New Drug update
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Transcript 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:
SSRI
Antagonist: 5-HT3 and 5-HT1A
No effect on dopamine or NE
Kinetics
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)
Pregnancy: C
Warnings/precautions
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
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
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