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New Drug update

Jim Hoehns, Pharm.D . New Drug update. Outline. Objective - To review the following new medications and determine their place in therapy: Vortioxetine ( Brintellix ) Levomilnacipran ( Fetzima ) Ospemifene ( Osphena ) Mirabegron ( Myrbetriq ). Vortioxetine ( Brintellix ).

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New Drug update

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

  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: 7-11 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)

  10. 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

  11. 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

  12. 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)

  13. Levomilnacipran (Fetzima) • Pregnancy: C • Warnings/precautions • Suicidalityin 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

  14. 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

  15. 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

  16. 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%)

  17. 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

  18. 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

  19. Ospemifene (Osphena) 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

  20. Ospemifene (Osphena) Adverse Events

  21. 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

  22. 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

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

  24. 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

  25. 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

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

  27. Mirabegron (Myrbetriq)

  28. Drugs for OAB - Cost

  29. 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

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