New Drug update
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Transcript of New Drug update
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NEW DRUG UPDATE
Jim Hoehns, Pharm.D.
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Outline Objective - To review the following new
medications and determine their place in therapy:Vortioxetine (Brintellix)Levomilnacipran (Fetzima)Ospemifene (Osphena)Mirabegron (Myrbetriq)
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Vortioxetine (Brintellix) Indications: treatment of MDD MOA:
SSRIAntagonist: 5-HT3 and 5-HT1ANo effect on dopamine or NE
KineticsHalf-life: 66 hrsTmax: 7-11 hrs!Bioavailability: 75%Food: no effect on absorption
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Vortioxetine (Brintellix) Metabolism
Extensive P450 metabolism○ Seven different isoenzymes involved
CYP2D6 – primary site; inactive metabolite○ Poor 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 tablets
Cost: 20mg QD #30 is $244
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Vortioxetine (Brintellix) Drug-drug interactions
Reduce vortioxetine dose by half if given with strong CYP2D6 inhibitor○ Bupropion, fluoxetine, paroxetine, quinidine
Bupropion: >2X increase in [vortioxetine]MAOIs: do not use within 21 daysIncrease dose with CYP inducers
○ Rifampin, carbamazepine, phenytoin Pregnancy: C
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Vortioxetine (Brintellix) Warnings/Precautions
Serotonin syndrome: MAOIs, TCAs, fentanyl, lithium, tramadol, buspirone
Suicidality in adolescents/young adultsIncreased risk of bleedingHyponatremia
Adverse reactionsNo effect on weight (short-term studies)
○ 1 year: 1.1kg weight gainNo notable QTc effectsNo effect on psychomotor performance
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Vortioxetine (Brintellix)
NNH: 71
NNH: 200
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Vortioxetine (Brintellix)
Nausea was more common in females
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Vortioxetine (Brintellix)
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Vortioxetine (Brintellix) - Summary New SSRI with long half-life (66hrs) Not evaluated for use in pediatric patients Nausea is most common adverse reaction
#1 reason for discontinuation Perhaps a favorable profile regarding sexual
dysfunction Remember LONG Tmax if overdose situation No more efficacious than other SSRIs 5mg daily not effective in 6-8 week studies
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Levomilnacipran (Fetzima) Indication: treatment of MDD MOA:
SNRI○ Greater effect on NRI than SRI
KineticsHalf-life: 12 hrsFood: no effect on absorptionMetabolism: CYP3A4
○ Metabolites eliminated via urine
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Levomilnacipran (Fetzima) Dosage
Start: 20mg QD x 2 days, then 40mg QDMax: 120mg QDRenal impairment
○ Clcr 30-59 ml/min: do not exceed 80mg/day○ Clcr 15-29 ml/min: do not exceed 40mg/day
Forms20, 40, 80, 120 mg extended-release capsules
Cost Drug-drug interactions
MAOIs, serotonergic drugsCYP3A4 inhibitors
○ Ketoconazole: 1.5 x ↑ AUC (max: 80mg QD Fetzima)
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Levomilnacipran (Fetzima) Pregnancy: C Warnings/precautions
Suicidality in adolescents/young adultsSerotonin syndromeElevated BPElevated HRAbnormal bleedingControlled narrow angle glaucomaUrinary hesitation or retentionActivation of mania/hypomaniaSeizuresDiscontinuation syndromeHyponatremia
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Levomilnacipran (Fetzima) Adverse reactions
9% discontinued med due to ADR○ Nausea was most common reason
Increased heart rateFetzima: ↑ 7.4 bpm
Increased BPFetzima:
○ SBP: 3.0 mm Hg increase○ DBP: 3.2 mm Hg increase
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Levomilnacipran (Fetzima) - Summary New SNRI for MDD
Others: Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Venlafaxine XR (Effexor XR)
Nausea and constipation are most common ADRs
Not approved for use in pediatrics May be favorable regarding weight gain Increased HR and BP are relevant
concerns Not approved for fibromyalgia
Milnacipran (Savella) is
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Ospemifene (Osphena) MOA: estrogen agonist/antagonist
Fourth approved SERM in USAEstrogen agonist on vaginal epitheliumAgonist: bone and endometrial tissueAntagonist: breast tissue
Indication: moderate to severe dyspareunia due to menopause
KineticsHalf-life: 26 hrsFood: 2-3 x ↑ in absorptionMetabolism: CYP3A4, 2C9, 2C19Excretion: feces (75%)
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Ospemifene (Osphena) Dosage
60mg tablet QD with food Drug-drug interactions
Estrogen: concomitant use not recommendedFluconazole: 2.7 x ↑ in [ospemifene]Warfarin: no interaction
Pregnancy: X
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Ospemifene (Osphena) Warnings/precautions
Stroke - unknownCHD - unknownVenous thromboembolism
○ Ospemifene: 1.45 per 1000 women○ Placebo: 1.04 per 1000 women
Endometrial CA○ No case seen for up to 1 year
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Ospemifene (Osphena)
Outcome Ospemifene PlaceboEndometrial thickening
≥ 5 mm60.1 per 1000 21.2 per 1000
Any proliferative endometrium
86.1 per 1000 13.3 per 1000
Uterine polyps 5.9 per 1000 1.8 per 1000
Ospemifene Effects on the Uterus
Should 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, diabetes
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Ospemifene (Osphena)
Adverse Event Ospemifene (N=1242)
(%)
Placebo(N=958)
(%)Hot flush 7.5 2.6
Vaginal discharge 3.8 0.3
Muscle spasm 3.2 0.9
Hyperhidrosis 1.6 0.6
Adverse Events
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Ospemifene (Osphena) Efficacy
Short duration trials (two 12 week trials)
One long duration trial (52 weeks)
Significant improvement in dyspareunia symptoms
Ospemifene cost: $153 for a 30 day supply
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Ospemifene (Osphena) - Summary New SERM with estrogen agonism on
vaginal epithelium Small 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 defined
Vaginal estrogens may still be preferred
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Mirabegron (Myrbetriq) Indications: overactive bladder with
symptoms of urge incontinence, urgency and frequency
MOA:Beta-3 adrenergic agonistRelaxes detrusor muscle; increases bladder
capacity
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Mirabegron (Myrbetriq) Kinetics
Half-life: 50 hrsElimination: 25% renal (primarily active tubular secretion)Metabolism: multiple pathways
○ Limited role of CYP2D6 and 3A4Food: ↓ absorption (20-50%)
Dosage25mg QD with or without foodClcr 15-30 ml/min: do not exceed 25mg QDMax: 50mg daily
Forms25 and 50mg extended release tablet
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Mirabegron (Myrbetriq) Drug-drug interactions
Digoxin: ↑ [digoxin] 27%Myrbetriq is a moderate CYP2D6 inhibitor
○ ↑ [metoprolol] 229%○ ↑ [desipramine] 241%○ Similar concern for propafenone
Pregnancy: C Warnings/precautions
Increased blood pressure○ Do not use if uncontrolled HTN
Urinary retention if BOO or taken with anticholinergic meds for OAB
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Mirabegron (Myrbetriq)
Afib: 0.2%; rate greater than with placebo
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Mirabegron (Myrbetriq)
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Drugs for OAB - Cost
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Mirabegron (Myrbetriq) - Summary First beta-3 agonist approved by FDA
Indication: overactive bladder/urge incontinence Efficacy appears modest Side-effect profile is unique among OAB
treatmentsMay be better tolerated than anticholinergicsAvoid if HTN, CAD, or arrhythmias
Expensive: $200/month Long-term safety is unknown