New Drug update

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Jim Hoehns, Pharm.D . New Drug update. Outline. Objective - To review the following new medications and determine their place in therapy: Vortioxetine ( Brintellix ) Levomilnacipran ( Fetzima ) Ospemifene ( Osphena ) Mirabegron ( Myrbetriq ). Vortioxetine ( Brintellix ). - PowerPoint PPT Presentation

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New Drug update

New Drug updateJim Hoehns, Pharm.D.OutlineObjective - To review the following new medications and determine their place in therapy:Vortioxetine (Brintellix)Levomilnacipran (Fetzima)Ospemifene (Osphena)Mirabegron (Myrbetriq)Vortioxetine (Brintellix)Indications: treatment of MDDMOA: SSRIAntagonist: 5-HT3 and 5-HT1ANo effect on dopamine or NEKineticsHalf-life: 66 hrsTmax: 7-11 hrs!Bioavailability: 75%Food: no effect on absorptionVortioxetine (Brintellix)MetabolismExtensive P450 metabolismSeven different isoenzymes involvedCYP2D6 primary site; inactive metabolitePoor metabolizers: 2X the [serum]DosageStart: 10mg QD, then increase to 20mg QDMax: 20mg QDDiscontinuing: to 10mg QD for 1 week before DCForms: 5, 10, 15, 20 mg tabletsCost: 20mg QD #30 is $244

Vortioxetine (Brintellix)Drug-drug interactionsReduce vortioxetine dose by half if given with strong CYP2D6 inhibitorBupropion, fluoxetine, paroxetine, quinidineBupropion: >2X increase in [vortioxetine]MAOIs: do not use within 21 daysIncrease dose with CYP inducersRifampin, carbamazepine, phenytoinPregnancy: CVortioxetine (Brintellix)Warnings/PrecautionsSerotonin syndrome: MAOIs, TCAs, fentanyl, lithium, tramadol, buspironeSuicidality in adolescents/young adultsIncreased risk of bleedingHyponatremiaAdverse reactionsNo effect on weight (short-term studies)1 year: 1.1kg weight gainNo notable QTc effectsNo effect on psychomotor performance

Vortioxetine (Brintellix)

NNH: 71NNH: 200Vortioxetine (Brintellix)

Nausea was more common in femalesVortioxetine (Brintellix)

Vortioxetine (Brintellix) - SummaryNew SSRI with long half-life (66hrs)Not evaluated for use in pediatric patientsNausea is most common adverse reaction#1 reason for discontinuationPerhaps a favorable profile regarding sexual dysfunctionRemember LONG Tmax if overdose situationNo more efficacious than other SSRIs5mg daily not effective in 6-8 week studies

Levomilnacipran (Fetzima)Indication: treatment of MDDMOA:SNRIGreater effect on NRI than SRIKineticsHalf-life: 12 hrsFood: no effect on absorptionMetabolism: CYP3A4Metabolites eliminated via urine

Levomilnacipran (Fetzima)DosageStart: 20mg QD x 2 days, then 40mg QDMax: 120mg QDRenal impairmentClcr 30-59 ml/min: do not exceed 80mg/dayClcr 15-29 ml/min: do not exceed 40mg/dayForms20, 40, 80, 120 mg extended-release capsulesCost Drug-drug interactionsMAOIs, serotonergic drugsCYP3A4 inhibitorsKetoconazole: 1.5 x AUC (max: 80mg QD Fetzima)Levomilnacipran (Fetzima)Pregnancy: CWarnings/precautionsSuicidality in adolescents/young adultsSerotonin syndromeElevated BPElevated HRAbnormal bleedingControlled narrow angle glaucomaUrinary hesitation or retentionActivation of mania/hypomaniaSeizuresDiscontinuation syndromeHyponatremia

Levomilnacipran (Fetzima)Adverse reactions9% discontinued med due to ADRNausea was most common reasonIncreased heart rateFetzima: 7.4 bpmIncreased BPFetzima:SBP: 3.0 mm Hg increaseDBP: 3.2 mm Hg increase

Levomilnacipran (Fetzima) - SummaryNew SNRI for MDDOthers: Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Venlafaxine XR (Effexor XR)Nausea and constipation are most common ADRsNot approved for use in pediatricsMay be favorable regarding weight gainIncreased HR and BP are relevant concernsNot approved for fibromyalgiaMilnacipran (Savella) is

Ospemifene (Osphena)MOA: estrogen agonist/antagonistFourth approved SERM in USAEstrogen agonist on vaginal epitheliumAgonist: bone and endometrial tissueAntagonist: breast tissueIndication: moderate to severe dyspareunia due to menopauseKineticsHalf-life: 26 hrsFood: 2-3 x in absorptionMetabolism: CYP3A4, 2C9, 2C19Excretion: feces (75%)Ospemifene (Osphena)Dosage60mg tablet QD with foodDrug-drug interactionsEstrogen: concomitant use not recommendedFluconazole: 2.7 x in [ospemifene]Warfarin: no interactionPregnancy: X

Ospemifene (Osphena)Warnings/precautionsStroke - unknownCHD - unknownVenous thromboembolismOspemifene: 1.45 per 1000 womenPlacebo: 1.04 per 1000 womenEndometrial CANo case seen for up to 1 year

Ospemifene (Osphena)OutcomeOspemifenePlaceboEndometrial thickening 5 mm60.1 per 100021.2 per 1000Any proliferative endometrium86.1 per 100013.3 per 1000Uterine polyps5.9 per 10001.8 per 1000Ospemifene Effects on the UterusShould women take a progestin??

Medical Letter suggests to follow closely for vaginal bleeding/spotting.

Consider a progestin for those with risk factors for endometrial CA: obesity, hypertension, nulliparity, diabetesOspemifene (Osphena)Adverse EventOspemifene (N=1242)(%)Placebo(N=958)(%)Hot flush7.52.6Vaginal discharge3.80.3Muscle spasm3.20.9Hyperhidrosis1.60.6Adverse EventsOspemifene (Osphena)EfficacyShort duration trials (two 12 week trials)One long duration trial (52 weeks)Significant improvement in dyspareunia symptoms

Ospemifene cost: $153 for a 30 day supplyOspemifene (Osphena) - SummaryNew SERM with estrogen agonism on vaginal epitheliumSmall number of patients studied and for a short period of timeMany unknowns about ADRsToo few patients to ascertain stroke riskUnclear long-term endometrial effectsEven common ADRs are poorly definedVaginal estrogens may still be preferredMirabegron (Myrbetriq)Indications: overactive bladder with symptoms of urge incontinence, urgency and frequencyMOA:Beta-3 adrenergic agonistRelaxes detrusor muscle; increases bladder capacity Mirabegron (Myrbetriq)KineticsHalf-life: 50 hrsElimination: 25% renal (primarily active tubular secretion)Metabolism: multiple pathwaysLimited role of CYP2D6 and 3A4Food: absorption (20-50%)Dosage25mg QD with or without foodClcr 15-30 ml/min: do not exceed 25mg QDMax: 50mg dailyForms25 and 50mg extended release tablet

Mirabegron (Myrbetriq)Drug-drug interactionsDigoxin: [digoxin] 27%Myrbetriq is a moderate CYP2D6 inhibitor [metoprolol] 229% [desipramine] 241%Similar concern for propafenonePregnancy: CWarnings/precautionsIncreased blood pressureDo not use if uncontrolled HTNUrinary retention if BOO or taken with anticholinergic meds for OABMirabegron (Myrbetriq)

Afib: 0.2%; rate greater than with placeboMirabegron (Myrbetriq)

Drugs for OAB - CostMirabegron (Myrbetriq) - SummaryFirst beta-3 agonist approved by FDAIndication: overactive bladder/urge incontinenceEfficacy appears modestSide-effect profile is unique among OAB treatmentsMay be better tolerated than anticholinergicsAvoid if HTN, CAD, or arrhythmiasExpensive: $200/monthLong-term safety is unknown