New therapeutic agents marketed in 2017: Part 1

Transcription

1 New therapeutic agents marketed in 2017: Part 1 Abstract Objective: To provide information on the most important properties of new therapeutic agents marketed in Data sources: Product labeling supplemented selectively with published studies and drug information reference sources. Data synthesis: Seven new therapeutic agents marketed in the United States in early 2017 are considered in this first part of a series: ocrelizumab, safinamide mesylate, edaravone, valbenazine tosylate, deutetrabenazine, crisaborole, and dupilumab. Indications, mechanisms of action, and information on dosage and administration for these new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, and other risks and precautions. The new drugs are compared with older drugs marketed for the same indications, and advantages and disadvantages are identified. Summary: Ocrelizumab is the first drug shown to be effective in the treatment of primary progressive multiple sclerosis and is more effective than interferon beta-1a in the treatment of relapsing multiple sclerosis. Safinamide is the third monoamine oxidase type B inhibitor for the treatment of patients with Parkinson disease, joining rasagiline and selegilene. Edaravone is only the second drug to be approved for the treatment of amyotrophic lateral sclerosis (ALS), joining riluzole, and has been reported to slow the worsening of ALS symptoms. Valbenazine is the first drug demonstrated to be effective for the treatment of tardive dyskinesia, a neurological disorder that is most often experienced by patients treated for long periods with antipsychotic medications. Deutetrabenazine is the deuterated form of tetrabenazine in which deuterium, the heavy hydrogen isotope of regular hydrogen, is used instead of hydrogen in two of the substituent groups. Both agents are used to treat chorea associated with Huntington disease, but deutetrabenazine has a longer duration of action, may be administered less frequently, and may be better tolerated. Crisaborole joins the topical corticosteroids and topical calcineurin inhibitors as options for the topical treatment of mild to moderate atopic dermatitis. Dupilumab, which inhibits interleukins 4 and 13, is administered subcutaneously for the treatment of adults with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Pharm Today. 2017;23(9):54 65 Daniel A. Hussar, PhD, FAPhA, Remington Professor of Pharmacy, University of the Sciences Philadelphia College of Pharmacy Terra L. Hussar, MD, Department of Neurology, Hershey Medical Center, Hershey, PA Correspondence: Daniel A. Hussar, University of the Sciences Philadelphia College of Pharmacy, 600 S. 43rd St., Philadelphia, PA ; d.hussar@ usciences.edu Accreditation information Provider: APhA Target audience: Pharmacists, pharmacy technicians Release date: September 1, 2017 Expiration date: September 1, 2020 Learning level: 1 APhA is accredited by the Accreditation Council for Pharmacy Education (A) as a provider of continuing pharmacy education (). The A University Activity Number assigned to this activity by the accredited provider is H01-P/T. Advisory board: Mark S. Johnson, PharmD, BCPS, professor, department of pharmacy practice and director of postgraduate education, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA. Disclosures: Mark S. Johnson, PharmD, BCPS, declares that he and his spouse hold stock in Merck & Co. Daniel A. Hussar, PhD, FAPhA; Terra L. Hussar, MD; and APhA s editorial staff declare no conflicts of interest or financial interests in any product or service mentioned in this activity, including grants, employment, gifts, stock holdings, and honoraria. For complete staff disclosures, please see Development: This home-study activity was developed by APhA. 54 PharmacyToday SEPTEMBER 2017 A Universal Activity Number: H01-P/T credit: 2 hours (0.2 CEUs) Fee: There is no fee associated with this activity for APhA members. There is a $25 fee for nonmembers. Learning objectives At the conclusion of this knowledge-based activity, pharmacists and pharmacy technicians will be able to Identify the new therapeutic agents and explain their appropriate use. Identify the indications and mechanisms of action of the new agents. Identify the most important adverse events and other risks of the new agents. State the route of administration for each new drug and the most important considerations for dosage and administration. Compare the new agents with older medications to which they are most similar in properties and/or use, and identify the most important advantages and disadvantages of the new drugs.

2 Preassessment questions Before participating in this activity, test your knowledge by answering the following questions. These questions will also be part of the assessment. 1. Which of the following drugs : use pairings is correct? a. Safinamide: multiple sclerosis b. Edaravone: amyotrophic lateral sclerosis c. Deutetrabenazine: Parkinson disease d. Valbenazine: atopic dermatitis 2. Which of the following drugs is administered once a day? a. Dupilumab b. Ocrelizumab c. Valbenazine d. Edaravone 3. Which of the following statements is correct about ocrelizurnab? a. Its action is directed against CD20-expressing B cells. b. It should be used in combination with interferon beta-1a. c. When used for maintenance treatment, it is administered every 3 weeks. d. It is the first drug demonstrated to be effective in the treatment of relapsing multiple sclerosis. Objective Seven new therapeutic agents are considered in this review, the first in a series of articles on new medications marketed in Five of the new drugs treat neurologic disorders, and the other two treat atopic dermatitis (see Table 1). Following the discussion of each of the new therapeutic agents, the authors compare, when possible, the new drug with the older medication(s) with which it is most similar in properties and uses and identify advantages and disadvantages. Advantages and disadvantages are identified at the time the new drug is first marketed and do not reflect approvals of additional new drugs and/or other changes that occur after the drug is initially marketed. Agent for multiple sclerosis Multiple sclerosis (MS) is a chronic, inflammatory autoimmune disease of the central nervous system that affects approximately 400,000 people in the United States. It occurs more often in women than in men, and most individuals first experience symptoms between the ages of 20 and 40. Relapsing-remitting MS, also designated as relapsing MS, is the most common form of the disease, in which patients experience episodes of worsening function (relapses) that are followed by recovery periods (remissions) of varying duration. As the disease continues, remissions may be incomplete, and eventually, some patients become disabled and experience cognitive decline. Approximately 15% of patients with MS have primary progressive MS (PPMS), which is characterized by steadily worsening function from onset of symptoms, sometimes without early relapses and remissions. Treatment of MS includes the use of disease-modifying drugs, as well as medications that treat specific symptoms such as pain and corticosteroids for acute exacerbations. The disease-modifying drugs have been of value in reducing the frequency and severity of relapses but are of limited benefit in more progressive disease. Interferon beta was the first disease-modifying drug to be approved for the treatment of MS, and it continues to be used in several forms and products, including interferon beta-1a (e.g., Rebif EMD Serono), pegylated interferon beta-1a (Plegridy Biogen), and interferon beta-1b (e.g., Betaseron Bayer), which are administered subcutaneously, as well as a formulation of interferon beta-1a (Avonex Biogen) that is administered intramuscularly. Other drugs approved for the treatment of patients with relapsing-remitting MS are glatiramer acetate (e.g., Copaxone Teva), alemtuzumab (Lemtrada Genzyme), natalizumab (Tysabri Biogen), mitoxantrone, fingolimod (Gilenya Novartis), teriflunomide (Aubagio Sanofi, Genzyme), and dimethyl fumarate (Tecfidera Biogen). The latter three agents offer the convenience of oral administration and are now often used as first-line treatment of MS. Natalizumab may be the most effective of these drugs, but there is concern about rare but serious adverse events, including progressive multifocal leukoencephalopathy (PML), a potentially fatal opportunistic viral infection of the brain. In addition to these agents, rituximab (Rituxan) has been used off-label for the treatment of patients with more severe forms of MS. Ocrelizumab (Ocrevus Genentech) is a humanized monoclonal antibody that, like the chimeric monoclonal antibody rituximab, is directed against CD20-expressing B cells. CD20 is a cell surface antigen present on pre-b and mature B lymphocytes. B cells are believed to play a role in immune system mediated damage to brain and spinal cord tissues in MS, and following cell surface binding to B lymphocytes, ocrelizumab causes antibody-dependent cellular cytolysis and complement-mediated lysis. Administered by I.V. infusion, it is indicated for the treatment of patients with relapsing or primary progressive forms of MS. As the first drug demonstrated to be effective in the treatment of PPMS, it represents an important advance for patients with more severe forms of the disease. Effectiveness of ocrelizumab in the treatment of relapsing MS was established in two 96-week studies of 1,656 patients. The new drug was compared with interferon beta-1a (Rebif) in both studies, in which the primary endpoint was the annualized relapse rate. The annualized relapse rate for the patients treated with ocrelizumab was and 0.155, compared with rates of and for those treated with interferon beta-1a. In addition, 83% and 82% of the ocrelizumab-treated patients were relapse free, compared with 71% and 72% of the interferon beta-treated patients. The proportion of patients with 12-week confirmed disability progression was 9.8% with ocrelizumab treatment and 15.2% with interferon beta-1a treatment. Ocrelizumab was evaluated in 732 patients with PPMS in a placebo-controlled trial that continued for at least 120 weeks. There was a longer time to worsening of disability in patients treated with the new drug; the proportion of patients with 12- week confirmed disability progression was 32.9%, compared with 39.3% for those receiving placebo. In all three studies, MRI evaluations (e.g., number and volume of MS-associated brain lesions) indicated greater effectiveness of ocrelizumab SEPTEMBER 2017 PharmacyToday 55

3 compared with interferon beta-1a or placebo. Infusion reactions are an important concern with use of ocrelizumab and occurred in 40% of the patients in the placebo-controlled study, with the highest incidence occurring at first infusion. Manifestations ranged from relatively mild dermatological events to serious reactions such as bronchospasm and hypotension. Although there were no fatal infusion reactions in the clinical studies, 0.3% of patients experienced serious reactions, and some required hospitalization. Ocrelizumab is contraindicated in patients with a history of life-threatening infusion reactions to the drug, and if such reactions occur during treatment, the infusion should be immediately and permanently stopped and appropriate supportive treatment initiated. To reduce the frequency and severity of infusion reactions, a corticosteroid and antihistamine should be administered as premedications, and addition of an antipyretic can also be considered. Many patients treated with ocrelizumab experience infections, the most common of which are upper respiratory tract infections (49%), skin infections (14%), lower respiratory tract infections (10%), and herpes virus associated infections (5%), although these infections were also commonly reported, but at a lower incidence, in patients receiving placebo. In the clinical studies there were no reports of reactivation of hepatitis B virus (HBV) infection or of PML. Because the other anti-cd20 antibody, rituximab, has been associated with reactivation of HBV infection, ocrelizumab is contraindicated in patients with active HBV infection. Vaccination with live or live-attenuated vaccines is not recommended during treatment with ocrelizumab or following treatment until B-cell repletion. Immunizations according to guidelines should be administered at least 6 weeks prior to initiating treatment with ocrelizumab. An increased risk of malignancy, including breast cancer, may be associated with use of ocrelizumab. Breast cancer occurred in 6 of 781 females treated with the new drug and in none of the 668 females treated with interferon beta- 1 or placebo. Patients should follow standard breast cancer screening guidelines. There are insufficient data to assess the risk of using ocrelizumab in pregnant and nursing women. Results of animal studies suggest a potential for fetal harm if used during pregnancy. Although this risk with ocrelizumab may be less than with certain other agents used for the treatment of MS (e.g., teriflunomide, mitoxantrone), glatiramer acetate appears to have a lower risk of problems if used during pregnancy. Effectiveness and safety of ocrelizumab in pediatric patients have not been established. Concomitant use of ocrelizumab and other immunemodulating or immunosuppressive medications, including corticosteroids, may increase the risk of immunosuppression. Caution must be observed when these agents and certain other medications are used concurrently and also sequentially because ocrelizumab has a long duration of action. A potential exists for immunogenicity with use of ocrelizumab, but approximately only 1% of patients tested positive for antidrug antibodies, and only 2 of 1,311 patients tested positive for neutralizing antibodies. 56 PharmacyToday SEPTEMBER 2017 Prior to initiating ocrelizumab treatment, clinicians should screen patients for active HBV infection and, before each dose, exclude the presence of active infection of any type. If an active infection exists, the infusion of ocrelizumab should be delayed until the infection resolves. Patients should be premedicated with an antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes before each infusion, and 100 mg of methylprednisolone (or an equivalent corticosteroid) should be administered intravenously approximately 30 minutes before. Addition of an antipyretic (e.g., acetaminophen) may also be considered. Ocrelizumab injection is supplied in single-dose vials containing 300 mg of the drug in 10 ml. The vials should be stored in a refrigerator. The I.V. infusion must be prepared by a health professional and administered under supervision. Patients should be observed for infusion reactions during the infusion and for at least 1 hour after its completion. The intended dose should be withdrawn from the vial and diluted into an infusion bag containing 0.9% sodium chloride injection, to a final drug concentration of approximately 1.2 mg/ ml. The diluted infusion solution should be administered through a dedicated line using an infusion set with a 0.2- or 0.22-micron in-line filter. The initial dose of ocrelizumab is 300 mg in 250 ml of diluted solution, followed 2 weeks later by a second 300-mg infusion. Each of these infusions should be started at a rate of 30 ml per hour, which may be increased by 30 ml per hour every 30 minutes to a maximum of 180 ml per hour for a total infusion duration of 2.5 hours or longer. Subsequent doses are administered as a single 600-mg infusion (in 500 ml) every 6 months. These infusions should be started at a rate of 40 ml per hour, which may be increased by 40 ml per hour every 30 minutes to a maximum of 200 ml per hour for a total infusion duration of 3.5 hours or longer. Consult the product labeling for recommended dosage modifications if infusion reactions occur. If a planned infusion is missed, it should be administered as soon as possible. The dosage schedule should then be adjusted so that the next scheduled dose is administered 6 months after the missed dose is administered. Doses of the drug must be separated by an interval of at least 5 months. Comparison of ocrelizumab with interferon beta-1a Advantages Is the first drug shown to be effective in treatment of PPMS Is more effective than interferon beta-1a in treatment of relapsing MS Has a unique mechanism of action (is a CD20-directed cytolytic antibody) among the medications with a labeled indication for treatment of patients with MS Is administered less frequently (every 6 mo compared with three times/wk with interferon beta-1a) Disadvantages Is administered by I.V. infusion under the supervision of a health professional (whereas interferon beta-1a is selfadministered subcutaneously or intramuscularly) Often causes infusion reactions Is more likely to be associated with occurrence of infection May be associated with an increased risk of malignancy

4 Table 1. New therapeutic agents marketed in the United States in 2017: Part 1 Generic name Trade name Manufacturer Therapeutic classification Route of administration FDA classification a Crisaborole Eucrisa Pfizer Atopic dermatitis Topical 1-S Deutetrabenazine Austedo Teva Chorea of Huntington Oral 1-S disease Dupilumab Dupixent Regeneron, Sanofi Atopic dermatitis S.C. P b Edaravone Radicava Mitsubishi/ Tanabe Amyotrophic lateral sclerosis I.V. 1-S Ocrelizumab Ocrevus Genentech Multiple sclerosis I.V. P b Safinamide mesylate Xadago Newron Parkinson disease Oral 1-S Valbenazine tosylate Ingrezza Neuroscience Tardive dyskinesia Oral 1-P a FDA classification of new drugs: 1 = new molecular entity; S = standard review; P = priority review. b A biological approved through an FDA procedure that does not assign a numerical classification. Antiparkinson agent Safinamide mesylate (Xadago Newron) is the third monoamine oxidase type B (MAO-B) inhibitor to be marketed in the United States for the treatment of patients with Parkinson disease, joining selegilene (e.g., Eldepryl Somerset) and rasagiline (Azilect Teva). By inhibiting MAO-B activity, these agents reduce the catabolism of dopamine, resulting in increased dopamine concentrations and dopaminergic activity in the brain. Inhibition of MAO-B activity by safinamide is considered to be reversible, whereas selegilene and rasagiline irreversibly inhibit MAO-B activity. However, whether this distinction is of clinical importance is not known. The selective action of these three drugs in inhibiting MAO-B has been suggested to decrease the risk of adverse events and drug interactions associated with the use of nonselective monoamine oxidase inhibitors ([MAOIs] e.g., phenelzine, tranylcypromine) that also inhibit MAO type A (MAO-A). However, selectivity of the action is related to the dosage of the medications, and the experience of patients treated with the same dosage may vary widely. Accordingly, many of the warnings and precautions for the nonselective MAOIs should also be observed for the selective MAO-B inhibitors, including safinamide. Safinamide is specifically indicated as adjunctive treatment to levodopa/carbidopa (e.g., Sinemet Merck) in patients with Parkinson disease who are experiencing off episodes (periods during treatment when there is an increase in Parkinson symptoms such as tremor and difficulty walking). Although rasagiline also has labeled indications as monotherapy and as adjunctive treatment without levodopa, it is usually used with levodopa. Effectiveness of safinamide was evaluated in two placebo-controlled studies in patients also being treated with levodopa/carbidopa, dopamine agonists, catechol-o-methyl transferase inhibitors, anticholinergics, and/or amantadine. The primary measure of effectiveness was the change from baseline in on time without troublesome dyskinesia. In both studies, safinamide significantly increased on time compared with placebo, and this increase was accompanied by a similar significant reduction in off time ( 0.56 h in mean daily off time), as well as a reduction in the Unified Parkinson s Disease Rating Scale Part III scores, which were assessed during on time. Safinamide has not been shown to be effective as monotherapy for the treatment of patients with Parkinson disease. In addition to its use in the treatment of Parkinson disease, selegilene is also used in a transdermal system (Emsam Mylan) for the treatment of patients with major depressive disorder. However, this is not a labeled indication for safinamide. Adverse events most often experienced in the clinical studies (and their incidence with the recommended maintenance dosage of 100 mg/d) included dyskinesia (17%), fall (6%), nausea (6%), insomnia (4%), and increased serum alanine aminotransferase (7% to above the upper limit of normal). The new agent may cause dyskinesia or exacerbate preexisting dyskinesia, and reducing the dosage of levodopa or other dopaminergic treatment should be considered. Patients treated with dopaminergic medications, including the MAO-B inhibitors, have experienced complications for which precautions must be observed with use of safinamide. Some patients have experienced sleep attacks/sudden onset of sleep and/or have fallen asleep while engaged in daily activities (e.g., driving). Use of the drug should usually be discontinued if such experiences occur, but if treatment is continued, patients should be advised to avoid driving and other potentially dangerous activities. These medications have also been reported to cause problems with impulse control and compulsive behaviors, such as intense urges to gamble, spend money, and/or binge eat, and increased sexual urges. Patients with a major psychotic disorder should ordinarily not be treated with safinamide. Treatments for psychosis that antagonize the effects of dopaminergic medications, as well as use of metoclopramide, may exacerbate Parkinson disease symptoms. Safinamide may cause hypertension or exacerbate existing hypertension, and patients must be monitored accordingly. Concurrent use with another MAOI, including the SEPTEMBER 2017 PharmacyToday 57

5 antibacterial agent linezolid, is contraindicated because of the potential for a hypertensive crisis. At least 14 days should elapse between discontinuation of safinamide and initiation of treatment with another MAOI. Because isoniazid has some MAO-inhibiting activity, concurrent use of safinamide must be closely monitored. MAO in the gastrointestinal tract and liver is primarily MAO-A, which protects against pressor effects of exogenous amines such as tyramine, which may be present in large amounts in aged, fermented, cured, smoked, and pickled foods (e.g., aged cheese). Patients should be advised to avoid foods containing a large amount of tyramine while being treated with safinamide. Concurrent use of safinamide with certain sympathomimetic medications (amphetamine, methylphenidate, and their derivatives) is contraindicated. If safinamide is used concurrently with other prescription or nonprescription sympathomimetic medications, including oral, nasal, or ophthalmic decongestants and cold remedies, caution must be observed, and patients should be monitored for hypertension. Because of the risk of serotonin syndrome, concomitant use of safinamide with certain serotonergic drugs, including serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine), and with tricyclic, tetracyclic, or triazolopyridine antidepressants, cyclobenzaprine, or St. John s wort, is contraindicated. Concurrent use of safinamide with a selective serotonin reuptake inhibitor (e.g., fluoxetine, sertraline), although not specifically contraindicated, is best avoided. Serious reactions have also resulted from concomitant use of safinamide with opioid drugs (e.g., meperidine, methadone, propoxyphene, tramadol), and their concurrent use is contraindicated. At least 14 days should elapse between discontinuation of safinamide and initiation of treatment with a serotonergic drug or opioid. Use of safinamide with dextromethorphan is also contraindicated because of reports of psychosis or bizarre behaviors in patients taking other MAO inhibitors and dextromethorphan. There have been reports of retinal degeneration and other ocular adverse events when safinamide was used in animal studies. Patients with a history or family history of retinal/ macular disease should be monitored for visual changes. Safinamide is classified in Pregnancy Category C and should be used during pregnancy only if the anticipated benefit justifies fetal risk. Nursing mothers will need to decide whether to discontinue nursing or not use the drug. Effectiveness and safety of safinamide in pediatric patients have not been established. Following oral administration, the absolute bioavailability of safinamide is 95%, and it may be administered without regard to meals. The drug is extensively metabolized to inactive metabolites, and approximately 75% of a dose is recovered in the urine in the form of metabolites. The pharmacokinetics of safinamide are not affected by impaired renal function. However, a reduced dosage should be used in patients with moderate hepatic impairment, and its use is contraindicated in patients with severe hepatic impairment. Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BRCP) and could increase plasma concentrations of BRCP substrates such as 58 PharmacyToday SEPTEMBER 2017 methotrexate, imatinib, and rosuvastatin. Concurrent use should be closely monitored for increased activity and risk of the BRCP substrate. The recommended starting dosage of safinamide is 50 mg once a day at the same time each day. After 2 weeks, the dosage may be increased to 100 mg once a day, based on individual need and tolerability. If a dose is missed, the next dose should be taken at the same time the next day. In patients with moderate hepatic impairment, the maximum recommended dosage is 50 mg once a day. If a patient receiving treatment with this dosage experiences worsening of hepatic impairment, the drug should be discontinued. A symptom complex resembling neuroleptic malignant syndrome has been reported in association with rapid dose reduction of, withdrawal of, or changes in drugs that increase central dopaminergic tone. If treatment of safinamide is to be discontinued, the dosage should be decreased to 50 mg once a day for 1 week prior to stopping therapy. Safinamide mesylate is supplied in tablets in quantities equivalent to 50 mg and 100 mg of safinamide free-base. Comparison of safinamide with rasagiline and selegilene Advantages May be used in patients with renal impairment (compared with selegilene, which is not recommended in patients with severe renal impairment) Disadvantages Has not been directly compared in clinical trials with comparable drugs Labeled indications are more limited (compared with rasagiline, for which the labeled indications also include monotherapy and adjunctive therapy without levodopa) Is contraindicated in patients with severe hepatic impairment Agent for amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig disease, is a progressive neurodegenerative disease that affects 12,000 to 15,000 Americans, with approximately 5,000 patients diagnosed with the disease each year. It is characterized by the destruction of nerve cells that control the voluntary muscles involved in functions such as chewing, swallowing, talking, walking, and breathing. As the activity of the nerve cells declines, the muscles become weaker, and paralysis results. Most patients with ALS die from respiratory failure, usually within 3 to 5 years from the time symptoms first appear. Riluzole (Rilutek Covis Pharma Sarl), approved by FDA in 1995, has been the only drug available that is indicated for the treatment of ALS. It is thought to act by reducing glutamate release and reducing the accumulation of this amino acid in nerve cell synapses. This agent has been demonstrated to prolong survival and/or time to tracheostomy but prolongs survival on average by only 3 months. Edaravone (Radicava Mitsubishi Tanabe), the second drug to be approved for treatment of ALS, is administered by I.V. infusion. The placebo-controlled clinical trial on which its approval was based was conducted in Japan in 137 pa-

6 tients with a disease duration of 2 years or less, of whom 69 patients were in the edaravone arm and 68 were in the placebo arm. More than 90% of the patients in each group were being treated with riluzole. The ALS Functional Rating Scale Revised (ALSFRS-R) was used to assess the patients in the study and consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/ hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency). Each item is scored from 0 to 4, with higher scores representing greater functional ability. The primary efficacy endpoint was a comparison of the change between treatment arms in the ALSFRS-R total scores from baseline to week 24. The decline in these scores from baseline was significantly less in the edaravone-treated patients ( 5.01) compared with those treated with placebo ( 7.50). The mechanism of action through which the drug provides its benefit, and whether it prolongs survival, is not yet known. Adverse events experienced most often with use of edaravone include contusion (bruising; 15%), gait disturbance (13%), headache (10%), dermatitis (8%), eczema (7%), and respiratory failure, respiratory disorder, and/or hypoxia (6%). Hypersensitivity reactions including anaphylaxis have been reported, and patients should be monitored closely for such responses. The formulation of edaravone contains sodium bisulfite, which may cause serious allergic and asthmatic reactions in susceptible individuals. Sulfite sensitivity occurs more frequently in patients with asthma, and use of the new drug is contraindicated in patients with a history of hypersensitivity to either the medication or any of its inactive ingredients. ALS is very rare in women of childbearing age, and there are insufficient data to determine the risks of using edaravone during pregnancy. However, based on studies in animals, the drug appears to have the potential for causing fetal harm. Edaravone is metabolized to a sulfate conjugate and a glucuronide conjugate, which are not pharmacologically active. The drug is excreted almost entirely in the urine in the form of metabolites, with the glucuronide conjugate form representing 70% to 90% of a dose. Edaravone injection is supplied in a single-dose polypropylene bag containing 30 mg of the drug in 100 ml of aqueous solution. The product should be protected from light and stored in an overwrapped package to protect it from oxygen degradation until time of use. The oxygen indicator will turn blue or purple if the oxygen has exceeded acceptable levels. Once the overwrap package is opened, the medication should be used within 24 hours. The recommended dosage of edaravone is an I.V. infusion of 60 mg as two consecutive 30-mg I.V. infusion bags over a total of 60 minutes (infusion rate approximately 1 mg/min [3.33 ml/min]). The initial treatment cycle is 60 mg once a day for 14 days, followed by a 14-day drug-free period. In subsequent treatment cycles, a 60-mg dose is administered once a day for 10 days out of 14-day periods, followed by 14- day drug-free periods. Comparison of edaravone with riluzole Advantages Slows the worsening of ALS symptoms Disadvantages Prolongation of survival has not been demonstrated Is administered intravenously (whereas riluzole is administered orally) Agent for tardive dyskinesia Tardive dyskinesia is a neurological disorder characterized by repetitive involuntary movements, usually of the mouth, lips, and tongue and, occasionally, by rapid movement of the arms and legs. Some individuals may experience difficulty in speaking, swallowing, and breathing, and the problem can be disabling and further stigmatizing for patients with mental illness. Tardive dyskinesia occurs most often in patients treated for long periods with older antipsychotic medications (e.g., phenothiazines, haloperidol) and may develop during the treatment period or even after treatment is discontinued. Long-term use of metoclopramide for gastrointestinal conditions has also been associated with occurrence of tardive dyskinesia. Treatment has generally been limited to discontinuing or reducing the dosage of the causative medication or using different medications. However, symptoms usually persist even when the medication is discontinued, and discontinuing an antipsychotic medication can have serious consequences in patients with conditions like schizophrenia. Valbenazine tosylate (Ingrezza Neurocrine), the first drug to be approved for the treatment of adult patients with tardive dyskinesia, represents an important advance in the treatment of this disorder. Its specific mechanism of action is unknown, but its therapeutic effect is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), which regulates monoamine (e.g., dopamine) uptake from the cytoplasm to the synaptic vesicle for storage and release. Inhibition of VMAT2 reduces synaptic monoamine concentrations. The actions of valbenazine are most similar to those of tetrabenazine (Xenazine Lundbeck), a drug that was initially marketed in 2008 as the first drug for the treatment of chorea associated with Huntington disease, a rare, inherited neurological disorder. Both valbenazine and tetrabenazine are converted to the active metabolite, alphadihydrotetrabenazine. Effectiveness of valbenazine was demonstrated in a placebo-controlled clinical trial in 234 patients with moderate to severe tardive dyskinesia who had underlying schizophrenia, schizoaffective disorder, or mood disorder, of whom approximately 85% were being treated with antipsychotic agents. The Abnormal Involuntary Movement Scale (AIMS) was used to assess tardive dyskinesia severity, and the primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of week 6. Patients treated with valbenazine experienced improvement in the severity of abnormal involuntary movements compared with those who received placebo. At the end of week 6, patients initially assigned to placebo were re-randomized to SEPTEMBER 2017 PharmacyToday 59

7 receive valbenazine, and follow-up was continued through week 48, followed by a 4-week period off the drug. When valbenazine treatment was discontinued, the mean AIMS dyskinesia total score appeared to return toward baseline, thereby suggesting a need for ongoing treatment. Adverse events reported most often in the clinical study included somnolence (11%) and anticholinergic effects (5%; e.g., dry mouth, blurred vision), although the latter effects occurred at approximately the same incidence in patients receiving placebo. Patients should be advised to avoid activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they know how the drug affects them. Valbenazine may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with the recommended dosage. However, its use should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a long QT interval. In patients who are CYP2D6 poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor, drug concentrations may be higher and QT prolongation clinically significant, and a reduction in dosage of valbenazine will usually be necessary. Labeling for the related agent tetrabenazine includes a boxed warning on depression and suicidality, as well as several contraindications. Although these risks are not emphasized in the valbenazine labeling, the similarities of the two drugs and limited experience with the new drug warrant close monitoring of its use. Patients at significant risk for suicidal or violent behavior and patients with unstable psychiatric symptoms were excluded from the clinical trial. If used during pregnancy, valbenazine may cause fetal harm, and patients of childbearing potential should be informed of this risk. It is likely that valbenazine and its metabolites will be present in human milk, and women should be advised not to breastfeed during treatment and for 5 days after the final dose. Effectiveness and safety of valbenazine have not been established in pediatric patients. Valbenazine may be administered with or without food. It is extensively metabolized by hydrolysis to its active metabolite, alpha-dihydrotetrabenazine, and by oxidative metabolism, primarily by CYP3A4/5, to other metabolites. The active metabolite appears to be further metabolized in part by CYP2D6. Approximately 60% of a dose is eliminated in the urine and approximately 30% in the feces. Less than 2% of a dose is excreted as unchanged valbenazine or alphadihydrotetrabenazine in either urine or feces. Dosage adjustment is not necessary in patients with mild or moderate renal impairment. However, use of valbenazine is not recommended in patients with severe renal impairment (i.e., creatinine clearance <30 ml/min). In patients with moderate or severe hepatic impairment, valbenazine should be used in a reduced dosage. Valbenazine should not be used concurrently with an MAOI (e.g., isocarboxazid, phenelzine, selegilene) because the resultant increased concentration of monoamines in synapses may increase the risk of adverse events such as serotonin syndrome or a reduction in the effect of valbenazine. 60 PharmacyToday SEPTEMBER 2017 The concentrations, actions, and risks of valbenazine and its active metabolite are increased by concurrent use of a strong CYP3A4 inhibitor (e.g., clarithromycin, itraconazole) or a strong CYP2D6 inhibitor (e.g., paroxetine, fluoxetine, quinidine), and a reduction in dosage of the new drug is often necessary. Strong CYP3A4 inducers (e.g., carbamazepine, St. John s wort) reduce the concentration and action of valbenazine, and concurrent use of these agents is not recommended. Valbenazine may inhibit intestinal P-glycoprotein and increase digoxin concentrations, possibly necessitating a reduction in dosage of digoxin. The initial dosage of valbenazine is 40 mg once a day orally. After 1 week, the dosage should be increased to the recommended dosage of 80 mg once a day. However, the 40- mg daily dosage should be continued in patients with moderate or severe hepatic impairment and in patients treated concurrently with a strong CYP3A4 inhibitor. A reduction in dosage should be considered in patients who are known to be CYP2D6 poor metabolizers and in patients treated concurrently with a strong CYP2D6 inhibitor. Valbenazine tosylate is supplied in capsules that contain 73 mg of the tosylate salt, which is equivalent to 40 mg of valbenazine free-base. The high cost of valbenazine (>$100,000/y) to manage a clinical problem that is usually caused by other medications will often be reason to reassess the underlying medical problems and their treatment. Valbenazine is only available through certain specialty pharmacies. Valbenazine (no comparable drugs) Advantages Is the first drug demonstrated to be effective for the treatment of tardive dyskinesia Limitations May prolong QT interval and increase risk of arrhythmia May interact with numerous other medications Agent for chorea in Huntington disease Huntington disease is an inherited neurological disorder that results in the progressive breakdown of nerve cells in the brain. It is caused by an inherited defect in a single gene, and each child of a parent with the disease has a 50% chance of inheriting the mutation. Approximately 30,000 people in the United States have Huntington disease, symptoms of which usually appear between the ages of 30 and 50 years. Symptoms include a wide spectrum of movement (e.g., chorea), cognitive, and psychiatric manifestations. Chorea is primarily characterized by involuntary jerking or writhing movements and is experienced by 90% of patients with Huntington disease. Tetrabenazine (e.g., Xenazine) was the first drug to be approved (in 2008) for the treatment of chorea associated with Huntington disease. It is thought to reversibly inhibit the human VMAT2, resulting in a decreased uptake of monoamines (dopamine, norepinephrine, serotonin, histamine) into synaptic vesicles of monoamine stores. Its therapeutic benefit is the improvement of chorea in some patients, but it does not cure or otherwise modify the underlying disease.

8 Deutetrabenazine (Austedo Teva) is the deuterated form of tetrabenazine, in which deuterium, the heavy hydrogen isotope of regular hydrogen because it has an additional neutron in it, is used instead of hydrogen in two places in its chemical structure. The structure of tetrabenazine includes two methoxy groups (OCH3) on an aryl ring that are a primary target of metabolizing enzymes. The deutetrabenazine molecule, which includes two OCD3 substituents instead of the OCH3 substituents, is metabolized at a slower rate than tetrabenazine and can be administered less frequently. As with tetrabenazine, deutetrabenazine is thought to act as a reversible VMAT2 inhibitor and is indicated for the treatment of chorea associated with Huntington disease. Effectiveness of the new drug was demonstrated in a placebo-controlled study in which the primary efficacy endpoint was the Total Maximal Chorea Score (range 0 28). These scores improved by approximately 4.4 units from baseline in patients treated with deutetrabenazine, compared with approximately 1.9 units in the placebo group. In a self-assessment, 51% of patients treated with deutetrabenazine rated their overall symptoms as much improved or very much improved, compared with 20% of placebo-treated patients. Deutetrabenazine has not been directly compared with tetrabenazine in clinical studies, but the separate studies of the two drugs suggest that they are similar in effectiveness. Deutetrabenazine is also being evaluated for treatment of patients with tardive dyskinesia. However, this is not a labeled indication at present. Both deutetrabenazine and tetrabenazine may increase the risk of depression and suicidality and cause other serious adverse events. A boxed warning on depression and suicidality is included in their labeling, and they are contraindicated in patients who are suicidal or in patients with untreated or inadequately treated depression. Both agents are also contraindicated in patients with hepatic impairment and in patients treated with an MAOI or reserpine. At least 20 days should elapse following the discontinuation of reserpine, and 14 days following the discontinuation of an MAOI, before initiating treatment with deutetrabenazine. Deutetrabenazine is also contraindicated in patients currently taking tetrabenazine, but the new agent may be initiated the day following discontinuation of tetrabenazine. Adverse events most frequently reported with use of deutetrabenazine in the clinical trial included somnolence (11%), diarrhea (9%), dry mouth (9%), fatigue (9%), urinary tract infection (7%), and insomnia (7%). Somnolence/sedation is the most common dose-limiting adverse event, and patients should be cautioned about engaging in activities requiring mental alertness (e.g., driving, operating machinery) until they know how the drug affects them. Consuming alcoholic beverages or using other sedating drugs further increases the likelihood of central nervous system depressant effects. Other adverse events that may be associated with use of both deutetrabenazine and tetrabenazine include parkinsonism, akathisia, agitation, restlessness, neuroleptic malignant syndrome, hyperprolactinemia, and binding to melanincontaining tissues (e.g., in the eye). The risk of some of these adverse events may be increased in patients with certain neurologic disorders or those who are being treated concurrently with dopamine antagonists or antipsychotic medications. The labeling for tetrabenazine, but not for deutetrabenazine, includes warnings and precautions about hypotension and orthostatic hypotension, dysphagia, and tardive dyskinesia, and the new drug should be considered to have the potential for causing these responses. Although the two drugs have not been directly compared, data from the separate clinical studies suggest that deutetrabenazine is less likely to cause adverse events. Deutetrabenazine and tetrabenazine may cause prolongation of the QT interval of the ECG. They should not be used concurrently with other drugs that are known to prolong the QT interval, such as certain antipsychotic agents (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone) and certain antimicrobial agents (e.g., moxifloxacin), or with Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications. They should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Data are very limited on use of deutetrabenazine in pregnant women. However, based on animal studies, the drug may cause fetal harm if it is used during pregnancy. Effectiveness and safety of the new drug in pediatric patients have not been established. Following oral administration, at least 80% of a dose of deutetrabenazine is absorbed. Food had no effect on the area under the plasma concentration time curve of the active metabolites. However, the maximum plasma concentration was increased by approximately 50% in the presence of food, and it is recommended that the drug be administered with food. It is rapidly and extensively metabolized in the liver to the active deuterated dihydro metabolites, which are subsequently metabolized primarily via the CYP2D6 pathway. It is likely that a large increase in exposure to the drug will occur in patients with hepatic impairment, and its use is contraindicated in these patients. Most of a dose of the drug is excreted in the urine in the form of metabolites. Concurrent use of a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine, bupropion) has been shown to increase systemic exposure to the active metabolites of deutetrabenazine by approximately three-fold, and a reduced dosage of the new drug should be used. The recommended starting dosage of deutetrabenazine is 6 mg once a day orally with food. The dosage should be titrated upward at weekly intervals by 6 mg per day to a tolerated dose that reduces chorea, up to a maximum recommended daily dosage of 48 mg (24 mg twice/d). Total daily dosages of 12 mg or above should be administered in two divided doses, whereas maintenance dosages of tetrabenazine are administered in three divided doses per day. In patients who are being treated concurrently with a strong CYP2D6 inhibitor or who are poor CYP2D6 metabolizers, the total daily dosage of deutetrabenazine should not exceed 36 mg (maximum single dose of 18 mg). In patients who are being switched from tetrabenazine to deutetrabenazine, the product labeling should be con- SEPTEMBER 2017 PharmacyToday 61

9 sulted for dosage recommendations. Deutetrabenazine tablets are supplied in 6-mg, 9-mg, and 12-mg potencies. The tablets should be swallowed whole and should not be chewed, crushed, or broken. Comparison of deutetrabenazine with tetrabenazine Advantages May be less likely to cause adverse events Is administered less frequently for maintenance treatment (twice/d, whereas tetrabenazine is administered three times/d) Disadvantages Has not been directly compared with tetrabenazine in clinical studies Agents for atopic dermatitis The term eczema has been used to identify many dermatologic conditions associated with inflammation. Atopic dermatitis, the most common type of eczema, is a chronic inflammatory skin disease that typically begins in childhood and can last through adulthood. It is caused by a combination of genetic, immune, and environmental factors and may be characterized by red, scaly lesions, pruritus, inflammation, cracking, exudation, and eventually, coarsening and thickening of the skin. Approximately 18 million Americans have atopic dermatitis, of whom 90% have the mild to moderate form of the condition. Use of moisturizers (e.g., Aquaphor Beiersdorf) and emollients may relieve the symptoms of atopic dermatitis. For patients who do not experience adequate benefit from these nonpharmacologic products, a low-potency topical corticosteroid (e.g., hydrocortisone) is often effective in the treatment of mild atopic dermatitis, and a medium-potency (e.g., triamcinolone) or high-potency (e.g., fluocinonide) topical corticosteroid is typically used to treat moderate to severe disease. The topical calcineurin inhibitors tacrolimus (Protopic Astellas) and pimecrolimus (Elidel Valeant) are indicated as second-line therapy for the treatment of atopic dermatitis in nonimmunocompromised patients who have not responded adequately to other topical prescription treatments, or when those treatments are not advisable. Pimecrolimus is indicated for the treatment of mild to moderate atopic dermatitis and tacrolimus for moderate to severe forms of the condition. The labeling for both agents includes a boxed warning on the limited information regarding longterm safety because of rare reports of malignancy (skin and lymphoma). However, a causal relationship has not been established. Two new drugs were approved in early 2017 for the treatment of patients with atopic dermatitis, and these medications are considered individually in the following discussions. Crisaborole Crisaborole (Eucrisa Pfizer) is a phosphodiesterase type 4 inhibitor that, by increasing concentrations of cyclic adenosine monophosphate, may suppress the production of proinflammatory cytokines. Its mechanism of action is the same as that of apremilast (Otezla Celgene), which was approved in 62 PharmacyToday SEPTEMBER and is administered orally for the treatment of patients with psoriatic arthritis and plaque psoriasis. Crisaborole is applied topically and is indicated for the treatment of mild to moderate atopic dermatitis in patients 2 years of age and older. Effectiveness of crisaborole was evaluated in two vehiclecontrolled studies in which the Investigator s Static Global Assessment (ISGA) score was determined on the basis of erythema, induration/papulation, and oozing/crusting on a severity scale of 0 to 4 at baseline and the day following completion of the 28-day course of twice-daily treatment. Success was defined as an ISGA grade of clear (score of 0) or almost clear (score of 1) with a two-grade or greater improvement from baseline. Patients treated with crisaborole achieved a greater response, with successful results experienced in 33% and 31% of the patients in the two studies, compared with 25% and 18% of the patients treated with the vehicle. The most common adverse event in the clinical studies was application site pain (4%) such as stinging and burning. There were infrequent reports of hypersensitivity reactions, and the medication should be discontinued if such events occur. Crisaborole is systemically absorbed, but problems in pregnant and nursing women appear unlikely. The new agent is substantially metabolized to inactive metabolites, and renal excretion is the major route of elimination. Crisaborole ointment contains the medication in a concentration of 2%, and a thin layer of ointment is applied twice a day to the affected areas. Patients should be advised to wash their hands following application of the ointment, unless the hands are being treated. Comparison of crisaborole with topical corticosteroids (e.g., hydrocortisone, triamcinolone) Advantages May be more effective in some patients May be less likely to cause systemic adverse events Disadvantages Has not been directly compared with other drugs in clinical studies Labeled indications are more limited (topical corticosteroids have numerous other dermatologic indications) Dupilumab Dupilumab (Dupixent Regeneron, Sanofi) is a human monoclonal antibody that is designated as an interleukin-4 (IL-4) receptor alpha inhibitor. It inhibits IL-4 and interleukin-13 (IL-13) signaling by specifically binding to the IL-4R alpha subunit that is shared by the IL-4 and IL-13 receptor complexes. The new drug inhibits IL-4 signaling via the type I receptor and both IL-4 and IL-13 signaling through the type II receptor. By blocking IL-4R alpha, dupilumab inhibits IL-4 and IL-13 cytokine-induced responses, including the release of proinflammatory cytokines, chemokines, and IgE. Dupilumab, which is administered subcutaneously, is indicated for the treatment of adult patients with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. It may be used with or without