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Original Article

The Effects of Supratherapeutic Doses of Duloxetine on Blood Pressure and Pulse Rate

Derby, Michael A DO, PhD*†; Zhang, Lu MS*; Chappell, Jill C PharmD*; Gonzales, Celedon R MS, PhD*; Callaghan, J T MD, PhD*‡; Leibowitz, Mark MD§; Ereshefsky, Larry PharmD§; Hoelscher, David MD; Leese, Philip T MD; Mitchell, Malcolm I MBBS, MFPM**

Author Information
Journal of Cardiovascular Pharmacology: June 2007 - Volume 49 - Issue 6 - p 384-393
doi: 10.1097/FJC.0b013e31804d1cce
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Abstract

Serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) have highly complex actions in the central and peripheral nervous systems. Increasing the availability of these neurotransmitters in the synaptic cleft via alteration of the functioning of pre- and postsynaptic components of the 5-HT and NE systems is a well-established mechanism of action of many antidepressants.1,2 Increases in peripheral neurotransmitter activity, however, particularly the activity of NE, may stimulate the cardiovascular system. As a result, cardiac effects at both therapeutic and supratherapeutic dosages are an important measure of safety for antidepressants.

Duloxetine is a potent dual inhibitor of 5-HT and NE uptake.3-6 It also weakly inhibits dopamine reuptake, but has low affinity for histaminergic, dopaminergic, cholinergic, or adrenergic receptors.3 Duloxetine has been studied for the treatment of depression7-12 and in the management of diabetic neuropathic pain13-15 at doses of 40 to 120 mg/day.

The cardiovascular profile of duloxetine at doses of 40 to 120 mg/day was evaluated in an analysis of pooled data from 1,139 patients treated for 8 or 9 weeks with duloxetine in eight double-blind, randomized, placebo-controlled depression trials.16 The analysis revealed a modest difference in the changes in pulse rate from baseline to end point between the duloxetine 120 mg/day [1.8 beats per minute (bpm)] and placebo (−0.6 bpm) groups (P < 0.001). Duloxetine treatment also resulted in small mean increases across all doses in systolic blood pressure from baseline to endpoint (+1.0 mm Hg with duloxetine versus −1.2 mm Hg with placebo; P < 0.001), but the difference in the changes in diastolic blood pressure between the treatment groups was not significant. Mean changes in systolic and diastolic blood pressures did not appear to be consistently dose related, and the incidence of sustained (at least three consecutive time points) elevations in systolic or diastolic blood pressures did not differ significantly between duloxetine and placebo.

Because duloxetine is metabolized primarily by cytochrome P450 1A2 (CYP1A2), with minor clearance by cytochrome P450 2D6 (CYP2D6),17 patients taking recommended doses of duloxetine concomitantly with an inhibitor of CYP1A2 could be exposed to high levels of duloxetine. To assess the safety of supratherapeutic doses of duloxetine, a double-blind, placebo-controlled study of duloxetine at doses up to 200 mg twice daily (BID) was conducted in healthy female subjects. The primary objective of this study was to confirm that supratherapeutic exposure to duloxetine would not increase the mean QTc interval compared with placebo. These results appear in a companion paper.18 The secondary objective of the study was to evaluate the overall safety and tolerability of duloxetine at high systemic exposures.

METHODS

Study Design

This was a double-blind, randomized study of duloxetine and placebo conducted at six centers in the United States. Qualified subjects were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing groups. Subjects in groups 1 and 2 received duloxetine and placebo regimens in a two-way crossover, followed by moxifloxacin, a fluoroquinolone known to mildly prolong the QTc interval. Moxifloxacin was incorporated into the study design as a control to establish assay sensitivity for the QT evaluation.18 Subjects in groups 3 and 4 received moxifloxacin, followed by the duloxetine and placebo crossover regimen. Dosing with moxifloxacin was followed by a 3-day washout period. In the crossover portion of the study, subjects in groups 1 and 3 first received duloxetine for 20 days (period 1) followed by placebo for 22 days (period 2); subjects in groups 2 and 4 followed a similar schedule, but received placebo during the first period and duloxetine during the second period. The study was conducted in accordance with good clinical practices and the ethical principles that have their origin in the Declaration of Helsinki. The protocol was approved by the appropriate Institutional Review Boards.

Subjects

The study enrolled healthy female volunteers between the ages of 18 and 75 years, inclusive. Subjects were required to have normal blood pressure and pulse rate (supine and standing) as determined by the investigator. Subjects with clinically significant abnormal physical examination findings or laboratory test results or an electrocardiogram reading considered outside the normal limits by the investigator were excluded. Subjects who were genotyped as CYP2D6 poor metabolizers or intended to use inhibitors or inducers of CYP1A2 or CYP2D6 within 2 weeks before or during the study were also excluded. Written informed consent was obtained from all subjects prior to entry into the study.

Dosing Regimen

Duloxetine was administered to a maximum dose level of 200 mg BID. To assess individual safety at this dose level, subjects progressed through a dose-escalation procedure in which duloxetine (or placebo) was given at four dose levels [60 mg BID (level 1), 120 mg BID (level 2), 160 mg BID (level 3), and 200 mg BID (level 4)]. Subjects were dosed at each level for 4 days to reach steady-state exposures based on an approximate 12-hour elimination half-life for duloxetine. Subjects who failed to tolerate study drug during the first two dose levels were discontinued from the study. After completing the highest dose-level in period 1, subjects began a 4-day taper period during which they received duloxetine 120 mg BID for 2 days and then 60 mg BID for 2 days, or the corresponding placebo for 4 days. After completing the highest dose-level of period 2, subjects began a 6-day taper period during which they received duloxetine 160 mg BID for 2 days, 120 mg BID for 2 days, and 60 mg BID for 2 days, or the corresponding placebo for 6 days. A washout period of at least 4 days followed the final day of duloxetine deescalation.

In an effort to mitigate adverse events that commonly occur with initiation of duloxetine dosing, such as nausea, the initial dose of study drug and the first dose of each successive dose escalation were taken after the evening meal. The second dose at each dose level was taken in the morning with the morning meal. Thus, in this study, the twice-daily dosing regimen began with the evening dose and ended with the morning dose. During dose escalation, subjects took the final dose of drug at each level on the morning of the fourth day.

Prescription medications and over-the-counter medications were permitted during the dosing period as long as they did not induce or inhibit CYP1A2, or inhibit CYP2D6.

Vital Sign Measurements and Assessment

Vital sign measurements included blood pressure and pulse rate in the supine position (after approximately 5 minutes) and standing position (after approximately 2 minutes). Vital signs were measured to monitor safety each day before morning dosing and as clinically indicated. In addition, sequential vital sign evaluations were scheduled at baseline (prior to study drug administration on day 1) and on the fourth day of dosing at dose levels 3 and 4 at approximately 2, 6, 10, and 12 hours after the morning dose of duloxetine or placebo. The timing of these measurements was chosen to provide measurements at trough, at peak, and during ascending and descending exposures based on pharmacokinetic profiles from previous clinical pharmacology studies.19

Hypertension was defined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure20 as a supine blood pressure ≥140 mm Hg or a supine diastolic blood pressure ≥90 mm Hg. Orthostatic hypotension was defined according to the Consensus Criteria for Orthostatic Hypotension21 as a decrease of ≥20 mm Hg in systolic blood pressure or ≥10 mm Hg in diastolic blood pressure between sequential supine and standing blood pressures.

Measurement of Duloxetine Plasma Concentrations

Blood samples for pharmacokinetic analysis of plasma duloxetine concentrations were collected from each subject on the fourth day of dosing at dose levels 3 and 4 at time points that coincided with vital signs measurements (2, 6, 10, and 12 hours). Plasma samples were assayed by validated liquid chromatography with tandem mass spectrometry (LC/MS/MS) methods. Maximum steady-state plasma concentrations (Cmax) were observed from individual concentration-time data.

Safety Assessments

Physical examinations were performed at screening and at study discontinuation. Routine laboratory tests, including hematology, urinalysis, and clinical chemistry, were performed at screening, during the study, and before study discharge. In addition to formal QT assessments (see analysis18), 12-lead electrocardiograms were collected for safety purposes at screening, during the study, and when clinically indicated.

All adverse events reported during the study were recorded by the investigators using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, similar types of events were grouped into a smaller number of standardized event categories defined according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 6.1.22 The MedDRA terms that were considered to be descriptive of symptomatic orthostatic-related adverse events were orthostatic hypotension, postural dizziness, and syncope.

Statistical Analysis

The mean and standard deviation of supine and orthostatic changes in blood pressures and pulse rates, which were measured daily before the morning dose, were calculated and plotted. The number and percentage of subjects who met the criteria for hypertension20 or orthostatic hypotension21 were summarized by study drug (“treatment”) and dose level. A mixed-effect analysis of covariance model was used to compare the effects of duloxetine and placebo on blood pressures and pulse rate at the highest dose levels. This model included baseline as a covariate; treatment, time, and treatment-by-time interaction as fixed effects; and subject, subject-by-treatment, and subject-by-time interactions as random effects. SAS 8.2 software (SAS Institute, Cary, NC) was used for all statistical analyses, and the mixed models were fit using the MIXED procedure. The restricted maximum likelihood estimation and the Kenward and Roger approximation23 of denominator degrees of freedom were specified in the mixed models.

RESULTS

Subjects and Disposition

A total of 117 healthy female volunteers between the ages of 19 and 74 years were enrolled in this study; 56 (48%) were between the ages of 40 and 74 years. Most (59%) were white and most (89%) were nonsmokers. Ninety-two (79%) subjects completed the duloxetine 160-mg BID dose level and 84 (72%) completed the duloxetine 200-mg BID dose level. Overall, 70 (60%) subjects completed all protocol requirements. A total of 47 subjects discontinued (Table 1). Sixteen of the 18 subjects who discontinued because of investigator decision discontinued when one entire site withdrew from the study. Four of the 10 subjects who discontinued because of “subject's decision” asked to be discontinued because of general intolerance (including nausea and vomiting) or discomfort (uncomfortable with the way the drug made her feel). The remaining six asked to be discontinued for administrative or personal reasons.

T1-7
TABLE 1:
Subject Disposition (n = 117)

Vital Signs

Supine Blood Pressure Changes

Initiation of duloxetine at a dosage of 60 mg BID led to increases in supine systolic and diastolic blood pressures over the first few days. Duloxetine produced an increase in supine systolic and diastolic blood pressures, which reached maximums of ~12 mm Hg and ~7 mm Hg, respectively, during dosing at 120 mg BID and then stabilized (Fig. 1A, 1B). Mean supine systolic and diastolic blood pressures taken during dosing with duloxetine 160 mg BID were significantly (P < 0.05) greater than those taken during placebo level 3 (data not shown). Mean blood pressures at the 160-mg BID dose of duloxetine were 3.2 to 7.7 mm Hg (systolic) and 3.6 to 7.1 mm Hg (diastolic) greater than those for placebo up to 12 hours after dosing. Mean supine systolic and diastolic blood pressures taken during dosing with duloxetine 200 mg BID were significantly (P < 0.001) greater than those taken during placebo level 4 (Table 2). Mean blood pressures at the 200-mg BID dose of duloxetine were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7.0 mm Hg (diastolic) greater than those for placebo up to 12 hours after dosing. Supine blood pressures decreased during the taper period, and then returned to normal baseline values upon discontinuation of drug (Fig. 1A, 1B).

T2-7
TABLE 2:
Comparison of Supine Vital Signs Measurements During Treatment With Duloxetine 200 mg BID and Level 4 Placebo at 2, 6, 10, and 12 Hours Postdose on Day 4
F1-7
FIGURE 1:
Mean and standard deviation of vital sign measurements taken each day during treatment before morning dosing with duloxetine or placebo. Solid dots (•) represent subjects in Groups 1 and 3. These subjects received duloxetine for up to 20 days and then placebo for up to 22 days. Asterisks (*) represent subjects in Groups 2 and 4. These subjects received placebo for up to 20 days and then duloxetine for up to 22 days. Broken horizontal line marks the overall mean of all groups at baseline. Broken vertical lines mark each dose level [B = baseline; L1 = level 1 (placebo or duloxetine 60 mg); L2 = level 2 (placebo or duloxetine 120 mg); L3 = level 3 (placebo or duloxetine 160 mg); L4 = level 4 (placebo or duloxetine 200 mg); T1 = tapered dose 1 (placebo or duloxetine 60 mg); T2 = tapered dose 2 (placebo or duloxetine 120 mg); T3 = tapered dose 3 (placebo or duloxetine 160 mg)]. (A) Supine systolic blood pressures. (B) Supine diastolic blood pressures. (C) Supine pulse rate. (D) Orthostatic change in systolic blood pressure. (E) Orthostatic change in diastolic blood pressure. (F) Orthostatic change in pulse rate.

Systolic and diastolic blood pressures were averaged for individual subjects at 0, 2, 6, 10, and 12 hours at baseline, on day 4 of dosing with placebo, and on day 4 of dosing with duloxetine 200 mg BID. Mean blood pressures changed very little between baseline and day 4 of placebo dosing. In contrast, mean blood pressures on day 4 of dosing with duloxetine 200 mg BID were greater than those both at baseline and day 4 of placebo dosing (Fig. 2A, 2B). At any of the five measurement time points on the baseline day, roughly 12% (14 of 116 subjects) of the study population had single blood pressure values that met criteria for hypertension. This percentage increased to 27% (24 of 90 subjects) at any measurement time point after subjects reached steady-state exposure at 200 mg BID, compared with 14% (13 of 96 subjects) at placebo level 4. Blood pressure changes within individual duloxetine-treated subjects appeared to be similar across the study population. At high-dose levels, mean blood pressure increases resulted from similar increases across individuals in the study population, rather than large increases in a few subjects. Scatter plots of the changes from baseline in supine systolic and diastolic blood pressures versus plasma concentrations of duloxetine at the time of the vital signs measurements are shown in Figure 2C and D. There was no discernable effect of duloxetine concentration on the change in supine systolic blood pressure, whereas supine diastolic blood pressure increased slightly with increasing duloxetine plasma concentration.

F2-7
FIGURE 2:
Mean systolic (A) and diastolic (B) blood pressures for each subject averaged over 5 time points (0, 2, 6, 10, and 12 hours) measured at baseline, on day 4 of level 4 placebo treatment, and on day 4 of treatment with duloxetine 200 mg BID. Scatter plots of changes from baseline in supine systolic blood pressure (C) and diastolic blood pressure (D) versus plasma duloxetine concentration.

Supine pulse rate increased asymptotically with increasing duloxetine dose up to steady state at the 160 mg BID level, and then remained relatively constant, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID (Fig. 1C). The mean pulse rates at the 160-mg BID dose were 3.4 to 5.3 bpm greater than those for placebo (P < 0.01), and the mean pulse rates at the 200-mg BID dose were 5.0 to 6.8 bpm greater than those for placebo (P < 0.001; Table 2). As with blood pressures, pulse rates decreased during the taper period, returning to normal values within 1 to 2 days after discontinuation of the drug.

Scatter plots of the changes from baseline in supine pulse rate versus plasma concentrations of duloxetine at the time of the vital signs measurements are shown in Figure 3. Supine pulse rate increased slightly with increasing duloxetine plasma concentration.

F3-7
FIGURE 3:
Scatter plot of changes from baseline in pulse rates versus plasma duloxetine concentration.

Orthostatic Blood Pressure Changes

Orthostatic changes in systolic blood pressures (Fig. 1D), diastolic blood pressures (Fig. 1E), and pulse rates (Fig. 1F) occurred with duloxetine, with mean population changes reaching a plateau near the end of the 160-mg BID dosing period. At baseline, measurements for 12.9% (15 of 116) of subjects met consensus criteria for orthostatic changes. During the 4-day course of dosing with duloxetine 200 mg BID, 70.0% (63 of 90) of subjects met the consensus criteria on at least one occasion; however, fewer than half that number (32.5%) met the criteria at any time point during the steady-state, maximal exposures present on day 4 of dosing with 200 mg BID. During level 4 of placebo dosing, 19.8% (19 of 96) of subjects met the consensus criteria for orthostatic changes.

The differences between orthostatic blood pressures on day 4 of dosing with duloxetine 160 mg BID and day 4 of level 3 placebo dosing were significant (P < 0.001) and ranged from −12.6 to −10.0 mm Hg (systolic) and −7.1 to −4.6 mm Hg (diastolic). The differences between orthostatic blood pressures on day 4 of dosing with duloxetine 200 mg BID and day 4 of level 4 placebo dosing were significant (P < 0.001) and ranged from −13.9 to −9.7 mm Hg (systolic) and −8.1 to −6.7 mm Hg (diastolic; Table 3). All values resolved rapidly during the taper period and reached normal baseline values immediately upon discontinuation of drug (Fig. 1D, 1E).

T3-7
TABLE 3:
Comparison of Orthostatic Changes in Vital Signs During Treatment With Duloxetine 200 mg BID and Level 4 Placebo at 2, 6, 10, and 12 Hours Postdose on Day 4

Scatter plots of the changes from baseline in orthostatic systolic and diastolic blood pressures and pulse rate versus plasma concentrations of duloxetine at the time of the vital signs measurements are shown in Figure 4A-C. Orthostatic decreases in systolic and diastolic blood pressures became slightly more pronounced with increasing duloxetine plasma concentration, whereas orthostatic changes in pulse rates diminished slightly.

F4-7
FIGURE 4:
Scatter plots of changes from baseline in orthostatic systolic blood pressure (A), diastolic blood pressure (B), and pulse rate (C) versus plasma duloxetine concentration.

Adverse Events

Overall Adverse Events

A total of 1776 adverse events were reported during this study; of these, 926 were determined by the investigator to be probably related to study drug (either duloxetine or placebo). All subjects reported at least one adverse event. The most commonly reported drug-related adverse events (≥5%) were headache, nausea, insomnia, dizziness, somnolence, and constipation (Table 4). Except for headache, these events occurred more frequently during duloxetine treatment than during placebo treatment.

T4-7
TABLE 4:
Most Commonly Reported (≥2% of Events) Adverse Events Categorized as Possibly or Probably Related to Study Drug Reported During Treatment with Placebo or Duloxetine

The first day of dosing with duloxetine (60 mg BID) was accompanied by a high incidence of new-onset, mild-to-moderate adverse events, primarily nausea, vomiting, and sleep disturbances. In general, subjects averaged more than two new-onset, drug-related adverse events during initial exposure to duloxetine 60 mg BID. The onset of new events declined by 90% within a few days of the start of dosing, and by day 3-4 had stabilized to a rate of occurrence about twice that during placebo dosing. However, existing adverse events tended to persist throughout dose escalation such that, even though the number of new-onset events was very low after the first few days, the total number of events remained steady throughout dosing. As dosing progressed, the percentage of adverse events related to the gastrointestinal system, such as nausea and diarrhea, tended to decrease, whereas the percentage of adverse events related to the nervous system, such as tremor, insomnia, and dizziness, tended to increase. Tapering of the study drug did not substantially alter the adverse event profile; however, discontinuation of the study drug after the taper (washout period) was accompanied by abnormal or vivid dreams and nightmares, and a recurrence of nausea.

Eighteen severe drug-related adverse events were reported during duloxetine dosing, compared with 14 during placebo or moxifloxacin dosing. Severe adverse events reported during duloxetine dose escalation included gastrointestinal symptoms, insomnia, and restlessness. All subjects except one continued with study procedures and recovered from these severe adverse events, usually within several days and without further sequelae. One subject who reported severe nausea as well as other mild adverse events discontinued the study after taking one dose of duloxetine 60 mg, and one subject who reported severe insomnia began the taper period early, after taking eight doses of duloxetine 160 mg, because of severe insomnia and was discontinued.

Comparisons of the frequencies of adverse events to plasma duloxetine concentrations showed that the three subjects with the highest duloxetine concentrations at the 200-mg BID dose level and the one subject with the highest concentration at the 160-mg BID dose level had adverse event profiles comparable to those of the other subjects. Consistent with this, there was no apparent relationship between reasons for discontinuation and duloxetine dose levels.

One death, a suicide, occurred during this study, which the investigator judged to be unrelated to study drug. At the time of death, the subject had completed duloxetine dosing through the 200-mg dose level, a 4-day taper according to the study schedule, and 4 days of placebo dosing. With the exception of appetite loss, all adverse events associated with duloxetine had resolved prior to the suicide.

Orthostatic-Related Adverse Events

Although the incidence of vital sign changes that met consensus criteria for orthostatic hypotension increased with duloxetine dosage, the incidence of subject-reported orthostatic adverse events, including syncope, appeared unrelated to duloxetine exposure. Overall, 21 adverse events descriptive of symptomatic orthostatic hypotension were reported during the study, and these occurred throughout dosing and showed no clear relationship with dose. Eighteen of these 21 events were reported during the duloxetine dose escalation phase, with 5 occurrences at 60 mg BID, 5 occurrences at 120 mg BID, 6 occurrences at 160 mg BID, and 2 occurrences at 200 mg BID. All of these events were classified as either orthostatic hypotension or postural dizziness; syncope was not reported for any subject. During the duloxetine taper phase, postural dizziness was reported by one subject at 60 mg BID. During the placebo dosing period, there were two reported orthostasis-associated adverse events: postural dizziness was reported by one subject at level 2 dosing and by one subject at level 4 dosing.

Of these 21 subject-reported orthostatic-related adverse events, vital signs were measured within 1 hour of the event in 14 instances (12 with duloxetine and 2 with placebo). Of these 14 cases, orthostatic-related adverse events were correlated with vital sign changes that met consensus criteria only 5 times. Consistent with this finding, adverse event profiles for subjects with the greatest orthostatic changes did not differ substantially from those of other subjects.

Three subjects discontinued because of orthostatic-related adverse events. One subject discontinued after six doses of placebo because of moderate dizziness accompanied by hypotension, one subject discontinued after one dose of 120 mg duloxetine because of moderate intermittent vertigo, and one discontinued after four doses of 200 mg duloxetine because of moderate postural dizziness.

Laboratory Analyses

No clinically significant trends in the serum biochemistry, hematology, or urinalysis data related to study drug were observed. Although results for some clinical laboratory parameters were outside the appropriate reference ranges, these findings were generally transient and occurred at isolated time points. No changes considered by the study investigators to be clinically important were observed for liver analytes.

Electrocardiograms

There were no clinically significant safety-related electrocardiogram (ECG) findings. One subject was discontinued after complaining of non-radiating chest pain accompanied by nonspecific ST- and T-wave abnormalities on ECG. However, the chest pain resolved, there were no sequelae, and the ECG changes were deemed not clinically relevant by the investigator. In this study, duloxetine did not adversely affect ventricular repolarization as assessed by both mean changes and outliers in QT, regardless of correction method.18

DISCUSSION

Supratherapeutic dosages of duloxetine up to 200 mg BID were not well tolerated in this predominantly female, nonsmoking population, but were generally not associated with severe, clinically important adverse events. At doses 3 to 5 times the recommended dose for major depressive disorder (MDD), no significant medical safety issues were attributed to duloxetine. As in patients treated with therapeutic dosages of duloxetine,16 supratherapeutic doses of duloxetine were associated with changes in blood pressure. Most notably, supine systolic and diastolic blood pressures rose rapidly up to the 120-mg BID dosage before stabilizing. Upon withdrawal of duloxetine, blood pressures rapidly returned to predose levels.

Blood pressure changes within individual duloxetine-treated subjects appeared to be similar across the study population. At high-dose levels, mean blood pressure increases were a result of a uniform upward shift in each individual, rather than relatively large increases in a few individuals. As a result, subjects who were borderline hypertensive at baseline would be more likely to meet the criteria for hypertension when exposed to supratherapeutic doses of duloxetine. Duloxetine did not appear to affect subjects with high-end normotensive pressure differently from subjects with lower blood pressures. Normal standards of medical practice, which would include routine assessment of blood pressure, should obviate potential significant medical problems in these subjects. Nevertheless, patients meeting hypertension criteria at baseline may require a more rigorous risk-benefit assessment before beginning treatment.

Supratherapeutic dosages of duloxetine caused dose-dependent orthostatic changes in blood pressures and pulse rate, but values returned to baseline values immediately upon discontinuation of the drug. The average orthostatic fall in systolic and diastolic blood pressure was relatively small. These changes were generally asymptomatic and not associated with orthostatic-related adverse events. These data suggest that the frequency of symptomatic or clinically important orthostasis is very low.

Our findings are consistent with those from two preliminary studies in healthy women (N = 12; data on file, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN) and CYP2D6 poor metabolizers24 (N = 15) that examined supratherapeutic exposure to duloxetine. When considered in conjunction with the present study, the preliminary studies confirm that high doses of duloxetine are associated with events expected of NE uptake inhibition, as well as the well-known adverse events associated with 5-HT reuptake inhibitors. The initial exposure to duloxetine 60 mg BID was associated primarily with gastrointestinal intolerance. With progressively higher duloxetine exposure, the nature of the adverse events reported by subjects (tremor, insomnia, and dizziness) evolved to become more closely related to the mixed pharmacology of the drug.25 Predictable peripheral effects of NE uptake inhibition, such as tachycardia and raised blood pressure, were mild and generally asymptomatic. There appeared to be no laboratory safety issues associated with the relatively short-term exposures to high levels of duloxetine in this study and the QT interval at higher doses was not prolonged. Upon discontinuation of the drug, but not during taper, there was a slight increase in new-onset events typical of those seen with discontinuation of other selective-serotonin reuptake inhibitor-like drugs.26

The adverse events in the current study were consistent with those reported in previous studies of duloxetine at therapeutic doses27 and were overwhelmingly associated with the initial dose of 60 mg duloxetine. These events did not occur more frequently or with more severity than those associated with a first dose of 40 mg duloxetine,12 although first doses at higher drug levels (such as 100 mg BID) have been associated with a higher incidence of initial adverse events (data on file, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN). Typically, events associated with the initial dose are transient and resolve with no need for treatment adjustment,27,28 there are few new-onset drug-related events with continued dosing,29 and the drug is well tolerated.10 In this study, the incidence of new-onset adverse events dropped with continued dosing as expected, but existing events persisted throughout dose-escalation such that the total number of events reported by each subject remained very high throughout the study. The tolerability of high levels of duloxetine appeared limited by the additive effects of a spectrum of persistent mild to moderate events over time, and not by any one specific continuing or new-onset event. Severe adverse events did not appear to be related to dose level and occurred about as often when subjects were taking duloxetine as when they were not. These findings suggest that the adverse event profile depended more on subjective experience than on plasma drug concentrations. Overdosing should require only temporary discontinuation of duloxetine dosing.

Clinically significant events linked to supratherapeutic drug exposures can be due to the interruption of an extensive elimination pathway by a “strong” inhibitor of the pathway.30 CYP1A2 and, to a lesser extent, CYP2D6 are responsible for duloxetine metabolism. Concomitant use of duloxetine with fluvoxamine, a strong inhibitor of CYP1A2, ciprofloxacin, a moderate inhibitor of CYP1A2, or paroxetine, a strong inhibitor of CYP2D6, has been shown or is projected to increase duloxetine concentrations.31 We report in this study that some patients may show higher blood pressures or orthostatic hypotension when concentrations of duloxetine attain supratherapeutic levels.

Duloxetine itself is a moderate inhibitor of CYP2D6 and caution should be exercised when duloxetine is coadministered with CYP2D6 substrates that have a narrow therapeutic index. Examples include some antidepressants [tricyclic antidepressants (TCAs), such as nortriptyline, amitriptyline, and imipramine], phenothiazines, and type 1C antiarrhythmics (eg, propafenone, flecainide). In this circumstance, monitoring plasma concentrations and lowering the dose of these agents may be warranted. Because of the risk of lethal ventricular arrhythmias potentially associated with elevated plasma levels of thioridazine, duloxetine and thioridazine should not be coadministered.

This study was conducted in healthy subjects and was powered to detect changes in QT intervals; therefore, our conclusions are limited by the sample size and the fact that duloxetine was administered to healthy subjects. Moreover, the study population was restricted to women only. Because women generally achieve higher duloxetine plasma concentrations than men achieve (unpublished data, Eli Lilly and Company, Indianapolis, IN), enrolling only women ensured that the study population would have the highest possible exposure to duloxetine. Thus, these women were expected to be less tolerant of the adverse effects of duloxetine, particularly those related to orthostasis, although previous studies have not shown differences between men and women with respect to the effects of duloxetine.10,32 These analyses did not assess the incidence of adverse events by age group; 48% of the subjects in this study were between 40 and 74 years of age. An additional limitation is that the study design did not incorporate assessment of the effect of treatment on circadian blood pressure fluctuations.

CONCLUSIONS

Supratherapeutic duloxetine exposures produce small and generally asymptomatic changes in supine and orthostatic vital signs. Some prehypertensive subjects may become hypertensive upon initial dosing with duloxetine, but this can be predicted from predose blood pressure values. Overall, the data indicate that short-term exposure to supratherapeutic dosages of duloxetine up to 200 mg BID is not well tolerated but is generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.

ACKNOWLEDGMENTS

The authors thank Mary G. Royer, MS, ELS, for assistance with preparing the manuscript. Ms. Zhang and Drs. Derby, Chappell, Gonzales, Callaghan, and Mitchell are employees of Eli Lilly and Company, or were at the time the study was conducted. The authors had full access to the data from the study and participated in the decision to publish the data.

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Keywords:

duloxetine; vital signs; orthostasis; blood pressure; supratherapeutic dose

© 2007 Lippincott Williams & Wilkins, Inc.