The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1501 Volume 56 August 15, 2016 IN THIS ISSUE Drugs for Bipolar Disorder p 97 Sofosbuvir/Velpatasvir (Epclusa) for Hepatitis C p 101 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Volume 58 August 15, 2016 Take CME Exams ISSUE ISSUE No 1433 1501 ALSO IN THIS ISSUE Sofosbuvir/Velpatasvir (Epclusa) for Hepatitis C p 107 Volume 56 ▶ Drugs for Bipolar Disorder Recommendations for Treatment of Bipolar Disorder ▶ Second-generation antipsychotics, lithium, and Bipolar disorder is characterized by intermittent episodes of mania and/or depression.1 Even with maintenance treatment, recurrences of manic or (more frequently) depressive episodes are common Some of the drugs and dosages recommended here have not been approved by the FDA for use in bipolar disorder TREATMENT OF MANIA — Second-generation antipsychotics, lithium, and valproate are effective for treatment of acute manic episodes.2 Both lithium and valproate may take days to weeks to have a full therapeutic effect; treatment of an acute manic episode with these agents generally requires addition of an antipsychotic drug TREATMENT OF DEPRESSION — The secondgeneration antipsychotics quetiapine and lurasidone and the combination of olanzapine and fluoxetine have been shown to be effective in treating bipolar depression.3-6 Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) or bupropion can be effective for treatment of bipolar depression, but they can precipitate mania and generally should be used only as an adjunct to mood-stabilizing drugs such as lithium.7 Lithium has been shown to have protective effects against suicide and self-harm when used for treatment of bipolar depression.8 Lamotrigine may be modestly effective for this indication, but its usefulness in treating an acute episode is limited by the amount of time required for safe titration to an effective dose.9 MAINTENANCE — Lithium remains the drug of choice for maintenance treatment of bipolar disorder, especially for prevention of manic episodes.10,11 The anticonvulsant lamotrigine is effective for prevention of recurrent depressive episodes Antiepileptic drugs such as valproate and carbamazepine are also valproate are effective for treatment of acute episodes of mania; treatment of an acute manic episode with lithium or valproate generally requires addition of an antipsychotic drug ▶ Lithium, quetiapine, lurasidone, and a combination of olanzapine and fluoxetine have been shown to be effective for treatment of bipolar depression ▶ Lithium is generally the drug of choice for maintenance treatment of bipolar disorder ▶ Lamotrigine is effective in preventing recurrent depressive episodes widely used for maintenance treatment, but they are generally less effective than lithium Maintenance therapy with lithium alone or in combination with valproate, carbamazepine, or lamotrigine decreases the risk of recurrent manic and depressive episodes Second-generation antipsychotics may also be effective in preventing recurrences of manic and depressive episodes, especially when taken in combination with lithium ADVERSE EFFECTS — Lithium – Nausea and fatigue may occur in the first days to weeks of lithium treatment, even when serum concentrations are within the recommended range Tremor, thirst, polyuria, edema, and weight gain may persist for the duration of treatment Lithium-induced tremor can be managed by reducing the dosage or adding a beta blocker such as propranolol Toxic renal effects, including tubular lesions, interstitial fibrosis, and decreased creatinine clearance, have been reported with long-term use of lithium Nephrogenic diabetes insipidus can occur; it further increases the risk of lithium toxicity and may be irreversible Hypothyroidism can occur with long-term lithium treatment and can contribute to exacerbations of bipolar disorder Confusion and ataxia can occur with high serum lithium concentrations Lithium 103 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® Vol 58 (1501) August 15, 2016 Table Some Oral Drugs for Bipolar Disorder Drug Some Available Formulations Initial Adult Dosage1 Usual Adult Dosage1 150, 300, 600 mg caps; 300 mg tabs; mEq/5 mL soln5 300, 450 mg tabs 300 mg tabs 900-1800 mg divided tid or qid 900-1800 mg divided bid or tid 900-1200 mg divided tid or qid 900-1200 mg divided bid or tid 200 mg tabs; 100 mg chewable tabs 200 mg tabs; 100 mg/5 mL susp7 100, 200, 400 mg tabs; 100, 200, 300 mg caps 100, 200, 300 mg caps 100, 200, 400 mg tabs 100, 200, 300 mg caps 200-600 mg divided tid or qid 600-1200 mg divided bid or tid 200-600 mg divided bid 600-1200 mg divided bid 25, 100, 150, 200 mg tabs; 5, 25 mg chewable tabs9 25, 50, 100, 200 mg ODT 25 mg once/d10 200 mg once/d 8.10 442.80 270.90 372.50 332.10 652.80 250 mg caps; 250 mg/5 mL soln11 250 mg tid 1500-2000 mg divided bid 125, 250, 500 mg tabs 750 mg/d divided 72.00 797.40 59.40 530.40 322.20 576.00 256.20 531.90 Cost2 Antimanic Agent Lithium carbonate3,4 – generic extended release – generic Lithobid (Ani) $7.10 25.80 669.60 Anticonvulsants Carbamazepine – generic6 Tegretol (Novartis)6 extended release – generic6 Carbatrol (Shire)6 Tegretol XR (Novartis)6 Equetro (Validus)3,8 Lamotrigine – generic4 Lamictal (GSK)4 orally disintegrating – generic4 Lamictal ODT4 extended release – generic6 Lamictal XR6 Valproate Valproic acid – generic6 Depakene (Abbvie)6 Divalproex sodium – generic3 Depakote (Abbvie)3 delayed release – generic6 Depakote Sprinkle6 extended release – generic3,8 Depakote ER3,8 200 mg bid 125 mg caps 25 mg/kg once/d12 171.50 172.30 212.40 182.40 211.00 25, 50, 100, 200, 250, 300 mg tabs 250, 500 mg tabs 111.60 25-40 mg/kg once/d12 soln = solution; susp = suspension; ODT = orally disintegrating tablet Dosage for maintenance treatment Dosage may need to be adjusted for serum concentrations, renal or hepatic impairment, or drug interactions (see Table on p 106) Approximate WAC for 30 days’ treatment with tablets or capsules for a 70-kg patient at the lowest usual daily dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly July 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/ drug-pricing-policy FDA-approved for acute treatment of manic episodes FDA-approved for maintenance treatment of bipolar disorder Available as lithium citrate may cause mild leukocytosis, hypercalcemia, or hyperparathyroidism It can also cause severe acne, folliculitis, hair loss, and other skin reactions, and induce or exacerbate psoriasis Lithium has a narrow therapeutic window and requires careful monitoring Serum lithium concentrations should be monitored every 6-12 months in stable patients (every months in unstable patients) Concentrations should be measured about 12 hours after the last dose For acute treatment, target serum concentrations are 0.8-1.2 mEq/L For maintenance treatment, serum concentrations should be 0.6-1.0 mEq/L Thyroid and renal function should be monitored before starting lithium and every six months during treatment Patients should also be monitored for signs of toxicity such as vomiting, diarrhea, tremor, lethargy, slurred speech, and weakness 104 Valproate – Adverse effects of valproate include somnolence, fatigue, weight gain, nausea, and diarrhea; tremor has been reported, but it is less common than with lithium Reversible hair loss can occur Thrombocytopenia may occur and appears to be dose-related Transient elevations of hepatic transaminases are common; fatal hepatotoxicity has occurred rarely, particularly in young children and with use of multiple anticonvulsants Polycystic ovary syndrome has occurred Rare idiosyncratic reactions include hemorrhagic pancreatitis, hyperammonemic encephalopathy, and agranulocytosis Carbamazepine — Adverse effects of carbamazepine include rash, dizziness, diplopia, nausea, somnolence, headache, hyponatremia, elevated transaminases and, rarely, Stevens-Johnson syndrome, agranulocytosis, and aplastic anemia Han Chinese may have a tenfold increased risk of Stevens-Johnson syndrome.12 The Medical Letter Vol 58 (1501) ® August 15, 2016 Table Some Oral Drugs for Bipolar Disorder (continued) Some Available Formulations Initial Adult Dosage1 Usual Adult Dosage1 2, 5, 10, 15, 20, 30 mg tabs 2, 5, 10, 15, 20, 30 mg tabs13 10, 15 mg ODT 15 mg once/d 15-30 mg once/d Asenapine3,8 – Saphris (Allergan) 2.5, 5, 10 mg sublingual tabs 10 mg bid 5-10 mg bid 1006.10 Cariprazine3,8 – Vraylar (Allergan) 1.5, 3, 4.5, mg caps 1.5 mg once/d 3-6 mg once/d 1006.10 Drug Cost2 Second-Generation Antipsychotics Aripiprazole3,8 – generic Abilify (BMS/Otsuka) orally disintegrating – generic $770.70 892.00 919.10 Lurasidone14 – Latuda (Sunovion) 20, 40, 60, 80, 120 mg tabs 20 mg once/d 20-120 mg once/d 921.90 Olanzapine3,4,8 – generic Zyprexa (Lilly) orally disintegrating – generic Zyprexa Zydis 2.5, 5, 7.5, 10, 15, 20 mg tabs13 10-15 mg once/d 5-20 mg once/d 7.00 367.10 53.60 396.50 50-100 mg once/d or divided bid 50-300 mg once/d 300-800 mg divided bid 300-800 mg once/d 56.40 782.40 638.40 5, 10, 15, 20 mg ODT Quetiapine – generic3,4,14 Seroquel (AstraZeneca)3,4,14 extended release – Seroquel XR3,4,8,14 25, 50, 100, 200, 300, 400 mg tabs Risperidone3,8 – generic Risperdal (Janssen) orally disintegrating – generic Risperdal M-Tab 0.25, 0.5, 1, 2, 3, mg tabs; mg/mL soln15 0.25, 0.5, 1, 2, 3, mg ODT 0.5, 1, 2, 3, mg ODT 2-3 mg once/d 4-6 mg once/d 11.20 714.30 373.20 857.10 Ziprasidone3,4,8 – generic Geodon (Pfizer) 20, 40, 60, 80 mg caps 40 mg bid 40-80 mg bid 116.00 880.40 6/25 mg once/d in the evening 6/25-12/50 mg once/d in the evening 347.60 402.30 50, 150, 200, 300, 400 mg tabs Second-Generation Antipsychotic/SSRI Combination Olanzapine/fluoxetine14 – generic Symbyax (Lilly) 10 11 12 13 14 15 3/25, 6/25, 6/50, 12/25, 12/50 mg caps Not FDA-approved for treatment of bipolar disorder Patients taking conventional tablets can be switched to the suspension on a mg-per-mg basis, but in smaller, more frequent doses FDA-approved for treatment of mixed episodes Chewable tablets should be administered whole If necessary, the dose should be rounded down to the nearest whole tablet For monotherapy, titrate to a goal of 200 mg/day as follows: 25 mg/day for weeks, then 50 mg/day for weeks, then 100 mg/day for week, then 200 mg/day Available as valproate sodium When switching from Depakote to Depakote ER, an 8-20% increase in the dosage may be required to maintain serum concentrations Also available for rapid intramuscular injection for agitation associated with bipolar mania FDA-approved for treatment of depressive episodes in bipolar disorder Also available as a long-acting injectable for maintenance treatment of bipolar disorder DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) has been reported with use of carbamazepine.13 Lamotrigine – Adverse effects of lamotrigine include nausea, dizziness, and somnolence About 10% of patients develop a mild rash Severe, life-threatening rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis, has occurred in