1. New Drug update
Jim Hoehns, Pharm.D.

2. Outline
Objective - To review the following new medications and determine their place in therapy:
Vortioxetine (Brintellix)
Levomilnacipran (Fetzima)
Ospemifene (Osphena)
Mirabegron (Myrbetriq)

3. 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: hrs!
Bioavailability: 75%
Food: no effect on absorption

4. 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

5. 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

6. 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

7. Vortioxetine (Brintellix)
NNH: 71
NNH: 200

8. Vortioxetine (Brintellix)
Nausea was more common in females

9. Vortioxetine (Brintellix)

12. 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

13. 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

14. Levomilnacipran (Fetzima)
Dosage
Start: 20mg QD x 2 days, then 40mg QD
Max: 120mg QD
Renal impairment
Clcr ml/min: do not exceed 80mg/day
Clcr 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)

15. 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

16. 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

18. 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

19. 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%)

20. Ospemifene (Osphena) Dosage Drug-drug interactions Pregnancy: X
60mg tablet QD with food
Drug-drug interactions
Estrogen: concomitant use not recommended
Fluconazole: 2.7 x ↑ in [ospemifene]
Warfarin: no interaction
Pregnancy: X

21. Ospemifene (Osphena) Warnings/precautions Stroke - unknown
CHD - unknown
Venous thromboembolism
Ospemifene: per 1000 women
Placebo: per 1000 women
Endometrial CA
No case seen for up to 1 year

22. Ospemifene (Osphena) Ospemifene Effects on the Uterus Outcome
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

23. 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

24. 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

25. 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

26. Mirabegron (Myrbetriq)
Indications: overactive bladder with symptoms of urge incontinence, urgency and frequency
MOA:
Beta-3 adrenergic agonist
Relaxes detrusor muscle; increases bladder capacity

27. 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 ml/min: do not exceed 25mg QD
Max: 50mg daily
Forms
25 and 50mg extended release tablet

28. 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

29. Mirabegron (Myrbetriq)
Afib: 0.2%; rate greater than with placebo

30. Mirabegron (Myrbetriq)

32. Drugs for OAB - Cost

33. 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