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:

 SSRI
 Antagonist: 5-HT3 and 5-HT1A
 No effect on dopamine or NE

Kinetics


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Half-life: 66 hrs
Tmax: 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]

Dosage
 Start: 10mg QD, then increase to 20mg QD
 Max: 20mg QD
 Discontinuing: ↓ to 10mg QD for 1 week before
DC
 Forms: 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 days
 Increase 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 adults
 Increased risk of bleeding
 Hyponatremia

Adverse reactions
 No effect on weight (short-term studies)
○ 1 year: 1.1kg weight gain
 No notable QTc effects
 No 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

Kinetics
 Half-life: 12 hrs
 Food: no effect on absorption
 Metabolism: CYP3A4
○ Metabolites eliminated via urine
Levomilnacipran (Fetzima)

Dosage
 Start: 20mg QD x 2 days, then 40mg QD
 Max: 120mg QD
 Renal impairment
○ Clcr 30-59 ml/min: do not exceed 80mg/day
○ Clcr 15-29 ml/min: do not exceed 40mg/day

Forms
 20, 40, 80, 120 mg extended-release capsules


Cost
Drug-drug interactions
 MAOIs, serotonergic drugs
 CYP3A4 inhibitors
○ Ketoconazole: 1.5 x ↑ AUC (max: 80mg QD Fetzima)
Levomilnacipran (Fetzima)
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
Pregnancy: C
Warnings/precautions
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Suicidality in adolescents/young adults
Serotonin syndrome
Elevated BP
Elevated HR
Abnormal bleeding
Controlled narrow angle glaucoma
Urinary hesitation or retention
Activation of mania/hypomania
Seizures
Discontinuation syndrome
Hyponatremia
Levomilnacipran (Fetzima)

Adverse reactions
 9% discontinued med due to ADR
○ Nausea was most common reason

Increased heart rate
 Fetzima: ↑ 7.4 bpm

Increased BP
 Fetzima:
○ 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


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Fourth approved SERM in USA
Estrogen agonist on vaginal epithelium
Agonist: bone and endometrial tissue
Antagonist: breast tissue
Indication: moderate to severe dyspareunia due to
menopause
 Kinetics




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Half-life: 26 hrs
Food: 2-3 x ↑ in absorption
Metabolism: CYP3A4, 2C9, 2C19
Excretion: feces (75%)
Ospemifene (Osphena)

Dosage
 60mg tablet QD with food

Drug-drug interactions
 Estrogen: concomitant use not recommended
 Fluconazole: 2.7 x ↑ in [ospemifene]
 Warfarin: no interaction

Pregnancy: X
Ospemifene (Osphena)

Warnings/precautions
 Stroke - unknown
 CHD - unknown
 Venous 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)
Ospemifene Effects on the Uterus
Outcome
Ospemifene
Placebo
Endometrial
thickening ≥ 5 mm
60.1 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
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 Events
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
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 time

 Many unknowns about ADRs
 Too few patients to ascertain stroke risk
 Unclear long-term endometrial effects
 Even “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 agonist
 Relaxes detrusor muscle; increases bladder
capacity
Mirabegron (Myrbetriq)

Kinetics
 Half-life: 50 hrs
 Elimination: 25% renal (primarily active tubular
secretion)
 Metabolism: multiple pathways
○ Limited role of CYP2D6 and 3A4
 Food: ↓ absorption (20-50%)

Dosage
 25mg QD with or without food
 Clcr 15-30 ml/min: do not exceed 25mg QD
 Max: 50mg daily

Forms
 25 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
treatments

 May be better tolerated than anticholinergics
 Avoid if HTN, CAD, or arrhythmias
Expensive: $200/month
 Long-term safety is unknown
