptor antagonists

7.

Pharmacokinetic and dynamic drug interactions with serotonin receptor antagonists and risk of QT prolongation

8.

Special issues with 5-HT3 receptor antagonists in patients with heart disease

9. 10.

Conclusion Expert opinion

Introduction: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. Areas covered: The purpose of this article is to outline the risk of cardiac adverse events (AEs) from 5-HT3-RAs, with focus on the three most commonly used, ondansetron, granisetron and palonosetron. Expert opinion: Most of the studies analyze electrocardiogram (ECG) changes after 5-HT3-RA administrations in healthy, young adults, or in noncancer patients to treat postoperative nausea and vomiting (PONV). Only a few studies have addressed ECG changes in cancer patients treated for chemotherapyinduced nausea and vomiting (CINV). Investigations in cancer patients are essential, because these patients are older and have a higher incidence of comorbidity, than those usually included in clinical trials. Furthermore, polypharmacy is frequent and drug--drug interactions between chemotherapy and other QTc-prolonging drugs may influence the pharmacokinetics and pharmacodynamics of the 5-HT3-RAs. During the next 10 -- 15 years a huge increase in the number of cancer patients is expected, primarily in the group of 65-plus-year old. Therefore it will be crucial to address the incidence of cardiac AEs in cancer patients with known heart disease receiving chemotherapy and a 5-HT3 RA for the prophylaxis of CINV. Keywords: 5-Hydroxytryptamine3-receptor antagonist, cardiac adverse events, cardiac side effects, granisetron, ondansetron, palonosetron, QT prolongation Expert Opin. Drug Saf. [Early Online]

1.

Introduction

Because nausea and vomiting are ranked by patients among the worst adverse effects of chemotherapy, the effective prevention of chemotherapy-induced nausea and vomiting (CINV) is a major achievement in cancer treatment. Developments in supportive care, including the progress in antiemetic therapy in CINV have enabled patients to tolerate treatment with new antineoplastic agents even when used in combination chemotherapy regimens and/or as part of multimodality therapy. A supportive care drug should help improving tolerability of antineoplastic therapy and quality of life and as such ideally be devoid of adverse effects. The tolerability of 5-hydroxytryptamine3receptor antagonists (5-HT3-RA) is high with mild constipation and headache as class adverse effects in ~ 10% of patients. Also QTC prolongation has been observed in a number of patients. Recently, the FDA withdrew the approval of the high (32 mg) dose of the 5-HT3-RA ondansetron, due to cardiac adverse effects reported in a number of patients [1]. The purpose of this article is to outline the risk of cardiac adverse effects from 5-HT3-receptor antagonists in the adult population, focusing cancer patients. 5-HT3-RA are the most widely used antiemetics in oncology [2], and it is estimated that in the US the utilization of 5-HT3 receptor antagonists doubled from 10.1517/14740338.2014.954546 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

1

L. Brygger & J. Herrstedt

Article highlights. .

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.

.

5-Hydroxytryptamine (5-HT)3-receptor antagonists are the most important antiemetics in the prophylaxis of chemotherapy-induced nausea and vomiting. QT prolongation is a class adverse effect of the 5-HT3-receptor antagonists. QT prolongation has resulted in retraction of the high 32 mg intravenous dose of ondansetron and of the intravenous formulation of dolasetron. Specific attention should be paid to risk populations such as patients with comorbidity, in particular cardiac disease, and older cancer patients using multiple medications constituting a risk of drug--drug interactions. Before initiating treatment with a 5-HT3-receptor antagonist, it is recommended to complete a check list, to identify risk patients and other medications with the potential of inducing QT prolongation.

This box summarizes key points contained in the article.

2007 through 2012 and > 20 million patients were billed for such a product in the hospital setting in 2011 [3]. Focus of this article will be on the cardiovascular safety profile of the three most commonly used, ondansetron, granisetron and palonosetron. 2.

Development of antiemetics

Assessment of cardiovascular adverse events induced by antiemetics

4.

Clinical trials in the 1960 -- 1980s investigating CINV focused on cannabinoids and agents that act at dopamine receptors, antagonizing the effect of dopamine. Randomized, placebocontrolled trials in the1980s showed that metoclopramide (MCP) in higher doses of 2 mg/kg 5 intravenously (i.v.) or 3 mg/kg 2 yielded marked antiemetic efficacy and were well tolerated [4,5]. Addition of dexamethasone to high-dose MCP increased the efficacy, and when a benzodiazepine was included the risk of extrapyramidal adverse reactions decreased significantly [6,7]. Studies showed that high-dose MCP affects the 5-HT3 receptor, a receptor that soon appeared to be important in CINV [8-10]. During the next years the synthetic highly selective 5-HT3-receptor antagonists were developed, showing a remarkable improvement in antiemetic effect [11-16]. This class of agents was the first one specifically developed for the purpose of antiemesis. The addition of corticosteroids to serotonin antagonists improved the efficacy [17], and this combination forms the cornerstone in the treatment of CINV today. Subsequent studies have demonstrated that the addition of the neurokinin (NK)1-receptor antagonist, aprepitant, further increases the antiemetic effect in patients receiving cisplatin-based or anthracycline--cyclophosphamide-based chemotherapy [18,19]. 3. What are the differences between serotonin antagonists?

Today seven classes and several subgroups of 5-HT receptors are recognized (5-HT1-5-HT7), but although 5-HT1A, 2

5-HT2A/2C and 5-HT4 receptors all seem to be involved in the induction of emesis, 5-HT3 receptor antagonists are, so far, the only clinically useful antiemetics among the 5-HT receptor antagonists [20]. Since the first clinical studies investigating the effect of 5-HT3-receptor antagonists were published in 1987 [11,16], investigators have discussed whether there are any differences within this group of antiemetics, and if these differences have clinical significance. Palonosetron, that was marketed > 10 years later than ondansetron and granisetron has a halflife of around 40 h, compared with < 10 h for the other 5-HT3-receptor antagonists [21]. Other pharmacological differences between palonosetron and the other 5-HT-receptor antagonists such as allosteric binding of palonosetron to 5-HT3 receptors and palonosetron-induced internalization of 5-HT3 receptors have been claimed [22]. Ondansetron is effective as a single dose before chemotherapy, but though it has been stressed that the dose--response curve is nonlinear, no significant differences in antiemetic effect has been shown between a single dose of 8 and 32 mg ondansetron i.v. [23]. Also granisetron is today dosed as a single i.v. dose of 1 mg or an oral dose of 2 mg. Palonosetron is dosed as a single oral dose of 0.5 mg or 0.25 mg i.v. In Japan the i.v. dose is 0.75 mg, due to the results of Phase II studies.

The most frequent cardiovascular adverse events (AEs) induced by antiemetic agents are orthostatic hypotension, prolongation of the QTc interval and other ECG segments and different arrhythmias. Prolonged QTc reflects cardiac repolarization prolongation and/or increased repolarization inhomogeneity known to be associated with increased risk of the polymorphic ventricular tachycardia called Torsades de Pointes (TdPs) [24-26]. QTc measurement standardization does not exist due to low reproducibility caused by difficulties in defining the end of the T wave [27]. By convention, lead II has been chosen to measure the QT interval [28]. In stable sinus rhythm, a QT interval corrected for heart rate (QTc) of > 440 ms for men and > 450 ms for women is considered abnormal. Prolongation of the QTc interval > 500 ms, or an increase of > 60 ms is considered to increase the risk of TdPs [25,26,29]. When diagnosing QT prolongation, one should keep in mind that the QT interval varies depending on autonomic tone and state of wakefulness, being ~ 19 ms longer in sleeping patients with a heart rate of 60 beats/min than in awake patients with the same heart rate [28]. Therefore, although Holter monitoring studies can be compared, comparison with standard ECGs may be inaccurate [28]. A prolonged QTc interval is associated with increased risk of coronary heart disease and cardiovascular disease (CVD) mortality in middle-aged, elderly and young adults [30]. In a large

Expert Opin. Drug Saf. (2014) 13(10)

5-hydroxytryptamine3 receptor antagonists and cardiac side effects

Table 1. Pharmacokinetics of a single oral dose of 5-HT3 receptor antagonists.

Cardiovascular AEs induced by older antiemetics

5.

Drug

Tmax (h)

Cmax (ng/ml)

t½ (h)

Ondansetron 8 mg

1.0-2.0

31.88

4.8

2.0

4.7

7.9

5.1

0.93

48

[116-118]

Granisetron 2 mg [119]

Palonosetron 0.5 mg [120]


5-HT: 5-Hydroxytryptamine.

prospective study (n = 7983), a prolonged QTc interval was associated with a more than twofold increased risk of sudden cardiac death (SCD) independent of other cardiovascular risk factors, and in patients below the median age of 68 years, a prolonged QTc interval was associated with an eightfold increased risk of SCD [31]. Congenital or inherited long QT syndrome (LQTS) is a disease characterized by prolonged ventricular repolarization and is associated with an elevated risk for SCD or survived cardiac arrest (SCA). The prevalence of the disease is around 1/2000 -- 1/3000 of the general population [26,32]. Typical hallmarks are a prolonged QT interval on the ECG, specific T-wave alterations, polymorphic ventricular arrhythmias of the TdP type, and an indicative family history. However, the electrocardiographic phenotype is variable and clinical symptoms may range from asymptomatic patients to lifethreatening arrhythmias such as SCA and SCD. Long QT type 1 is one of the most common forms of congenital LQT, and 25% of these demonstrate a normal QT interval -- a so called ‘concealed’ or ‘silent’ LQTS [10,33]. The latter population always carries a QT-prolonging predisposed genetic variant (mutation or SNP) but present normal QT interval at regular ECG. These patients are disposed to develop drug-induced LQT/TdP comparing to those without the gene variant. The concealed LQT syndrome can be demasked from sympathetic stimulation leading to TdP [11,34], but to our knowledge, no literature exist regarding concealed LQTS and drug-induced TdP from 5-HT3-receptor antagonists. When addressing the risk of QTc prolongation as an AE from 5-HT3-receptor antagonists, it is mandatory to do ECG monitoring at the time of the highest plasma concentration, because it is expected that the highest plasma concentration (Cmax) will induce the highest risk of QTc prolongation. The pharmacokinetics including the estimated time to maximal concentration (Tmax) of oral ondansetron, granisetron and palonosetron are seen in Table 1. Of the studies listed in Tables 2 -- 4, it should be noted that only a few of these studies would have been able to diagnose potential QTc prolongation, because ECG assessments were completed too early or too late as regards Tmax (Table 1).

The primary cardiac side effect induced by phenothiazines and butyrophenones are orthostatic hypotension, which can be severe [35]. Both haloperidol and droperidol are now known to be associated with QTc prolongation and risk of TdP, and in 2001 the FDA issued a black box warning on droperidol because of the risk of QTc prolongation and TdP arrhythmias [36-39]. MCP has with its central and peripheral dopamine2-receptor antagonistic function, been reported to induce cardiac side effects in particular increase in the QT/RR slope, QT variance and TdP arrhythmia [40-42]. Domperidone is a butyrophenone derivative and a dopamine2-receptor antagonist acting primarily on D2-receptors in the gut [43]. The i.v. domperidone was withdrawn from the market in the mid-1980s after reports linking it to QT prolongation, cardiac arrhythmias, cardiac arrest and sudden death. Oral domperidone is marketed over the counter in several European countries, but has also been reported with QTc prolongation, TdP and other cardiac arrhythmias, and EMA has recently completed a review of the risk--benefit profile of domperidone. Currently, domperidone should not be administered to patients with preexisting QTc prolongation or to those receiving other drugs that inhibit CYP3A4 [44].

Cardiovascular AEs induced by 5-HT3-receptor antagonists

6.

A large number of 5-HT3-receptor antagonists have completed Phase I--II trials, but only a few have completed Phase III and subsequently been marketed. Some serotonin antagonists induce hypotension [45] and arrhythmia with QTc prolongation and risk of TdP as the most serious AEs. When addressing the risk of drug-induced QTc prolongation, one should also explore to what extent it is a problem in the daily clinic and how many suffer from inherited QTc prolongation (as described in Section 2). In addition, many other drugs bear a risk of QTc prolongation, meaning that polypharmacy, including two or more of such drugs further increase the risk of QTc prolongation. Class-specific adverse effects of 5-HT3-receptor antagonists

6.1

Administration of the 5-HT3-receptor class of antiemetic agents has been associated with prolongation in the QRS, JT and QT intervals of the ECG [46]. The underlying mechanism is induction of Na+-channel blockage in the myocytes, especially during tachycardia, and blockage of the human Ether-a´-go-go-Related Gene (HERG) K+ channels, leading to prolongation of the cardiac repolarization phase [46,47]. However, none of these agents produces a current


3

4


N = 12 healthy adults 18--50 years


N = 85 PONV 28--60 years

N = 400 PONV 18--51 years

N = 136 PONV 34--45 years N = 70 PONV 38--66 years N = 45 CINV patients

N = 609 CINV patients 28--85 years

N = 696

R, DB, CO, 4 periods

R, DB, CO, 4 periods

Observational

R, SB, P

R, DB, P

R, SB, P

Open

R, DB, P

R, DB, P

[58]

[59]

[63]

[60]

[61]

[62]

[66]

[64]

[65]

Cisplatin < 50 mg/m2, CTX, DOX, carboplatin

Cisplatin > 70 mg/m2

Cisplatin < 100 mg/m2

None

None

None

None

None

None

None

Chemotherapy (mg/m2)

Ondansetron 4 mg i.v. versus droperidol 1.25 mg i.v. versus both versus placebo Ondansetron 1 mg i.v. versus 4 or 8 mg i.v. versus placebo Ondansetron 8 mg i.v. versus granisetron 1 mg i.v. Ondansetron 8 mg iv versus dolasetron 2.4 mg/kg i.v. Ondansetron 32 mg i.v. versus dolasetron 1.8 or 2.4 mg/kg i.v. Ondansetron 32 mg i.v. versus dolasetron 2.4 mg/kg i.v.

Ondansetron 32 mg i.v. versus dolasetron versus placebo Ondansetron 32 mg i.v. versus granisetron 10 µg/kg in 30 s versus in 5 min versus placebo Ondansetron 4 mg i.v. versus droperidol 1 mg i.v. versus both versus placebo Ondansetron 4 mg i.v. versus droperidol 0.75 mg i.v.

Antiemetic regimen

Prior to and 1--2 h and 8 days after AEM

Prior to and 1--2 and 24 h after AEM

Prior to and 2 and 24 h after AEM

Prior to surgery and 1, 3, 5, 10, 15, 20, 40, 60, 120, 240 and 360 min after AEM Prior to and 2, 5, 15 min, 1 and 2 h after AEM

Prior to surgery and prior to and 5 min -- and 3 h after AEM

Prior to and 1, 2, 3, 5, 10 and 15 min after AEM. In 16 pts also 30,45,60,90,120 and 180 min after AEM

Prior to and at 1 min intervals for 15 min, then 20, 30, 45, 60, 90, 120, 240, 420 and 600 min after AEM

Prior to and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h after AEM. A cardiologist checked QTc Prior to and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after AEM

ECG measurement

QTc and QRS prolongations were common changes, but did not result in clinical events or symptoms.

Small, transient, clinically insignificant changes in PR, QRS, QT, QTc, JT

Significant but asymptomatic and transient QTc prolongation after 4 and 8 but not after 1 mg Significant more QTc > 440 ms in the ondansetron group. ECG changes resolved after 2 h Significant reduction in heart rate

Significant and transient QTc prolongation, correlated with lower body tp and duration of anesthesia. 6 pts with QTc > 500 ms, no TdP. 1 pt developed supraventricular tachycardia Significant but asymptomatic and transient QTc prolongation (resolved after 3 h)

Significant but asymptomatic and transient QTc prolongation. None had QTc > 500 ms. No TdP. No significant changes in BP

Significant but asymptomatic and transient QTc and JT prolongation and a decrease in HR Significant, but asymptomatic and transient QTc prolongation

ECG changes (ondansetron)

AEM: Antiemetics; CO: Cross-over; CTX: Cyclophosphamide; CINV: Chemotherapy-induced nausea and vomiting; DB: Double-blind; DOX: Doxorubicin; ECG: Electrocardiogram; P: Parallel; PONV: Postoperative nausea and vomiting; R: Randomized; TdP: Torsades de Pointe.

N = 30 healthy young men

R, SB, CO, 5 periods

[57]

Patients and setting

Design

Ref.

Table 2. Trials investigating ECG changes induced by ondansetron.




N = 21 CINV 29--71 years




N = 30 CINV 25--80 years N = 22 CINV 2--16 years

N = 468 CINV

Observational

Observational

Observational study

R, DB, P

Observational

R, SB

R, DB, P

[74]

[75]

[72]

[121]

[73]

[70]

[77]

Cisplatin-based (72%) or noncisplatin (28%)

High-dose MTX

DOX or EPI

Cisplatin-based > 80 mg/m2

High-dose MTX, ifosfamide and others. 72 courses of chemotherapy completed

Cisplatin-based

Cisplatin or other emetogenic cytotoxic agents.

None


Granisetron 40 µg i.v. versus ondansetron 0.1 mg/kg i.v. Granisetron transdermal patch versus granisetron 2 mg po

Granisetron 3 mg i.v. versus dolasetron 1.8 or 2.4 mg/kg i.v. Granisetron 3 mg i.v.

Granisetron 50 µg/kg i.v.

Granisetron 80 µg i.v. or granisetron 120 µg i.v.

Granisetron 0,1 mg/10 kg i.v. versus granisetron 3.1 mg/24 h as a patch versus moxifloxacin versus placebo Granisetron 3 mg i.v.

Antiemetic regimens

Before and after AEM (not further specified)

Prior to and at the end of infusion and 10 min after AEM Prior to and at the end of infusion and1, 3, 6 and 24 h after AEM

Prior to and 1--2 h and 24 h after AEM

Continuously ECG monitoring from 10 min prior to and 24 h after AEM Continuous ECG monitoring from 1 h prior to and until 5 days after AEM

Continuously ECG monitoring from 6 h prior to and 1 h after AEM

ECG prior to and 0.25, 0.5, 1, 2, 4, 8, 12 h on days -- 1 and 3

ECG measurement

Significant, but asymptomatic and transient PR prolongation. No other ECG changes observed Significantly prolonged QTc after 1 h and a decrease in heart rate at 1 and 3 h after granisetron No clinically significant ECG changes were seen

Various transient arrhythmias were observed in 4 out of 12 cases all related to granisetron (before administration of chemotherapy Small increases in QTc, PR and QRS after 1--2 h but not clinically significant

A small, but statistically significant decline in diastolic blood pressure. No changes in ECG recorded post-infusion as compared to pre-infusion. No significant changes in blood pressure, pulse rate. No significant ECG changes

No statistical significant QTc prolongation or other ECG changes were seen with transdermal granisetron

ECG changes (granisetron)

AEM: Antiemetics; CINV: Chemotherapy-induced nausea and vomiting; DB: Double-blind; DOX: Doxorubicin; ECG: Electrocardiogram; EPI: Epirubicin; MTX: Methotrexate; P: Parallel; R: Randomized.


Patients and settings

R, SB, P

Design

[71]

Ref.

Table 3. Trials investigating ECG changes induced by granisetron.



5


Table 4. Trials investigating ECG changes induced by palonosetron.


Ref.

Design

Patients and settings


[87]

R, DB, P


None

[91]

Observational


Cisplatin-based > 50 mg/m2 or CTX + DOX/EPI

[89]

Observational


[90]

Observational

[88]

Observational

N = 50 CINV 45--69 years N = 76 CINV

Antiemetic regimens

ECG measurement

ECG changes (palonosetron)

Palonosetron 0.25 mg i.v. versus placebo for 3 consecutive days Palonosetron 0.75 mg i.v. plus DEX on day 1--3

ECG 5 min prior and 20 min after AEM on days 1 and 3

No changes from baseline in QTc or other ECG parameters

ECG before and day 2--4 and 8--10 after AEM

Non anthracycline high or moderately emetogenic chemotherapy

Palonosetron 0.25 mg iv

ECG prior to and 30, 60 and 90 min after AEM

Emetogenic chemotherapy, not specified Emetogenic chemotherapy, not specified

Palonosetron 0.25 mg i.v. plus DEX 8 mg i.v. Palonosetron 0.25 mg i.v. plus DEX 8 mg i.v.

ECG prior to and 30 min after AEM, but before chemotherapy ECG prior to and 30 min after AEM, but before chemotherapy

3--5% had QTc prolongation > 60 ms from baseline, but it is not possible to distinguish between AEM-related and chemotherapy-related No significant change in QTc, but a significant decrease in heart rate and prolongation of the PR interval No significant change in QTc or other ECG parameters No statistical significant changes in blood pressure or ECG parameters were observed. A 10 ms statistically insignificant increase of median QT

AEM: Antiemetics; CINV: Chemotherapy-induced nausea and vomiting; CTX: Cyclophosphamide; DB: Double-blind; DOX: Doxorubicin; ECG: Electrocardiogram; EPI: Epirubicin; P: parallel; R: Randomized.

blockade > 30% of HERG channels thought to be particularly important in the genesis of TdP [46]. In a review of reports published between 1963 and 2002, Navari and Koeller [48], concluded that i.v. 5-HT3-receptor antagonists do not pose a significant cardiovascular risk, but as pointed out by Keefe [49], available data are inadequate to classify the risk as negligible, especially in patients with preexisting CVD and those receiving cardiotoxic chemotherapeutic agents. Over the last 3 years, there have been changes in the labeling for several 5-HT3 receptor antagonists relating to cardiac repolarization effects. Prescribing information for both the oral [50] and i.v. [51]. formulations of ondansetron state that transient QT prolongation was identified during postapproval use rarely but predominantly with i.v. administration. A warning was recently added to the label to avoid the use of ondansetron in patients with congenital LQTS and to recommend ECG monitoring in certain patient groups [50,51]. Recently, the i.v. dose of 32 mg was withdrawn by FDA from the market due to new data (unpublished) demonstrating a significant risk of QTc prolongation with this dose. No safety concerns were expressed about the oral formulation or with lower i.v. doses. Oral and injection granisetron prescribing information was updated recently to state that QT 6

prolongation has been reported, but indicates that an adequate assessment has not been done [52,53]. Palonosetron prescribing information reports QT prolongation as an adverse reaction, with an incidence ‡ 2% among postoperative surgical patients and < 1% among patients with CINV, and reports that a double-blind randomized, parallel, placebo-controlled trial in healthy adults showed no significant effect on the duration of the corrected QT interval [54]. Ondansetron In electrophysiological studies, ondansetron has been shown to prolong action potential duration in purkinje fibers, which supports the theoretical risk of QT interval prolongation, as the QTc interval is the reflection of the action potential duration [55,56]. 6.2

Ondansetron and QTc prolongation The early studies of AEs from single doses of ondansetron 8 versus 32 mg i.v. did not report any ECG examinations, and as a consequence could not discover incidences of QTc prolongation. On the other side, no cardiac deaths were described [23-25]. Later several studies of ondansetron have found conflicting results about the risk of QTc prolongation (Table 2). The 6.2.1



studies differ in designs -- some testing healthy volunteers in nonchemotherapy settings, and other testing ondansetron in comparative studies versus other 5-HT3-RAs or placebo in chemotherapy settings. There is no consistency between studies in the time and intervals of ECG assessments in relation to ondansetron administration. The way of calculating QTc also varies. Some studies rely on computer-generated QTc measurements, while others calculate QTc using Bazett’s formula. Due to these differences it is difficult to compare studies.

knowledge, studies on the cardiac safety of ondansetron in lower doses in the CINV setting do not exist. Ondansetron and other dysrhythmias Two casuistic descriptions exist of patients developing atrial fibrillation after receiving ondansetron 4 mg i.v. for protection of PONV. Both cases were with former uncomplicated medical history [67,68]. 6.2.2

Ondansetron and blood pressure changes A study reported a single case of slightly blood pressure elevation after i.v. administration of 32 mg ondansetron, but without clinical consequences [58]. In a large prospective study of pre-hospital administration of 4 mg ondansetron i.v. or intramuscular (n = 2071), one case of significant hypertension, and three cases of mild hypotension were observed [69]. Based on the current literature, changes in blood pressure are very rare and do not seem to be clinically relevant. 6.2.3

Ondansetron and healthy volunteers Benedict et al. [57] made a placebo-controlled, randomized controlled trial in 30 healthy men and found that ondansetron 32 mg i.v. induced asymptomatic but significant QT prolongation between 0 and 4 h, returning to baseline after 8 h. However, when corrected for a decreased heart rate it did not result in significant QTc prolongation. In a small study, Boike et al. [58] found that ondansetron 32 mg i.v. induced significant QTc prolongation with mean post-dose QTc interval of 390 +/- 18 ms, but 1/12 subjects had a QTc > 440 ms. In another trial [59] ondansetron 4 mg i.v. caused significant QTc prolongation, but no incidences of TdP or QTc prolongation > 500 ms were observed.


6.2.1.1

Ondansetron and surgery Ondansetron has been investigated in randomized, placebocontrolled trials in the prevention of postoperative nausea and vomiting (PONV), primarily in the gynecological setting. Ondansetron 4 mg i.v. has been reported to induce insignificant [60] or significant [61] QTc prolongation (> 460 ms). In a third study, ondansetron 8 mg i.v. resulted in significant QTc prolongation (> 470 ms) [61]). In a recent randomized comparison between ondansetron 8 mg i.v. and granisetron 1 mg i.v. for PONV, ondansetron led to significant but asymptomatic higher mean QTc prolongation (QTc > 440 ms), but no incidence of clinically relevant cardiac AEs was recorded [62]. In an observational study in PONV, Charbit et al. [63] found that ondansetron 4 mg i.v. or droperidol 0.75 mg i.v. both induced significant QTc prolongation, but the results were confounded by the fact that many patients had QTc prolongation before administration of antiemetics, probably correlated to low body temperature and duration of anesthesia. Therefore, conclusions from studies investigating effects of 5-HT3-receptor antagonists administered during anesthesia should be interpreted with caution. 6.2.1.2

Ondansetron and chemotherapy As earlier mentioned, ECG changes have not been carefully monitored in early trials comparing the effect of 32 versus 8 mg ondansetron in CINV. We only found three studies evaluating cardiac adverse and ECG changes induced by i.v. ondansetron 32 mg in patients receiving chemotherapy. All found slightly but clinically insignificant QTc prolongations from 32 mg ondansetron i.v. [64-66]. To the best of our 6.2.1.3

Granisetron The arrhythmogenic effect of granisetron has been investigated in small studies with different dosage regimens in groups of healthy volunteers and cancer patients prior to chemotherapy. 6.3

Granisetron and QTc prolongation There are conflicting reports in the literature on the effects of granisetron on ECGs [70-76]. This is in part due to the fact that an appropriately designed study has not been conducted to accurately determine the repolarization effects of granisetron or any other drug in its class. Granisetron delivered by the i.v., oral or transdermal route is generally safe in healthy volunteers with respect to its effect on cardiac repolarization [71,73-77]. However, very high plasma concentrations of granisetron could be associated with clinically significant increases in QTc, although this possibility is only weakly supported by pharmacodynamic analyses [71]. Interestingly, data from a randomized, double-blind, Phase III trial of transdermal granisetron in patients who were receiving multiday moderately or highly emetogenic chemotherapy showed no clinically significant changes in ECG morphology and no cases of QTc prolongation [77]. The transdermal administration form will of course result in much lower peak concentrations than i.v. administration. A recent randomized, placebo-controlled study (n = 240) did not find significant differences in the QTc interval after transdermal or i.v. administration of granisetron [71]. It should however be noted that the study was carried out in healthy volunteers and that the dose of i.v. granisetron was low (0.1 mg per 10 kg body weight). 6.3.1

Granisetron and other dysrhythmias Only a few studies have investigated other cardiac side effects than QT prolongation. In a small group of pediatric oncology patients receiving noncardiotoxic chemotherapy (carboplatin), granisetron 40 µg/kg induced bradycardia, whereas 6.3.2


7


10 µg/kg did not [78]. In a study (n = 30) using computergenerated ECG monitoring, 3 mg of granisetron i.v. resulted in a small but significant prolongation of the PR interval [69]. In another study, using continuous Holter ECG recording no significant arrhythmias were seen after a 30-s infusion of granisetron 3 mg before chemotherapy [70]. Granisetron and blood pressure changes The potential change in blood pressure following administration of granisetron has primarily been tested in the PONV setting, where blood pressure changes could relate to blood loss or sympathetic stimulation as well [79]. We found no studies, demonstrating a direct effect of granisetron on blood pressure.


6.3.3

Palonosetron Palonosetron originally started its development almost at the same time as the ‘older’ 5-HT3-receptor antagonists, but the development was put on hold for a number of years and the agent was not approved by FDA until 2003. In comparison with the ‘older’ 5-HT3-receptor antagonists, palonosetron has a higher binding affinity to 5-HT3 receptors and a significantly longer half-life of 40 h (4--5 times as long as the T½ of ‘older’ 5-HT3-receptor antagonists). Also, palonosetron seems to have affinity for different subtypes of 5-HT3 receptors, allosteric binding and positive cooperativity [22,80]. The safety profile does not seem to differ significantly from that of the others of the same class as demonstrated in several Phase I -- III studies [81-87]. 6.4

Palonosetron and QTc prolongation Three small studies investigated the arrhythmogenic effect of palonosetron 0.25 mg i.v. and included ECG assessment before and 20--30 min after dosing. One of the studies continued ECG assessments after 60 and 90 min. None of these studies reported any significant QTc prolongation [88-90]. In a Phase III study (n = 538) exploring cardiac AE from palonosetron 0.75 mg i.v. administered to patients receiving highly emetogenic chemotherapy also no significant QTc alterations were observed. The timing of ECG assessment was not specified, meaning that the time for peak concentration may have been missed [91]. In comparative trials of palonosetron and ondansetron, ondansetron seems to consistently induce more frequent QTc prolongations. These studies, however, used ondansetron 32 mg for comparison, a dose that has now been withdrawn. Whereas no QT prolongation has been demonstrated with palonosetron in the CINV setting, two studies demonstrated QTc prolongation in the PONV setting [92,93]. It should be remembered that this could be due to anesthesia and therefore not necessarily induced by palonosetron. 6.4.1

Palonosetron and other dysrhythmias Gonullu et al. [89] found palonosetron to cause a significant decrease in heart rate and a prolongation of the PR segment on ECGs in cancer patients, but no other dysrhythmias were described. 6.4.2

8

Palonosetron and blood pressure changes No sign of palonosetron-induced hypotension has been described [83-85] including the large (n = 538) Phase III study of Aogi et al. [91]. 6.4.3

Other 5-HT3-receptor antagonists The most widely distributed of other 5-HT3-receptor antagonists, dolasetron, has been withdrawn as an i.v. formulation in CINV due to a FDA alert from December 2010. Health-care professionals and patients were alerted ‘that dolasetron injection is contraindicated in the prevention of chemotherapy induced nausea and vomiting due to increased risk of abnormal heart rhythms and other changes on the electrocardiogram (ECG).’ 6.5

Pharmacokinetic and dynamic drug interactions with serotonin receptor antagonists and risk of QT prolongation

7.

Cancer is primarily a disease of the elderly and ~ 60% of all cancers and 70% of all cancer deaths occur in people aged 65 years or older. In a recent study 70-plus-year-old cancer patients had an average daily use of five different prescription medications. On top of that come complementary and alternative medication plus antineoplastic and supportive care drugs [94]. Polypharmacy increases the risk of drug--drug interactions (DDIs) and as such the risk of QT prolongation. More than 50 prescription medications from multiple therapeutic classes, including serotonin antagonists, class Ia and III antiarrhythmics, antibiotics, tricyclic antidepressants, antihistamines, antipsychotics and selective serotonin reuptake inhibitors have been shown to cause QT prolongation [27,28,95]. DDIs from use of multiple QT-prolonging drugs, or agents that alter the biotransformation of a QT-prolonging medication can lead to increased risk of severe QTc prolongation [27]. The antifungals, ketoconazole and itraconazole are frequently used in cancer patients and are powerful inhibitors of CYP450 3A4 enzymes that metabolize many drugs, which can lead to large increases in plasma levels of QTc prolonging drugs [28].

Special issues with 5-HT3 receptor antagonists in patients with heart disease

8.

Due to old age, the vast majority of cancer patients have one or more comorbidities, including heart disease. In an observational study, Hafermann et al. investigated patients with heart failure or acute coronary heart syndrome and risk factors of developing TdP, and found that administration of i.v ondansetron 4 mg caused significant QTc prolongation up to 2h after administration [95]. A recent database study on DDIs included 187 patients from a cardiac intensive care unit with known QTc




prolongation > 500 ms. Most of these patients received twodrug combinations with the potential of pharmacodynamic or pharmacokinetic QTc prolongation, but observed QTc prolongation did not result in any cases of TdPs, but longterm outcomes were not evaluated [27]. The DDIs most commonly found in this study included ondansetron, amiodarone and haloperidol. A low potassium level in combination with bradycardia is known to increase the risk of QTc prolongation [28]. Tisdale et al. [96] investigated the prevalence of QTc prolongation among patients admitted to cardiac care units (defined as QTc > 470 ms for women, > 480 ms for men, and severe QTc prolongation > 500 ms). None of the patients received a 5-HT3-receptor antagonists, but amiodarone, fluoroquinolones, antibacterials and haloperidol accounted for ~ 80% of the QTc prolongations. Of the patients with QTc prolongation upon admission, 34.5% had QTc prolongation > 500 mg or and increase > 60 ms, and of these 57% developed additional QTc prolongation, although none developed TdP. The prevalence of hypomagnesemia and hypokalemia was significantly higher in the group of patients with QTc prolongation compared to the group without QTc prolongation. The prevalence of kidney or liver disease was not significantly different among groups. Because the incidence of hypomagnesaemia and hypokalemia is high among cancer patients receiving chemotherapy (e.g., cisplatin or carboplatin), and those vomiting or treated with diuretics, one must expect such cancer patients of having a particular high risk of QTc prolongation. Subsequently, Tisdale et al. developed and validated a risk score to predict QTc interval prolongation in patients admitted to cardiac care units. Independent predictors of QTc prolongation included the following: female gender, diagnosis of myocardial infarction, septic shock, left ventricular dysfunction, administration of ‡ 2 QT-prolonging drugs or loop diuretic, age > 68 years, serum potassium < 3.5 mEq/L, and admitting QTc > 450 ms [97]. This means that older cancer patients and in particular women have a high risk of QTc prolongation, that is further enhanced because of the high frequency of polypharmacy among elderly cancer patients [94]. 9.

Conclusion

5-HT3-receptor antagonists are the backbone of antiemetic prophylaxis in patients receiving emetogenic chemotherapy. As such millions of cancer patients have received one or more of these agents since the first one, ondansetron, was marketed in 1990. ECG changes in particular QTc prolongation is a class effect of the 5-HT3-receptor antagonists. However, the significant benefits from these agents seem to outweigh the theoretical small risk of symptomatic cardiovascular events. The highest risks seemed to be induced by i.v. dolasetron and high-dose (32 mg) i.v. ondansetron. Consequently, both i.v. dolasetron and high-dose ondansetron have been withdrawn

from the market. Granisetron has the risk of developing QTc prolongation in children, whereas palonosetron seems to be safe in the CINV setting.

10.

Expert opinion

Most of the studies analyzing ECG changes after 5-HT3receptor antagonist administration have limited inclusion to healthy, young adults or noncancer patients in the PONV setting. Many of these studies measured QTc intervals during or shortly after anesthesia, not taking into account the fact that the QT interval varies depending on autonomic tone and state of wakefulness [30]. Only a few studies addressed ECG changes in cancer patients receiving chemotherapy and a 5-HT3-receptor antagonist in the prophylaxis of CINV. The high dose of 32 mg i.v ondansetron was recently retracted from the marked. Typically, the pivotal studies [64-66] only found clinically insignificant ECG changes, and no cases of clinically cardiac AE. Specific trials in cancer patients are essential, because cancer is primarily a disease of old age resulting in a high frequency of comorbidity, including cardiac disease. Furthermore, dehydration and electrolyte disturbances are frequently induced by cancer therapies adding to the risk of drug-induced cardiac AEs. Old age and comorbidity predispose to polypharmacy increasing the risk of DDIs between chemotherapy, 5-HT3receptor antagonists and other QTc prolonging drugs. Many chemotherapeutic agents may cause cardiac dysrhythmias or other cardiotoxic AEs. These include anthracyclines [98-103], paclitaxel [104], cisplatin [105] and 5-fluorouracil [106,107]. Also high-dose cyclophosphamide [108], carboplatin [109] and interleukin-2 [110] are associated with cardiotoxicity. This may further increase the risk of cardiac AE in patients receiving a 5-HT3-receptor antagonist. Our knowledge of elderly cancer patients’ tolerance to and benefit from treatment is sparse due to underrepresentation of this patient group in clinical trials. In the period from 2007 to June 2010, 24 drugs were approved by FDA for the treatment of cancer, and only 33% of patients included in the registration trials were age 65 years or older compared to 59% of the US cancer population aged 65 years or older [111]. In addition, older cancer patients included in these trials were limited to those with no or little comorbidity only. Therefore, results obtained in these trials may not be applicable to the elderly without additional risk assessment. The biggest challenge in oncology is the ‘tsunami’ of older cancer patients, appearing during the coming decades. In high economic countries, a huge increase in the number of cancer cases is expected during the next 10--15 years. For example, in Denmark an increase in the number of new cancer cases during the next 10 years of 30% is expected [112]. The vast majority of this increase will be in 65-plus-year-old patients. It is therefore of utmost importance, that future trials are designed to include older cancer patients and that specific


9



Table 5. Drugs with known increased risk of QTc prolongation, frequently used among cancer patients. Drug class

Generic group

Generic name

Anti-emetics Anti-emetics

Dopamin-receptor antagonists 5-HT3-receptor antagonists

Anti-emetic/anti-psychotics Anti-cancer drugs, small molecules

5-HT1-receptor antagonist Kinase inhibitors

Anti-cancer drugs Analgesics Anti-fungal drugs

Estrogen agonist/antagonist Opiate Azoles

Antibiotics

Fluoroquinolones

Antibiotics

Macrolids

Antibiotics Antidepressants

Trimetoprim-sulfa SSRI

Antidepressants Antidepressants

SNRI Tricyclic

Antipsychotics Antipsychotics

Antipsycotis, typical Antipsycotics, atypical

Domperidone Granisetron Ondansetron Palonosetron Dolasetron Promethazine Crizotinib Vemurafenib Lapatinib Vandetanib Pazopanib Sorafenib Bosutenib Dasatenib Sunitinib Tamoxifen Methadone Voriconazole Fluconazole Itraconazole Ketoconazole Ciprofloxacin Moxifloxacin Azitromycin Clarithromycin Erythromycin Roxithromycin Trimetoprim-sulfa Fluoxetine Paroxetine Sertraline Citalopram Escitalopram Venlafaxine Amitryptoline Clomipramine Nortryptoline Haloperidol Clozapine Quetiapine Risperidone Olanzapine

Therapeutic use Nausea and vomiting Nausea and vomiting

Nausea and vomiting Cancer

Breast cancer Pain Fungal infection

Infection Infection

Infection Depression, anxiety

Depression Depression/neuropathic pain

Schizophrenia/agitation Schizophrenia

5-HT: 5-Hydroxytryptamine.

trials address older cancer patients with comorbidity such as heart disease. Although determination of QTc interval changes is less than a perfect marker of the risk of proarrhythmia, it has become a standard requirement in the development of new drugs. Thus, while all drugs that induce TdP lengthen the QT interval, not all drugs that lengthen the QT interval induce TdP [113-115]. Therefore, as described by Morganroth et al. [115], the biggest challenge is to test a drugs risk of QTc prolongation, and the risk of the QTc prolongation emerging to TdP in cancer patients, as the impact of the disease, together with comorbidities and comedications, in patients with cancer is such that they are unable to tolerate excessive testing. 10

To prevent arrhythmia related to QT prolongation induced by 5-HT3 receptor antagonist administration, the following check list could be useful: 1) Obtain a proper medical history and identify patients with the following risk factors for QTc prolongation: i) Congenital forms of LQTS, history of arrhythmia and syncope, presence of ischemic heart disease, cardiomyopathy and/or congestive heart failure; ii) Female sex and increasing age are independent risk factors and should also be take into consideration; iii) Patients receiving drugs that may prolong the QTc interval (in particular antipsychotics, antidepressants, see also



Table 5); iv) Patients receiving multiple drugs, including

2)

3)


4)

5)

a risk of DDI with 5-HT3-receptor antagonists resulting in drug accumulation (CYP3A4 inhibitors, in particular carbamazepine, rifampicin and phenobarbital). Obtain a baseline ECG, serum potassium and magnesium concentrations and correct abnormal values before initiating treatment with a 5-HT3-receptor antagonist. Repeat ECG, serum potassium and magnesium before each course of chemotherapy in risk patients. A baseline QTc interval > 440 ms for men and > 450 ms for women is considered abnormal. In this case, a follow-up ECG after administration of 5-HT3receptor antagonist on the expected time for Tmax (1 -- 2 h for p.o. ondansetron 8 mg, 2 h for p.o. granisetron 2 mg and 5 h for p.o. palonosetron 0.5 mg) is recommended. Prolongation of the QTc interval to > 500 ms, or an increase of > 60 ms is considered to increase the risk

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Affiliation


Louise Brygger1 & Jørn Herrstedt†2 MD DMSc on behalf of the Academy of Geriatric Cancer Research (AgeCare) † Author for correspondence 1 Odense University Hospital, Department of Oncology R, Odense, Denmark 2 Professor of Clinical Oncology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark Tel: +45 2933 6469; E-mail: [email protected]

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Side-effects, structure, and H2-receptor antagonists.

Side Effects of Leukotriene Receptor Antagonists in Asthmatic Children.

Cardiac side effects of targeted therapies.

[Cardiac side effects of 5-fluorouracil].

The renal effects of mineralocorticoid receptor antagonists.

Hemodynamic effects of different H2-receptor antagonists.

Haemodynamic effects of H2-receptor antagonists.

The cardioprotective effects of mineralocorticoid receptor antagonists.

GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists.

Effects of oral H1 and H2 receptor antagonists in asthma.

Side effects and contraindications of beta-receptor blocking agents.

Left Cardiac Sympathetic Denervation: Should We Sweat the Side Effects?

The liver X receptor agonist AZ876 protects against pathological cardiac hypertrophy and fibrosis without lipogenic side effects.

Triterpenes from Alisma orientalis act as androgen receptor agonists, progesterone receptor antagonists, and glucocorticoid receptor antagonists.

Cerebroprotective effects of angiotensin II (AT 1) receptor antagonists?

The antiallergic effects of antihistamines (H1-receptor antagonists).

Effects of H2-receptor antagonists on blood alcohol levels.

Effects of H2-receptor antagonists on blood alcohol levels.

Vasopressin and vasopressin receptor antagonists.

Development of NMDAR antagonists with reduced neurotoxic side effects: a study on GK11.

Differential sleep-promoting effects of dual orexin receptor antagonists and GABAA receptor modulators.

Effects of dopamine receptor and alpha 2-adrenoceptor agonists and antagonists on muscarinic receptor stimulation in cardiac sympathetic ganglia of the dog.

Thromboxane A2 receptor antagonists.

Drugs and side-effects.