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Drugs for Multiple Sclerosis Most patients with multiple sclerosis (MS) present with the relapsing-remitting form of the disease. Treatment usually includes disease-modifying drugs, various other drugs for managing symptoms... Pimavanserin (Nuplazid) for Parkinson''s Disease Psychosis The FDA has approved the atypical antipsychotic pimavanserin (Nuplazid – Acadia) for treatment of hallucinations and delusions associated with Parkinson''s disease. It is the first drug... Alternatives to Fluoroquinolones The FDA has announced that it is requiring changes in the labeling of systemic fluoroquinolones to warn that the risk of serious adverse effects, including tendinitis, peripheral neuropathy and... In Brief: New Indications for Secukinumab (Cosentyx) The FDA has approved the subcutaneous IL-17A antagonist secukinumab (Cosentyx - Novartis), which was first approved in 2015 for treatment of plaque psoriasis, for treatment of psoriatic... In Brief: Liposomal Irinotecan (Onivyde) for Pancreatic Cancer (online only) A liposomal formulation of irinotecan (Onivyde – Merrimack) has been approved by the FDA for use in combination with fluorouracil and leucovorin for treatment of metastatic pancreatic... In Brief: Trifluridine/Tipiracil (Lonsurf) for Metastatic Colorectal Cancer (online only) The FDA has approved Lonsurf (Taiho Oncology), a combination of the thymidine-based nucleoside analog trifluridine and the thymidine phosphorylase inhibitor tipiracil, for oral treatment of...
The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1496 Volume 56 June 6, 2016 IN THIS ISSUE Drugs for Multiple Sclerosis p 71 Pimavanserin (Nuplazid) for Parkinson’s Disease Psychosis p 74 Alternatives to Fluoroquinolones p 75 In Brief: New Indications for Secukinumab (Cosentyx) p 76 In Brief: Liposomal Irinotecan (Onivyde) for Pancreatic Cancer online only In Brief: Trifluridine/Tipiracil (Lonsurf) for Metastatic Colorectal Cancer online only 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 June 6, 2016 Take CME Exams ISSUE ISSUE No 1433 1496 Volume 56 ▶ ALSO IN THIS ISSUE Pimavanserin (Nuplazid) for Parkinson's Disease Psychosis p 74 Alternatives to Fluoroquinolones p 75 In Brief: New Indications for Secukinumab (Cosentyx) p 76 In Brief: Liposomal Irinotecan (Onivyde) for Pancreatic Cancer online only In Brief: Trifluridine/Tipiracil (Lonsurf) for Metastatic Colorectal Cancer online only Drugs for Multiple Sclerosis Most patients with multiple sclerosis (MS) present with the relapsing-remitting form of the disease.1 Treatment usually includes disease-modifying drugs, various other drugs for managing symptoms such as fatigue, depression, and pain, and corticosteroids for acute exacerbations INJECTABLE AGENTS — Interferons – Interferon beta was the first disease-modifying drug approved for treatment of MS Interferons have several immunemodulating and anti-inflammatory effects They can reduce clinical relapse rates by 30-35% and decrease the number of new T2 or gadolinium-enhancing brain lesions seen on MRI Whether these effects delay or prevent long-term disability is unclear.2,3 Interferons frequently cause injection-site reactions and a flu-like syndrome.4 Pegylated interferon beta-1a (Plegridy) injected SC every weeks appears to be similar in efficacy and adverse effects to older interferon formulations that must be injected every-other-day SC or weekly IM.5 Pregnancy – Interferons are classified as category C (abortifacient activity in animals at 2.8-40 times the recommended human dose; no adequate studies in pregnant women) for use during pregnancy Extensive data available on exposure of pregnant women to interferon beta suggest that it is safe to use.6 Glatiramer Acetate (Copaxone, Glatopa) – Glatiramer acetate is a mixture of synthetic polypeptides containing four naturally occurring amino acids (glutamic acid, alanine, tyrosine, and lysine) Its exact mechanism of action is unknown, but the drug has several immune-modulating effects including suppression of T-cell activation, and induction and activation of suppressor T-cells Glatiramer acetate can reduce clinical relapse rates by about 30% and Recommendations for Treatment of Multiple Sclerosis ▶ Interferon beta (Avonex, Plegridy, and others) and glatiramer acetate (Copaxone, Glatopa), both given by injection, have been used for first-line treatment ▶ Glatiramer acetate is better tolerated than interferon and equally effective, but it requires more frequent injections ▶ Use of oral agents or IV natalizumab (Tysabri) for first-line treatment is increasing ▶ Natalizumab is highly effective and needs to be infused only every weeks, but its adverse effects, especially progressive multifocal leukoencephalopathy (PML), are a concern ▶ Among the oral drugs, fingolimod (Gilenya) and dimethyl fumarate (Tecfidera) appear to be more effective than teriflunomide (Aubagio), but head-to-head trials are lacking decrease the number of new T2 or gadoliniumenhancing brain lesions seen on MRI.7 Glatiramer may be the safest of all the drugs used to treat MS, but it must be injected daily or three times a week SC Pregnancy – Glatiramer acetate is classified as category B (no adverse effects in animals; no adequate studies in pregnant women) for use during pregnancy Extensive data available on exposure of pregnant women to glatiramer acetate suggest that it is safe to use.6 Natalizumab (Tysabri) – A recombinant humanized monoclonal antibody, natalizumab prevents leukocyte migration across the blood-brain barrier, which may interrupt the inflammatory cascade in MS Natalizumab has decreased relapse rates by 68%, new or enlarging T2 brain lesion development by 83%, and disease progression rates by 42%,8,9 but progressive multifocal leukoencephalopathy (PML), a potentially fatal infection caused by the JC virus, has occurred in about 0.2% of patients; those who have anti-JC virus antibodies or are immunosuppressed have the highest risk The risk increases with the duration of treatment; it is very low during the first years of treatment in patients without anti-JC virus antibodies.10 Natalizumab was voluntarily 71 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 58 (1496) ® June 6, 2016 Table FDA-Approved Drugs for Relapsing-Remitting Multiple Sclerosis Drug Reduction in Clinical Relapse Rate Usual Maintenance Dosage Frequent or Serious Adverse Effects Cost1 Injectable Interferon beta-1a – 30%-35%2 Avonex (Biogen-Idec) Rebif (EMD Serono) Pegylated interferon beta-1a– Plegridy (Biogen-Idec) Interferon beta-1b – Betaseron (Bayer) Extavia (Novartis) Glatiramer acetate – Copaxone (Teva) 30 mcg IM once/wk 44 mcg SC 3x/wk 125 mcg SC q2 wks Injection-site reactions, flu-like symptoms, depression, transaminase elevations, possible cardiac toxicity, autoimmune disorders, allergic reactions, hepatotoxicity, seizures, suicidal ideation, lymphopenia with interferon beta-1b 250 mcg SC every other day ~30%2 20 mg SC once/d or 40 mg 3x/wk 20 mg SC once/d Glatopa (Sandoz) $72,072.00 77,797.20 72,072.00 78,920.60 65,902.00 Injection-site reactions, transient post-injection systemic reactions (flushing, chest pain, palpitations, and dyspnea) 80,216.10 70,251.50 63,192.50 Natalizumab – Tysabri (Biogen-Idec) 68%3 300 mg IV q4 wks Headache, fatigue, arthralgia, depression, infections, hypersensitivity reactions, hepatotoxicity, PML 71,773.00 Alemtuzumab – Lemtrada (Genzyme) 50-55%4 12 mg IV once/d x 5d followed year later by 12 mg IV once/d x 3d Infusion reactions (rash, headache, pyrexia, nausea, urticaria), nasopharyngitis, autoimmune disorders (immune cytopenias [especially thrombocytopenia], glomerular nephropathies, thyroid disorders), infections, pneumonitis, malignancies 59,250.005 Mitoxantrone – generic ~60%6 12 mg/m2 IV q3 mos Nausea, alopecia, amenorrhea, cardiotoxicity at cumulative doses >100 mg/m2, myelosuppression, acute and chronic myeloid leukemia Fingolimod – Gilenya (Novartis) ~55%8 0.5 mg PO once/d Transaminase elevations, bradycardia, AV block, macular edema, mild hypertension, lymphopenia, decreased pulmonary function, hypersensitivity reactions, malignancies, serious viral and fungal infections, PML 78,135.60 Teriflunomide – Aubagio (Genzyme) ~30%9 or 14 mg PO once/d Diarrhea, nausea, alopecia, transaminase elevations, neutropenia, leukopenia, peripheral neuropathy, hyperkalemia, hypophosphatemia, hypertension, hepatic failure, acute renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysis 74,379.70 Dimethyl fumarate – Tecfidera (Biogen-Idec) ~50%10 240 mg PO bid Flushing, abdominal pain, nausea, vomiting, diarrhea, lymphopenia, anaphylaxis, angioedema, PML 73,168.00 1330.407 Oral PML = progressive multifocal leukoencephalopathy Approximate WAC for year’s treatment at the usual maintenance 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 April 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Med Lett Drugs Ther 2015; 57:67 CH Polman et al N Engl J Med 2006; 354:899 Compared to interferon beta-1a (JA Cohen et al Lancet 2012; 380:1819; AJ Coles et al Lancet 2012; 380:1829) Cost for second year of treatment; cost for first year’s treatment is $98,750 HP Hartung et al Lancet 2002; 360:9018 Cost for treatment of a patient with a body surface area of 1.7 m2 using 12.5-mL multi-dose vials containing 25 mg (2 mg/mL) Med Lett Drugs Ther 2010; 52:98 Med Lett Drugs Ther 2012; 54:89 10 Med Lett Drugs Ther 2013; 55:45 withdrawn from the market in 2005 and re-introduced in 2006 with a Risk Evaluation and Mitigation Strategy (REMS) program which restricts its use to certified healthcare providers and settings.11 Based on crosstrial comparisons, it appears to be the most effective drug currently available for treatment of MS, but its safety remains a concern 72 Pregnancy – Natalizumab is classified as category C (fetotoxicity in animals; no adequate studies in pregnant women) for use during pregnancy An observational study in pregnant women found that exposure to natalizumab during the first trimester of pregnancy did not increase the risk of adverse pregnancy outcomes.12 The Medical Letter ® Alemtuzumab (Lemtrada) – A humanized monoclonal antibody directed against the lymphocyte cell surface molecule CD52, alemtuzumab causes rapid depletion of CD52-positive B- and T-cells It has been shown to be more effective than subcutaneous interferon beta1a in preventing relapses.13 The drug has an attractive dosing schedule; it is given as a daily IV infusion for consecutive days, followed 12 months later by an additional days of treatment However, because of the occurrence of serious autoimmune effects, infusion reactions, and malignancies, the FDA has approved labeling recommending that alemtuzumab generally be used only for patients who have had a suboptimal response to at least two other disease-modifying drugs for MS and has restricted its availability with a REMS program Pregnancy – Alemtuzumab is classified as category C (embryolethality in animals; no adequate studies in pregnant women) for use during pregnancy It can induce thyroid disorders; placental transfer of anti-thyroid antibodies resulting in neonatal Graves’ disease has been reported The manufacturer recommends that women of childbearing age use effective contraception while taking the drug and for four months after stopping it Mitoxantrone – An anthracenedione also used to treat cancer, mitoxantrone inhibits DNA replication It has decreased relapse frequency and slowed progression of disability in patients with severe MS, but it is potentially cardiotoxic, it can cause persistent amenorrhea in women, and it has been associated with a risk of developing acute or chronic myeloid leukemia, particularly with higher cumulative doses.14 Use of mitoxantrone for treatment of MS has declined because of concerns about its long-term risks Pregnancy – Mitoxantrone is classified as category D (may cause fetal harm) for use during pregnancy ORAL AGENTS — Fingolimod (Gilenya) – The first oral drug approved for treatment of MS, fingolimod blocks lymphocyte egress from lymph nodes, reducing the number of lymphocytes in peripheral blood and the central nervous system.15 A one-year study found that fingolimod was more effective than IM interferon beta-1a in reducing relapse rates and decreasing the number of new or enlarging brain lesions seen on MRI.16 PML has occurred in patients treated with fingolimod for years or more Pregnancy – Fingolimod is classified as category C (developmental toxicity in animals; no adequate Vol 58 (1496) June 6, 2016 studies in pregnant women) for use during pregnancy The manufacturer recommends that women of childbearing age use effective contraception while taking the drug and for two months after stopping it Teriflunomide (Aubagio) – A pyrimidine synthesis inhibitor, teriflunomide reduces T- and B-cell activation, proliferation, and function Teriflunomide has significantly reduced some MRI measures of disease activity (lesion volume, number of gadolinium-enhancing and unique active lesions), but cross-trial comparisons suggest that it is less effective than fingolimod or dimethyl fumarate in decreasing relapse rates.13 Pregnancy – Teriflunomide is teratogenic in animals and is contraindicated for use during pregnancy It is eliminated very slowly; women who wish to become pregnant and men wishing to father a child should discontinue the drug and undergo an accelerated elimination procedure (cholestyramine or activated charcoal for 11 days) Dimethyl Fumarate (Tecfidera) – An antioxidant that induces expression of anti-inflammatory proteins, dimethyl fumarate has significantly reduced relapse rates and development of new or enlarging T2 brain lesions In cross-trial comparisons, it appears to be more effective than teriflunomide.17 An increasing number of cases of PML have been reported following use of dimethyl fumarate, particularly in patients with lymphopenia for more than months Pregnancy – Dimethyl fumarate is classified as category C (embryofetal toxicity in animals at doses twice the approved human dose; no adequate studies in pregnant women) for use during pregnancy ■ FD Lublin et al Defining the clinical course of multiple sclerosis: the 2013 revisions Neurology 2014; 83:278 A Shirani et al Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis JAMA 2012; 308:247 T Derfuss and L Kappos Evaluating the potential benefit of interferon treatment in multiple sclerosis JAMA 2012; 308:290 V Annibali et al IFN-β and multiple sclerosis: from etiology to therapy and back Cytokine Growth Factor Rev 2015; 26:221 Peginterferon beta-1a (Plegridy) for multiple sclerosis Med Lett Drugs Ther 2015; 57:67 PK Coyle Management of women with multiple sclerosis through pregnancy and after childbirth Ther Adv Neurol Disord 2016; 9:198 Glatiramer acetate for relapsing multiple sclerosis Med Lett Drugs Ther 1997; 39:61 Natalizumab (Tysabri) for relapsing multiple sclerosis Med Lett Drugs Ther 2005; 47:13 CH Polman et al A randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis N Engl J Med 2006; 354:899 10 PS Sørensen et al Risk stratification for progressive multifo- 73 The Medical Letter ® cal leukoencephalopathy in patients treated with natalizumab Mult Scler 2012; 18:143 11 In brief: Natalizumab (Tysabri) returns Med Lett Drugs Ther 2006; 48:76 12 N Ebrahimi et al Pregnancy and fetal outcomes following natalizumab exposure in pregnancy A prospective, controlled observational study Mult Scler 2015; 21:198 13 New drugs for multiple sclerosis Med Lett Drugs Ther 2012; 54:89 14 VM Rivera et al Results from the 5-year, phase IV RENEW (Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis) study BMC Neurol 2013; 13:80 15 Oral fingolimod (Gilenya) for multiple sclerosis Med Lett Drugs Ther 2010; 52:98 16 JA Cohen et al Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis N Engl J Med 2010; 362:402 17 Dimethyl fumarate (Tecfidera) for multiple sclerosis Med Lett Drugs Ther 2013; 55:45 ▶ Pimavanserin (Nuplazid) for Parkinson’s Disease Psychosis The FDA has approved the atypical antipsychotic pimavanserin (Nuplazid – Acadia) for treatment of hallucinations and delusions associated with Parkinson’s disease It is the first drug to be approved in the US for this indication Pronunciation Key Pimavanserin : pim" a van' ser in Nuplazid : new plahz' id PARKINSON’S DISEASE PSYCHOSIS — Hallucinations and delusions occur in up to 60% of patients with Parkinson’s disease.1 Low doses of clozapine (Clozaril, and others) have been effective for treatment of these symptoms, but even in low doses clozapine can cause agranulocytosis, somnolence, and other significant toxicity.2,3 Low-dose quetiapine has been used off-label to treat Parkinson’s disease psychosis, but it has not been effective in controlled trials.4,5 Both clozapine and quetiapine block dopamine receptors and could exacerbate the motor symptoms of Parkinson's disease MECHANISM OF ACTION — Pimavanserin has no structural resemblance to other antipsychotic drugs and has no clinically significant effect on dopaminergic, Table Pharmacology Class Mechanism of action Formulation Route Tmax (median) Metabolism Elimination Half-life 74 Atypical antipsychotic Inverse agonist and antagonist at serotonin 5-HT2A receptors 17 mg tablets Oral hours Primarily by CYP3A4 and 3A5 Urine (