NEW DRUG UPDATE

Jim Hoehns, Pharm.D.

Outline Objective - 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 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

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

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

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

Vortioxetine (Brintellix)

NNH: 71

NNH: 200

Vortioxetine (Brintellix)

Nausea was more common in females

Vortioxetine (Brintellix)

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

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

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)

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

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

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

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%)

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

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

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

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

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

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

Mirabegron (Myrbetriq) Indications: overactive bladder with

symptoms of urge incontinence, urgency and frequency

MOA:Beta-3 adrenergic agonistRelaxes detrusor muscle; increases bladder

capacity

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

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

Mirabegron (Myrbetriq)

Afib: 0.2%; rate greater than with placebo

Mirabegron (Myrbetriq)

Drugs for OAB - Cost

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