CymbaltaCymbalta®®

(duloxetine hydrochloride) (duloxetine hydrochloride)

:: selective serotonin and selective serotonin and norepinephrine reuptake inhibitor norepinephrine reuptake inhibitor

(SSNRI)(SSNRI)

Generic name:Generic name: D Duloxetine HCl uloxetine HCl

Brand name: Cymbalta Brand name: Cymbalta

FDA Approval: August 4, 2004FDA Approval: August 4, 2004

SSelective serotonin elective serotonin

andand norepinephrinenorepinephrine reuptake inhibitor reuptake inhibitor

(SSNRI)(SSNRI)

Treatment forTreatment for Major depressive Disorder Major depressive Disorder

Generic name:Generic name: D Duloxetine HCl uloxetine HCl

Brand name: Cymbalta Brand name: Cymbalta

FDA Approval: August 4, 2004FDA Approval: August 4, 2004

SSelective serotonin elective serotonin

andand norepinephrinenorepinephrine reuptake inhibitor reuptake inhibitor

(SSNRI)(SSNRI)

Treatment forTreatment for Major depressive Disorder Major depressive Disorder

cymbaltacymbaltaIntroductionIntroduction

Major depressive DisorderMajor depressive Disorder ( (MDD)MDD)

MMD เป ็นหนึง่ในกลุ่มโรคความผิดปกติของอารมณ์ ( Mood Disorder)Mood Disorder การแสดงอาการอาจมีล ักษณะ

การซึมเศร ้า (Depression) การคล ุ้มคล ั่ง (Mania)

ทั้งสองแบบสลับก ัน (Bipolar)

MDD คือภาวะที่ผ ู้ป ่วยม ีอาการซมึเศร ้า(depressive symptom)มากกว่าปกติจนเก ิดการเส ื่อมเสยีหนา้ท ี่พบในหญิงมากกว่าชาย 2 เทา่ โรคนีพ้บมากในช่วงอาย ุ 25-40 ปี

IntroductionIntroduction

Unipolar

EMOTIONAL SYMPTOMSEMOTIONAL SYMPTOMS Sadness Loss of interest or

pleasure in activities Feeling overwhelmed Anxiety Poor concentration Excessive or

inappropriate guilt Recurrent thoughts of

death, suicidal thoughts or attempts

EMOTIONAL SYMPTOMSEMOTIONAL SYMPTOMS Sadness Loss of interest or

pleasure in activities Feeling overwhelmed Anxiety Poor concentration Excessive or

inappropriate guilt Recurrent thoughts of

death, suicidal thoughts or attempts

PHYSICAL SYMPTOMSPHYSICAL SYMPTOMS Headaches Sleep disturbances Fatigue Back Pain Changes in appetite

PHYSICAL SYMPTOMSPHYSICAL SYMPTOMS Headaches Sleep disturbances Fatigue Back Pain Changes in appetite

IntroductionIntroduction Symptoms & Causes of Depression

EtiologyEtiology สาเหตุของโรค ปัจจ ุบ ันยงัไมท่ราบแนช่ ัด

แต่สาเหตุต ่างๆทีไ่ดร้ ับการกล่าวถงึไดแ้ก ่Genetic factorsPsychosocial factorsOther biological factorsCatecholamine hypothesisDown-regulation hypothesisCholinergic hypothesis

Major depressive DisorderMajor depressive DisorderIntroductionIntroduction

Many researchers believeMany researchers believe depression is caused by an imbalance of two naturally-occurring chemicals serotonin and norepinephrine in the brain and the body

Major depressive DisorderMajor depressive DisorderIntroductionIntroduction

An imbalance in these chemicals may explain the emotional and painful physical symptoms of depression

Antidepressant Drugs

Monoamine oxidase inhibitor (MAOIs) Tricyclic antidepressants (TCAs) Atypical or second generation• Serotonin reuptake inhibitors (SRI)• Norepinephine reuptake inhibitors (NRI)

• Serotonin /Norepinephine reuptake inhibitors (SNRI)

• Selective SRI (SSRI)

• Selective NRI (SNRI)• Selective SNRI (SSNRI)

Monoamine oxidase inhibitor (MAOIs) Tricyclic antidepressants (TCAs) Atypical or second generation• Serotonin reuptake inhibitors (SRI)• Norepinephine reuptake inhibitors (NRI)• Serotonin /Norepinephine reuptake

inhibitors (SNRI)

• Selective SRI (SSRI)

• Selective NRI (SNRI)• Selective SNRI (SSNRI)

CymbaltaCymbalta

• molecular weight of 333.88molecular weight of 333.88• molecular weight of 333.88molecular weight of 333.88

•Each capsule contains enteric-coated pelletsEach capsule contains enteric-coated pellets of 20, 30, or 60mg of duloxetineof 20, 30, or 60mg of duloxetine hydrochloridehydrochloride•Each capsule contains enteric-coated pelletsEach capsule contains enteric-coated pellets of 20, 30, or 60mg of duloxetineof 20, 30, or 60mg of duloxetine hydrochloridehydrochloride

Mechanism of actionMechanism of action

PharmacokineticsPharmacokinetics

Absorption Absorption OralOrallyly duloxetine is well absorbed. duloxetine is well absorbed. C max of duloxetine occurring 6 hoursC max of duloxetine occurring 6 hours FoodFood• not affect the Cmaxnot affect the Cmax• but delays the time to reach peak but delays the time to reach peak

concentration from 6 to 10 hoursconcentration from 6 to 10 hours• decreases the extent of absorption (AUC) by decreases the extent of absorption (AUC) by

about 10%about 10%

Absorption Absorption OralOrallyly duloxetine is well absorbed. duloxetine is well absorbed. C max of duloxetine occurring 6 hoursC max of duloxetine occurring 6 hours FoodFood• not affect the Cmaxnot affect the Cmax• but delays the time to reach peak but delays the time to reach peak

concentration from 6 to 10 hoursconcentration from 6 to 10 hours• decreases the extent of absorption (AUC) by decreases the extent of absorption (AUC) by

about 10%about 10%

DistributionDistribution volume of distribution averages about volume of distribution averages about

1640 L1640 L highly bound (>90%) to proteins in highly bound (>90%) to proteins in

human plasmahuman plasma• albumin albumin

• α1-acid glycoproteinα1-acid glycoprotein

DistributionDistribution volume of distribution averages about volume of distribution averages about

1640 L1640 L highly bound (>90%) to proteins in highly bound (>90%) to proteins in

human plasmahuman plasma• albumin albumin

• α1-acid glycoproteinα1-acid glycoprotein

PharmacokineticsPharmacokinetics

MetabolismMetabolism extensive metabolism to numerousextensive metabolism to numerous

metabolitesmetabolites major biotransformation pathways major biotransformation pathways

• conjugation and oxidationconjugation and oxidation• Both CYP2D6 and CYP1A2 catalyze the Both CYP2D6 and CYP1A2 catalyze the

oxidation of the naphthyl ring oxidation of the naphthyl ring in vitroin vitro

MetabolitesMetabolites found in plasma includefound in plasma include• 4-hydroxy duloxetine glucuronide 4-hydroxy duloxetine glucuronide • 5-hydroxy, 6-methoxy duloxetine5-hydroxy, 6-methoxy duloxetine sulfatesulfate

MetabolismMetabolism extensive metabolism to numerousextensive metabolism to numerous

metabolitesmetabolites major biotransformation pathways major biotransformation pathways

• conjugation and oxidationconjugation and oxidation• Both CYP2D6 and CYP1A2 catalyze the Both CYP2D6 and CYP1A2 catalyze the

oxidation of the naphthyl ring oxidation of the naphthyl ring in vitroin vitro

MetabolitesMetabolites found in plasma includefound in plasma include• 4-hydroxy duloxetine glucuronide 4-hydroxy duloxetine glucuronide • 5-hydroxy, 6-methoxy duloxetine5-hydroxy, 6-methoxy duloxetine sulfatesulfate

PharmacokineticsPharmacokinetics

EliminationElimination Only trace(<1% of the dose) amounts Only trace(<1% of the dose) amounts

of unchanged duloxetine are present in of unchanged duloxetine are present in the urinethe urine

Most (about 70%) of the duloxetine Most (about 70%) of the duloxetine dose appears in the urine as metabolitdose appears in the urine as metabolites of duloxetinees of duloxetine

about 20% is excreted in the feces.about 20% is excreted in the feces. elimination half-life of about 12 hourselimination half-life of about 12 hours

EliminationElimination Only trace(<1% of the dose) amounts Only trace(<1% of the dose) amounts

of unchanged duloxetine are present in of unchanged duloxetine are present in the urinethe urine

Most (about 70%) of the duloxetine Most (about 70%) of the duloxetine dose appears in the urine as metabolitdose appears in the urine as metabolites of duloxetinees of duloxetine

about 20% is excreted in the feces.about 20% is excreted in the feces. elimination half-life of about 12 hourselimination half-life of about 12 hours

PharmacokineticsPharmacokinetics

Inhibitors of CYP1A2Inhibitors of CYP1A2 co-administered with fluvoxamineco-administered with fluvoxamine

((a potent CYP1A2 inhibitor)a potent CYP1A2 inhibitor)• AUC was increased approximately 6-foldAUC was increased approximately 6-fold

• Cmax was increased about 2.5-foldCmax was increased about 2.5-fold

• t1/2 was increased approximately 3-foldt1/2 was increased approximately 3-fold

Other drugs that inhibit CYP1A2 Other drugs that inhibit CYP1A2 metabolismmetabolism• include cimetidine and quinolone include cimetidine and quinolone

antimicrobials such as ciprofloxacin and enoxantimicrobials such as ciprofloxacin and enoxacinacin

Drug interactionsDrug interactions

Inhibitors of CYP2D6Inhibitors of CYP2D6 Concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations of duloxetine Paroxetine (20 mg QD) • increased the concentration of duloxetine

(40 mg QD) by about 60%• and greater degrees of inhibition are

expected with higher doses of paroxetine

DrugDrug interactionsinteractions

Drugs Highly Bound to PlasmaDrugs Highly Bound to Plasma

ProteinProtein Because duloxetine is highly bound to Because duloxetine is highly bound to

plasma proteinplasma protein• may cause increased free concentrationsmay cause increased free concentrations

of the other drug, potentially resulting in of the other drug, potentially resulting in adverse eventsadverse events

Drug interactionsDrug interactions

Hypersensitivity Monoamine Oxidase Inhibitors

Hypersensitivity Monoamine Oxidase Inhibitors

ContraindicationsContraindications

In clinical studiesIn clinical studies TThehe most common side effectmost common side effect waswas nauseanausea

• the nausea was mild to moderate, and the nausea was mild to moderate, and usually subsided within one to two weeksusually subsided within one to two weeks

Other most common side effects included Other most common side effects included (listed in order of frequency):(listed in order of frequency):

• Dry mouthDry mouth• ConstipationConstipation• Decreased appetiteDecreased appetite• FatigueFatigue• SleepinessSleepiness• Increased sweatingIncreased sweating

Side EffectsSide Effects

Cymbalta should be administeredCymbalta should be administered• at a at a total dose of 40 mg/daytotal dose of 40 mg/day (given as 20(given as 20

mg BID)mg BID)

• to 60 mg/dayto 60 mg/day (given either once a day or as (given either once a day or as 30 mg BID) without regard to meals30 mg BID) without regard to meals

Dosage and Dosage and administrationadministration

Clinical studies Clinical studies Clinical studies Clinical studies

European Psychiatry (2006)European Psychiatry (2006)

Duloxetine in the treatment of Duloxetine in the treatment of major depressive major depressive disorder:disorder:

a placebo- and paroxetine-controlled triala placebo- and paroxetine-controlled trial

Duloxetine in the treatment of Duloxetine in the treatment of major depressive major depressive disorder:disorder:

a placebo- and paroxetine-controlled triala placebo- and paroxetine-controlled trial

By By D.G.S. Perahia , F. Wang , C.H. Mallinckrodt ,D.G.S. Perahia , F. Wang , C.H. Mallinckrodt , D.J. Walker , M.J. Detke D.J. Walker , M.J. Detke

Duloxetine doses of 80 and 120 mg/Duloxetine doses of 80 and 120 mg/day were assessed for efficacy and sday were assessed for efficacy and safety in the treatment of major depreafety in the treatment of major depressive disorderssive disorder (MDD)(MDD)

Duloxetine doses of 80 and 120 mg/Duloxetine doses of 80 and 120 mg/day were assessed for efficacy and sday were assessed for efficacy and safety in the treatment of major depreafety in the treatment of major depressive disorderssive disorder (MDD)(MDD)

Objective:Objective:

PatientsPatients patients age patients age ≥≥ 18 18 DSM-IV criteria for MDDDSM-IV criteria for MDD CGI-S rating CGI-S rating ≥≥ 4 and HAMD17 total score 4 and HAMD17 total score

≥≥ 15 at the screening and baseline study 15 at the screening and baseline study visitsvisits

PatientsPatients patients age patients age ≥≥ 18 18 DSM-IV criteria for MDDDSM-IV criteria for MDD CGI-S rating CGI-S rating ≥≥ 4 and HAMD17 total score 4 and HAMD17 total score

≥≥ 15 at the screening and baseline study 15 at the screening and baseline study visitsvisits

Patients and methodsPatients and methods

Study designStudy design multi-site, randomized, double-blind, multi-site, randomized, double-blind,

placebo and paroxetine-controlled stuplacebo and paroxetine-controlled studydy

randomly assigned in a 1:1:1:1 ratio randomly assigned in a 1:1:1:1 ratio • placeboplacebo

• duloxetine 80 mg/dayduloxetine 80 mg/day

• duloxetine 120 mg/day duloxetine 120 mg/day • paroxetine 20 mg/day paroxetine 20 mg/day

Study designStudy design multi-site, randomized, double-blind, multi-site, randomized, double-blind,

placebo and paroxetine-controlled stuplacebo and paroxetine-controlled studydy

randomly assigned in a 1:1:1:1 ratio randomly assigned in a 1:1:1:1 ratio • placeboplacebo

• duloxetine 80 mg/dayduloxetine 80 mg/day

• duloxetine 120 mg/day duloxetine 120 mg/day • paroxetine 20 mg/day paroxetine 20 mg/day

Patients and methodsPatients and methods

Patients Screened n=480

Patients Screened n=480

Randomizedn=392

Randomizedn=392

Placebo n=90

Placebo n=90

Duloxetine 80mg n=93

Duloxetine 80mg n=93

Paroxetine20mgn=97

Paroxetine20mgn=97

acute phase8wk

acute phase8wk

primary efficacy

measureHAMD17 ≥30%

from baseline

continuation phase

6-month

continuation phase

6-month

Placebo n=71

Placebo n=71

Duloxetine 80mg n=71

Duloxetine 80mg n=71

Duloxetine20mgn=103

Duloxetine20mgn=103

Duloxetine 20mgn=81

Duloxetine 20mgn=81

Paroxetine20mgn=70

Paroxetine20mgn=70

completed continuation ph

n=62

completed continuation ph

n=58

completed continuation ph

n=62

completed continuation ph

n=61

Efficacy measures primary measures

• HAMD17 total score

Secondary measures

• HAMD17 subscales • (anxiety/somatization, core factor,Maier, sleep, and retardation)

• The Montgomery Asberg depression rating scale (MADRS) • The Hamilton anxiety rating scale (HAMA) • Patient global impression of improvement scales(PGI-I) • The Sheehan disability scale (SDS) • Visual analog scales (VAS) for pain • The somatic symptom inventory (SSI)

Efficacy measures primary measures

• HAMD17 total score

Secondary measures

• HAMD17 subscales • (anxiety/somatization, core factor,Maier, sleep, and retardation)

• The Montgomery Asberg depression rating scale (MADRS) • The Hamilton anxiety rating scale (HAMA) • Patient global impression of improvement scales(PGI-I) • The Sheehan disability scale (SDS) • Visual analog scales (VAS) for pain • The somatic symptom inventory (SSI)

Patients and methodsPatients and methods

Safety and tolerability assessmentsSafety and tolerability assessments RReported adverse eventseported adverse events RRecorded at each visitecorded at each visit

• vital signs, and weight vital signs, and weight

• Supine blood pressure Supine blood pressure • heart rate heart rate

Laboratory tests (hematology, clinical Laboratory tests (hematology, clinical chemistry, and urinalysis)chemistry, and urinalysis)

The Arizona sexual experiences scale The Arizona sexual experiences scale (ASEX)(ASEX)

Safety and tolerability assessmentsSafety and tolerability assessments RReported adverse eventseported adverse events RRecorded at each visitecorded at each visit

• vital signs, and weight vital signs, and weight

• Supine blood pressure Supine blood pressure • heart rate heart rate

Laboratory tests (hematology, clinical Laboratory tests (hematology, clinical chemistry, and urinalysis)chemistry, and urinalysis)

The Arizona sexual experiences scale The Arizona sexual experiences scale (ASEX)(ASEX)

Patients and methodsPatients and methods

Results: Efficacy Results: Efficacy (acute ph.)(acute ph.)

Fig. 2. (a) HAMD17 change over the 8-week treatment period. Effect of placebo(N = 99), duloxetine 80 mg/day (N = 93), duloxetine 120 mg/day (N = 102),and paroxetine 20 mg/day (N = 97) on HAMD17 total scores (mean changefrom baseline

Fig. 2. (a) HAMD17 change over the 8-week treatment period. Effect of placebo(N = 99), duloxetine 80 mg/day (N = 93), duloxetine 120 mg/day (N = 102),and paroxetine 20 mg/day (N = 97) on HAMD17 total scores (mean changefrom baseline

Results: Results: Summary of primary efficacy outcomes (acute ph.)Summary of primary efficacy outcomes (acute ph.)

HAMD17: 17-item Hamilton rating scale for depression; MADRS: Montgomery Asberg depression rating scale; HAMA: Hamilton anxiety rating scale; CGI-S:clinical global impression of severity; PGI-I: patient global impression of improvement; LS mean: least-square mean; S.E.: standard error. Items from theHAMD17 scale used in the following subscales include: anxiety/somatization (items 10–13, 15, 17), core factor (items 1–3, 7, 8), Maier (items 1, 2, 7–10); retardation(items 1, 7, 8, 14), and sleep (items 4–6). *P ≤ 0.05 vs. placebo; **P ≤ 0.01.a Results from MMRM analysis: mean change from baseline to week 8 ± S.E. Mean at week 8 for PGI-I.b Administered as 40 mg twice daily (BID).c Administered as 60 mg twice daily (BID).d Administered once daily.

Results: Results: Safet y and tolerabilit ySafet y and tolerabilit y (acute ph.)(acute ph.)

Summary of primary and secondary efficacy outcomes: continuation ph.

Results: Results: Safety and tolerability (continuation ph.)Safety and tolerability (continuation ph.)

ConclusionsConclusions

This study reinforces previous evidence for the efficacy and safety of duloxetine in the treatment of MDD in acute therapy.

Long-term efficacy cannot be unequivocally concluded from this trial

Because neither duloxetine dose differed significantly from placebo in maintenance

of effect during the continuation phase.

Cymbalta เป ็นยาตัวแรกในกลุ่มSSelective elective serotonin andserotonin and norepinephrinenorepinephrine reuptake inhibreuptake inhibitor (SSNRI)itor (SSNRI)

ออกฤทธิ์ยบัย ัง้การ ออกฤทธิ์ยบัย ัง้การ reuptakereuptake ของ ของ serotonin serotonin และและNE NE ทำาใหร้ะด ับของสารทัง้ ทำาใหร้ะด ับของสารทัง้ 2 2 ตวัในบริเวณ ตวัในบริเวณsynapsesynapseมากขึ้นมากขึ้น

ทีใ่ช ้ในการร ักษา ทีใ่ช ้ในการร ักษา Major depressive DisorderMajor depressive Disorder ขนาดทีแ่นะน ำาใหใ้ช ้ค ือ ขนาดทีแ่นะน ำาใหใ้ช ้ค ือ 40-60 40-60 mg/daymg/day SE SE ของยาไมร่ ุนแรงทีพ่บไดบ้ ่อยคือ อาการ ของยาไมร่ ุนแรงทีพ่บไดบ้ ่อยคือ อาการ

คลื่นไส ้ และอาการจะลดลงหลังได ้ยา คลื่นไส ้ และอาการจะลดลงหลังได ้ยา 1-1-22อาทติย ์อาทติย ์

summary

The end