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Brisdelle

"The U.S. Food and Drug Administration today approved Brisdelle (paroxetine)to treat moderate to severe hot flashes (vasomotor symptoms) associated with menopause. Brisdelle, which contains the selective serotonin reuptake inhibitor paroxetine mes"...

Brisdelle

CLINICAL PHARMACOLOGY

Mechanism of Action

Nonclinical studies have shown that paroxetine is an SSRI. BRISDELLE is not an estrogen, and its mechanism of action for the treatment of VMS is unknown.

Pharmacodynamics

Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a selective inhibitor of neuronal serotonin reuptake and has weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic alpha1-, alpha2-, beta-adrenergic-, dopamine (D2)-, 5-HT1-, 5-HT2-, and histamine (H1)-receptors.

Pharmacokinetics

Absorption

Paroxetine is completely absorbed after oral dosing of the mesylate salt. In a study in which healthy postmenopausal women (n=24) received BRISDELLE 7.5 mg capsules as a daily dose for 14 days, steady-state paroxetine concentrations were achieved by approximately 12 days of dosing for most subjects, although it may take substantially longer in an occasional patient. Peak concentrations were reached at a median of 6 hours (3 to 8 hours range). Steady-state mean values of Cmax, Cmin, and AUC0-last were 13.10 ng/mL (CV 91%), 7.17 ng/mL (CV 99%), and 237 hr*ng/mL (CV 94%), respectively.

Steady-state AUC0-24 values were about 3 times those of AUC0-inf following a single dose, indicating non-linear pharmacokinetics. Steady-state Cmax values were approximately 5 times greater than those attained after a single dose and steady-state exposure based on AUC0-24 was about 10 times greater than AUC0-24 after a single dose.

The nonlinear kinetics and excess accumulation are due to the fact that CYP2D6, an enzyme that is in part responsible for paroxetine metabolism, is readily saturable.

The effects of food on the bioavailability of paroxetine were studied with paroxetine tablets at higher strength. AUC was only slightly increased (6%) when drug was administered with food but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. BRISDELLE can be taken with or without food.

Distribution

Paroxetine distributes throughout the body, including the central nervous system, with only 1% remaining in the plasma.

Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 100 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

Metabolism

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by cytochrome CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions [see DRUG INTERACTIONS]. At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes, which, unlike CYP2D6, show no evidence of saturation.

Excretion

Approximately 64% of a 30 mg oral solution of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% of the dose was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.

Specific Populations

Renal and Liver Impairment

Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentration in patients with creatinine clearance below 30 mL/min was approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min and patients with hepatic impairment had about a 2-fold increase in plasma concentrations (AUC, Cmax). No BRISDELLE dose adjustment is considered necessary in patients with renal or hepatic impairment.

Elderly Patients

In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30, and 40 mg, Cmin concentrations were about 70% to 80% greater than the respective Cmin concentrations in nonelderly subjects. No BRISDELLE dose adjustment is considered necessary in elderly patients.

Drug Interaction Studies

Potential Effect of BRISDELLE on Other Drugs

Drugs Metabolized by CYP3A4

An in vivo drug interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for CYP3A4, including astemizole, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine's in vitro Ki and its lack of effect on terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Drugs Metabolized by CYP2D6

Many drugs are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients ( > 90%), this CYP2D6 isozyme is saturated early during paroxetine dosing.

Specific studies investigating the effect of paroxetine on drugs metabolized by CYP2D6 are listed below:

Pimozide: Higher doses of paroxetine have been shown to elevate plasma levels of pimozide. In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone [see DRUG INTERACTIONS].

Tamoxifen: It is uncertain whether the co-administration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine's irreversible inhibition of CYP2D6. However, other studies have failed to demonstrate such a risk [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Desipramine: In one study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively [see DRUG INTERACTIONS].

Risperidone: Daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day), a CYP2D6 substrate, increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold [see DRUG INTERACTIONS].

Atomoxetine: The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady-state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone [see DRUG INTERACTIONS].

Digoxin: Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine [see DRUG INTERACTIONS].

Beta Blockers: In a study in which propranolol (80 mg twice daily) was dosed orally for 18 days, the steady-state plasma concentrations of propranolol were unaltered during co-administration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated.

Potential Effect of Other Drugs on BRISDELLE

Concomitant use of paroxetine with other drugs that alter CYP enzymes activities including CYP2D6 may affect the plasma concentrations of paroxetine. Specific studies investigating the effect of other drugs on paroxetine are listed below:

Cimetidine: Cimetidine inhibits many cytochrome P450 enzymes. In a study in which paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during co-administration with oral cimetidine (300 mg three times daily) for the final week [see DRUG INTERACTIONS].

Phenobarbital: Phenobarbital induces many cytochrome P450 enzymes. When a single oral 30 mg dose of paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Because paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed [see DRUG INTERACTIONS].

Phenytoin: When a single oral 30 mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Because both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed [see DRUG INTERACTIONS].

Digoxin: A clinical drug interaction study showed that concurrent use of digoxin did not affect paroxetine exposure.

Diazepam: A clinical drug interaction study showed that concurrent use of diazepam did not affect paroxetine exposure.

Clinical Studies

The efficacy of BRISDELLE as a treatment for moderate to severe VMS associated with menopause was established in two Phase 3 studies (at a dose of 7.5 mg once daily at bedtime) in 1174 postmenopausal women with a minimum of 7-8 moderate to severe vasomotor symptoms per day at baseline ( ≥ 50 per week) for 30 days prior to receiving study drug.

Study 1 was a 12-week, randomized, double-blind, placebo-controlled clinical trial with a total of 606 postmenopausal women (average age 55 years, 65% Caucasian and 33% African American, 18% surgically menopausal and 82% naturally menopausal).

Study 2 was a 24-week, randomized, double-blind, placebo-controlled clinical trial with a total of 568 postmenopausal women (average age 54 years, 76% Caucasian and 22% African American, 20% surgically menopausal and 81% naturally menopausal).

The co-primary efficacy endpoints for both studies were the reduction from baseline in VMS frequency and severity at Weeks 4 and 12. Data from Study 1 showed a statistically significant reduction from baseline in the frequency of moderate to severe vasomotor symptoms at Week 4 and Week 12 and a statistically significant reduction in the severity of moderate to severe VMS at Week 4 for BRISDELLE compared to placebo (Table 4). Data from Study 2 showed a statistically significant reduction from baseline in the frequency and severity of moderate to severe vasomotor symptoms at Week 4 and Week 12 for BRISDELLE compared to placebo (Table 5).

Table 4 : Study 1: Changes in the Daily Frequency and Daily Severity of Moderate to Severe VMS at Weeks 4 and 12 (MITT Population)

  Frequency Severity
BRISDELLE Placebo BRISDELLE Placebo
Baseline
  n 301 305 301 305
  Median 10.4 10.4 2.5 2.5
Change from baseline at Week 4
  n 289 293 281 289
  Median -4.3 -3.1 -0.05 0
  Treatment Difference* -1.2 274 -0.05 253
  P-value# < 0.01 -5 < 0.01 -0.02
Change from baseline at Week 12
  n 264 236
  Median -5.9 -0.06
  Treatment Difference* -0.9 -0.04
  P-value# < 0.01 0.17
MITT population: all consented and randomized subjects with valid baseline daily hot flash diary data who had taken at least
1 dose of study medication and had at least 1 day of on-treatment daily hot flash diary data.
* Treatment Difference: the difference between the median changes from baseline.
# P-value is obtained from rank-ANCOVA model.

Table 5 : Study 2: Changes in the Daily Frequency and Daily Severity of Moderate to Severe VMS at Weeks 4 and 12 (MITT Population)

  Frequency Severity
BRISDELLE Placebo BRISDELLE Placebo
Baseline
  n 284 284 284 284
  Median 9.9 9.6 2.5 2.5
Change from baseline at Week 4
  n 276 274 268 271
  Median -3.8 -2.5 -0.04 -0.01
  Treatment Difference* -1.3 244 -0.03 236
  P-value# < 0.01 -3.9 0.04 0
Change from baseline at Week 12
  n 257 245
  Median -5.6 -0.05
  Treatment Difference* -1.7 -0.05
  P-value# < 0.01 < 0.01
MITT population: all consented and randomized subjects with valid baseline daily hot flash diary data who had taken at least
1 dose of study medication and had at least 1 day of on-treatment daily hot flash diary data.
* Treatment Difference: the difference between the median changes from baseline.
# P-value is obtained from rank-ANCOVA model.

Persistence of benefit at 24 weeks in Study 2 was evaluated with a responder analysis where responders were defined as those patients who achieved ≥ 50% reduction from baseline in the frequency of moderate to severe VMS at Week 24. The proportion of patients achieving a ≥ 50% reduction in the frequency of moderate to severe VMS from baseline to Week 24 was 48% in the BRISDELLE group and 36% in the placebo group at Week 24.

Last reviewed on RxList: 7/12/2013
This monograph has been modified to include the generic and brand name in many instances.

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