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Home , Deutetrabenazine, Valbenazine

continuing education for pharmacists Volume XXXVI, No. 1 New Drugs 2017: Central Nervous System

Karen L. Kier, PhD, MSc, R.Ph., BCPS, BCACP, CTTS, Professor of Clinical Pharmacy, Director of Drug and Health Information, Raabe College of Pharmacy, Ohio Northern University

Dr. Karen Kier has no relevant financial relationships to disclose. characterized by involuntary and/ mechanism, caution should be or restless rolling of the tongue taken with patients with a history or twitching of the face, trunk, or of depression or QT prolongation. Goal. The goal of this lesson is to limbs. medications has vasoconstriction provide a broad overview of central are a known cause of tardive dyski- properties and a clinical mono- nervous system drugs approved nesia, with some drugs being worse graph services caution about the by the Food and Drug Adminis- than others. concomitant use with vasoconstric- tration (FDA) in 2017, including Valbenazine is a highly- tor drugs such as epinephrine. indications, mechanisms of action, selective vesicular monoamine It should be noted that this adverse events, warnings/contra- transporter 2 (VMAT2) inhibitor. drug has some significant drug- indications, drug/food interactions, The exact mechanism of action of drug interactions with the other counseling information, and avail- valbenazine in the treatment of medications that inhibit or induce ability. is not known. the CYP3A4 and/or the CYP2D6 Valbenazine has little to no binding pathways. The parent drug, val- Objectives. At the completion of affinity for VMAT1 or dopaminer- benazine, is metabolized to an this activity, the participant will be gic, serotonergic, adrenergic, hista- active metabolite by the CYP3A4 able to: minergic or muscarinic receptors. enzyme system and that active 1. recognize the targeted pa- FDA granted breakthrough sta- metabolite is then metabolized thologies for the new CNS drugs tus for valbenazine due to the novel by the CYP2D6 enzyme system. discussed in this lesson; mechanism of action. The Kinect 3 Strong CYP3A4 inducers such 2. select the indication(s), phar- compared a once-daily as carbamazepine, rifampin, and macologic action(s), clinical appli- dose of 40 mg or 80 mg valbenazine St. John’s wort are not recom- cations, dosing regimens, mode of to placebo over a six-week period mended to be used concomitantly administration, and availability for in patients with schizophrenia, with valbenazine. Strong CYP3A4 each drug; schizoaffective disorder, or mood inhibitors like clarithromycin, 3. list the most relevant ad- disorders. After the initial six- ketoconazole, and itraconazole can verse effects, warnings, precau- week run-in period, all patients be used concurrently with valbena- tions, contraindications, and were placed on either 40 mg or zine, but at a 40 mg daily dose. The significant drug-drug or drug-food 80 mg capsules once daily for 48 manufacturer does not give specific interactions reported with these weeks. The clinical trial found this labeling information for changes in medications; and therapy to be effective in managing dose when valbenazine is combined 4. list important patient coun- the symptoms of tardive dyskinesia with strong CYP2D6 inhibitors like seling information to convey to with a tolerable side effect profile. and . Patients patients and/or caregivers. The most common adverse may require a dosage adjustment effect was at about based on tolerability when com- Valbenazine (Ingrezza®, [in- two times the rate seen with the bined with these drugs. Valbena- GREH-zah] Neurocrine Biosci- placebo. Potential side effects like zine is not recommended for use in ences) was approved by FDA on inducing depression, suicidality, patients with severe renal impair- April 11, 2017 for the treatment of and QT prolongation have not been ment defined as a creatinine clear- tardive dyskinesia. Tardive dyski- shown in clinical trials to-date. ance of less than 30 mL/minute, nesia is a very difficult disorder to However, the studies have been but no other dosing adjustments treat and very few therapy modali- limited in the number of patients are necessary if the patient’s renal ties are effective in controlling the included and long-term data are function exceeds the 30mL/minute tremors. Tardive dyskinesia is not yet known. Due to the VMAT2 threshold. Dosing adjustment to Table 1 Selected CNS drugs approved in 2017

Generic Indication Dose Dosage Form Side Effects (Trade Name)

Valbenazine tardive 40 mg daily for 1 week; then 40 mg, 80 mg somnolence (Ingrezza®) dyskinesia 80 mg daily capsules

Deutetrabenazine Huntington’s chorea: 6 mg daily for 1 week, 6 mg, 9 mg, 12 mg akathisia, (Austedo®) chorea; tardive increased as necessary; tablets Boxed Warning: depression dyskinesia tardive dyskinesia: 6 mg twice daily, increased as necessary

Ocrelizumab primary pro- 300 mg Day 1; 300 mg 2 weeks IV infusion infection (Ocrevus™) gressive and later; then 600 mg every relapsing MS 6 months

Edaravone amyotrophic initial cycle: 60 mg x 14 days; IV infusion gait disturbances, (Radicava®) lateral 14 days off; then subsequent bruising sclerosis cycles: 60 mg daily x 10 days; 14 days off, (cycle repeated)

Desmopressin nocturia due <65 y, 1.66 mcg nightly; nasal spray local nasal reactions, Boxed (Noctiva™) to nocturnal >65 y, 0.83 mcg nightly Warning: hyponatremia polyuria

40 mg once daily is necessary in results in a progressive degenera- for depression and it should not be patients with moderate to severe tion of brain nerve cells. The dis- started in a patient with untreated liver impairment. ease causes a series of functional depression or suicidal ideation. Pa- Valbenazine has a bioavail- abnormalities such as movement tients should be monitored closely ability of less than 50 percent, but disorders (chorea), changes in for signs of worsening depression. it has a fairly long half-life between cognition, and psychiatric disor- Patients may also experience 15 to 22 hours that allows for the ders. Signs and symptoms often akathisia, which is a movement once daily dosing. High-fat meals become apparent when patients are disorder characterized by a feeling can decrease the overall absorption in their 30s or 40s, but it can ap- of inner restlessness and a compel- of the product and patients should pear earlier or later in some cases. ling need to be in constant motion. be counseled to take on an empty There is no cure for Huntington’s If this occurs, consideration should stomach and be consistent in the disease at this time; therapy is be given for reducing the dose time of the day that they take the based on managing the symptoms or discontinuing the medication. medication. and improving quality of life. has significant Package labeling suggests Deutetrabenazine was evalu- drug-drug interactions related to starting patients on 40 mg once ated in a clinical trial of 90 pa- CYP2D6. Therefore, caution needs daily for one week, and then tients and showed a statistically to be taken when combined with increase to 80 mg once daily significant improvement in Total antidepressants such as paroxetine thereafter. Some patients may be Maximal Chorea Scores over and fluoxetine. maintained on 40 mg daily if they the 12-week study. At 12 weeks, Deutetrabenazine is structur- are achieving an adequate response the medication was stopped and ally related to (Xe- and are tolerating the mediation patients returned to their baseline nazine®) which was FDA-approved with minimal side effects. Ingrez- chorea score within one week of in August 2008 for tardive dyski- za® is available in 40 mg and discontinuation. nesia. On August 30, 2017, FDA 80 mg capsules. Patients should be counseled to approved deutetrabenazine for the take this medication with food and treatment of tardive dyskinesia Deutetrabenazine (Austedo®, to swallow the tablet whole without making it the second FDA-ap- [aw-STED-oh] Teva Pharmaceuti- chewing or crushing. The warn- proved drug for this condition. The cals) is a VMAT2 inhibitor ap- ings for this drug are similar to the indication for tardive dyskinesia proved in April 2017 for the treat- other VMAT2 inhibitor, valbena- resulted from two phase III clini- ment of chorea associated with zine, and include depression, QT cal trials that showed a significant Huntington’s disease. Huntington’s prolongation, and suicidal ideation. reduction in the severity of abnor- disease is an inherited disease that This drug has a Boxed Warning mal involuntary movements and an improvement in quality of life also demonstrated a reduction in days. The intravenous solutions are metrics as measured by the modi- brain lesions on MRI evaluation. available as 30 mg/100 mL. fied 24-item Craniocervical Dys- Ocrelizumab can increase the tonia Questionnaire. These were risk of infection. If patients present Desmopressin Acetate Nasal short-term 12 week trials. with signs and symptoms of infec- Spray (NoctivaTM [nok-TEE-va], Dosing is similar for both indi- tion, they should be referred to the Serenity Pharmaceuticals). On cations; however, the starting dose appropriate healthcare provider for March 3, 2017, FDA approved des- for tardive dyskinesia is higher. treatment. mopressin acetate, a vasopressin The starting dose for Hunting- Ocrelizumab is administered analog, nasal spray for the treat- ton’s disease is 6 mg once daily for as an intravenous infusion, 300 ment of nocturia due to nocturnal one week. The dose may then be mg on Day 1, followed by 300 polyuria. Other desmopressin prod- increased by 6 mg per day per week mg two weeks later. Subsequent ucts are currently on the market based on response and tolerability. doses of 600 mg are administered indicated for the management of For tardive dyskinesia, the starting once every six months, beginning diabetes insipidus, hemophilia A, dose is 6 mg twice daily, followed six months after the first 300 mg and von Willebrand disease. FDA by 6 mg per day per week increases dose. Patients may require pre- defined nocturnal polyuria as hav- as necessary. When the total daily medication with corticosteroids and ing to get up at least twice during dose is 12 mg or above per day, the to reduce infusion sleep to urinate. NoctivaTM has not dose should be split into a twice reactions. been studied for any other indica- daily regimen. The maximum daily Pharmacists can play a role en- tions at the time of writing, and dose should not exceed 48 mg. It is couraging patients to be compliant has not been studied in patients important to inform patients that with their clinic visits, as well as less than 50 years of age. dosing disruptions longer than to direct them to available patient Pharmacists should counsel seven days will necessitate restart- assistance programs. patients on minimizing fluid intake ing the titration process with 6 mg near bedtime, both to help reduce once or twice daily, depending on Edaravone (Radicava®, Mitsubi- nocturnal polyuria and also to re- the condition being treated. Pack- shi Tanabe Pharma) received FDA duce the risk of hyponatremia (low age labeling includes a chart for approval on May 5, 2017 as the serum sodium levels). This product converting patients from tetrabena- first drug approved in 20 years for includes a Boxed Warning for drug- zine to deutetrabenazine. the treatment of amyotrophic later- induced hyponatremia that can be Austedo® is available in 6 mg, 9 al sclerosis (ALS), also referred to life-threatening. Many medications mg, and 12 mg tablets. as Lou Gehrig’s disease. FDA gave (e.g., thiazide diuretics, loop diuret- orphan drug status to edaravone, ics, antidepressants, selec- Ocrelizumab (OcrevusTM [OAK- which is a free radical scavenger tive re-uptake inhibitors, rev-us], Genentech), the first drug that relieves the effects of oxidative nonsteroidal anti-inflammatory with an indication for both primary stress which is considered a likely drugs, glucocorticoids, , progressive (PPMS) and relapsing factor in the onset and progression lamotrigine, and carbamazepine) forms (RMS) of multiple sclerosis of ALS. can increase the risk of developing (MS), was approved by FDA on Edaravone was evaluated in hyponatremia and pharmacists March 28, 2017. Ocrelizumab is a a six-month clinical trial. At 24 should review the patient’s medica- humanized monoclonal antibody weeks, patients showed a slower tion profile prior to dispensing Noc- that selectively targets CD20-pos- decline in daily functioning com- tivaTM. Serum sodium levels should itive B cells. These cells play a key pared to the placebo group. be measured within seven days of role in the damage that MS causes The most common side effects initiating therapy, and then at one to both myelin and axonal nerve include gait disturbances and month with periodic measurements cells. bruising. Pharmacists can counsel thereafter. Sodium levels should Ocrelizumab had two pub- patients on complying with clinic also be repeated if the dosage is lished phase III trials in RMS visits and help monitor for side increased and consideration should called OPERA I and OPERA II, effects. be given to monitoring more often and one published phase III study Edaravone is administered in patients over the age of 65 years. in PPMS called ORATORIO. The as an intravenous infusion on a Pharmacists can help patients OPERA studies showed a signifi- 14-day cycle. For the first cycle, understand the need for this moni- cant decrease in the rate of relapse patients receive 60 mg, infused toring, making sure patients are in RMS within the first eight weeks over 60 minutes, daily for 14 days, getting blood levels drawn when of treatment and was shown to be followed by 14 days off. Then 60 mg appropriate. superior to interferon therapies. infusions are administered daily NoctivaTM should be avoided The ORATORIO study showed a for 10 days followed by 14 days off. in patients with congestive heart significant decrease in fatigue and This cycle is then repeated with failure, fluid overload, uncontrolled disability in PPMS. The studies active infusions starting every 24 hypertension, electrolyte distur- Table 2 Selected CNS drugs approved in 2017

Generic Indication Dose Dosage Form Side Effects (Trade Name)

Amphetamine ADHD 12.5 mg to 25 mg daily, 12.5 mg, 25 mg, decreased appetite, weight (Mydayis®) increased by 12.5 mg; 50 mg 37.5 mg, 50 mg loss, dry mouth, anxiety, maximum dose capsules increased heart rate; Boxed Warning: abuse potential and dependence

Methylphenidate ADHD for 17.3 mg daily, titrated to not 8.6 mg, 17.3 mg, decreased appetite, weight (Cotempla 6-17 year-olds exceed 51.8 mg 25.9 mg orally loss, dry mouth, increased XR-ODT™) disintegrating heart rate, anxiety; Boxed extended-release Warning: abuse potential tablets and dependence

Amphetamine ADHD 6.3 mg daily, increasing by 1.25 mg/mL decreased appetite, weight (Adzenys ER™) >6 years 3.1 mg or 6.3 mg at weekly 450 mL suspension loss, dry mouth, anxiety, intervals to not exceed 12.5 mg increased heart rate; or 18.8 mg based on patient age Boxed Warning: abuse potential and dependence

Oxycodone severe 5 mg to 15 mg every 4-6 hours 5 mg, 15 mg, drowsiness, itching, nausea, (RoxyBond™) pain as needed for pain 30 mg tablets constipation, abnormal dreams, euphoria, withdrawal

Naldemedine -induced 0.2 mg daily 0.2 mg tablets gastrointestinal perforation (Symproic®) constipation possible, but rare

Safinamide Parkinson’s 50 mg daily, increased after 50 mg, 100 mg dyskinesia, hypertension, (Xadago®) disease “off” two weeks to 100 mg daily tablets impulse control disorder, episodes serotonin syndrome

Amantadine levodopa- 137 mg nightly, increased 68.5 mg, 137 mg dizziness, hallucinations, dry (Gocovri™) induced after one week to 274 mg extended-release mouth, constipation, falls, dyskinesia capsules swelling of hands and feet

bances, syndrome of inappropriate carded. The product should not be Dosing of NoctivaTM is based antidiuretic hormone secretion exposed to extreme temperatures. on patient age. For those under 65 (SIADH) or poor renal function. It is important to store NoctivaTM in years of age without an increased Besides hyponatremia, common an upright position after opening, risk of hyponatremia, 1.66 mcg/0.1 adverse events for NoctivaTM noted and not in purses, glove boxes, or mL spray should be used in one in the clinical trials were mostly re- suitcases where the product can be nostril nightly, 30 minutes prior to lated to local reactions in the nasal tipped over. going to bed. The dose for patients cavity such as irritation, conges- Patients should be counseled 65 years or older, or those at risk tion, sneezing, and bleeding. This not to shake the product before de- for hyponatremia, is 0.83 mcg/0.1 drug may increase the patient’s livery into the nostrils. The spray mL nightly. This dose can be blood pressure and pharmacists needs to be primed before the first- increased if necessary if the serum can help monitor patients to make time use by pumping the actuator sodium remains normal. Note that sure they are meeting their blood five times into the air and away dosing is only in one nostril (either pressure goals. from the body or face. The product left or right) each night. Pharmacists should store does not need to be re-primed un- It is also important that phar- NoctivaTM in the refrigerator prior less it has not been used for more macists counsel patients that the to dispensing. Patients should be than three days. If this occurs, two dosage forms (1.66 mcg/0.1 mL counseled that the spray may re- the patient should be counseled to and 0.83 mcg/0.1mL) are not inter- main at room temperature for up to re-prime the pump with two actua- changeable. If a patient is taking 60 days after opening and then dis- tions in the air. 0.83 mcg/0.1 mL and the prescriber doubles the dose, a new prescrip- mg/day for adults and 25 mg/day in important to have dry hands when tion for 1.66 mcg/0.1 mL should pediatric patients. handling the blister pack and the be written rather than having the It is important for practitio- tablet. It is important to peel the patient double the dose. ners to note that Mydayis® is not foil from the blister pack rather interchangeable with other am- than pushing the tablet through Amphetamine Mixed Salt (My- phetamine mixed salt forms. These the foil. The tablet should be placed dayis® [my-DAY-is], Shire U.S.) products are not equivalent on a on the patient’s tongue and allowed received FDA approval on June 20, milligram to milligram basis. If a to dissolve without chewing or 2017 for the treatment of atten- patient is to be switched from an- crushing. The tablet will dissolve in tion deficit hyperactivity disorder other product, the package labeling the saliva and then be swallowed. (ADHD). Mydayis® is approved for specifically indicates that the other No additional liquid should be ages 13 years and older as a CII product should be discontinued taken with the tablet. CNS stimulant for once-daily ad- before the initial doses of Mydayis® This product is a CII controlled ministration. The extended-release are started and the patient then substance and carries a Boxed capsule is effective for 16 hours and titrated up to the appropriate dose. Warning for abuse potential and contains one immediate-release set Clinical studies did not show any dependence, and should be moni- of beads and two sustained-release additional benefit with doses over tored as other sets of beads formulated to re- 50 mg for adults and 25 mg for medications. lease at different times during the pediatrics. It is important to note that day. Patient counseling is simi- altering gastric pH can affect the Mydayis® was evaluated for lar to other amphetamine-based release of Cotempla XR-ODTTM. efficacy and safety in over 1600 ADHD products on the market. Medications such as proton pump patients in 16 clinical studies. The The capsule can be swallowed inhibitors (e.g., omeprazole) and studies were placebo-controlled whole or opened and sprinkled on -2 antagonists (e.g., and showed statistically significant applesauce; the beads should not famotidine) can alter the release of improvements in several ADHD be chewed. Cotempla XR-ODTTM and its phar- scales. Improvements were seen as macodynamics. Pharmacists should early as two hours after the dose. Methylphenidate (Cotempla counsel patients and caregivers The most common adverse XR-ODTTM, Neos Therapeutics) is to avoid these products, as well events were decreased appetite, an extended-release orally disin- as antacids and over-the-counter decreased weight, dry mouth, tegrating tablet approved on June sodium bicarbonate products. increased heart rate, and anxi- 19, 2017 for ADHD in pediatric pa- Cotempla XR-ODTTM is avail- ety. The drug is not approved in tients six to 17 years of age. It is an able in 8.6 mg, 17.3 mg and 25.9 younger pediatric patients at this innovative formulation designed for mg tablets. Cotempla XR-ODTTM time due to an increase in irritabil- oral disintegration without losing comes with a reusable travel ity that was shown in the clinical the extended-release properties. case that is ideal for storing and trials, as well as higher blood levels The recommended starting transporting medication to keep it of the drug. dose is 17.3 mg per day taken in protected from light, as well as to Mydayis® carries a warning the morning. Based on response, protect the integrity of the product. for cardiovascular events and a doses may be increased once week- Boxed Warning for abuse potential. ly in increments of 8.6 mg to 17.3 Amphetamine (Adzenys ERTM Patients at risk for cardiovascular mg per day. Doses exceeding 51.8 [ad-ZEN-es] (Neos Therapeutics) is events should be screened for ab- mg per day are not recommended. a once-daily extended-release sus- normalities which can be detected This medication can be taken pension, approved September 15, with an electrocardiogram (EKG). with or without food. However, 2017, for the treatment of ADHD in Mydayis® is available in 12.5 patients should take it consistently patients six years of age and older. mg, 25 mg, 37.5 mg, and 50 mg with either food or without food. It is a CII controlled substance. capsules. The salt mixture for the For example, if the patient takes Adzenys ERTM was designed 12.5 mg capsule includes dextro- the medication with breakfast, with the same modified-release amphetamine sulfate 3.125 mg, then it should never be taken on an system as Adzenys XR-ODTTM dextroamphetamine saccharate empty stomach. amphetamine orally disintegrating 3.125 mg, amphetamine aspartate Pharmacists should counsel tablet. Thus, the two formulations monohydrate 3.125 mg, and am- patients on the proper way to are interchangeable. Both Adzenys phetamine sulfate 3.125 mg. handle the drug. Cotempla XR- ERTM and Adzenys XR-ODTTM are Mydayis® is dosed initially at ODTTM should not be removed bioequivalent to Adderall XR®. The 12.5 mg to 25 mg once daily in the from the blister package until patient package insert for Adzenys morning, then increased by 12.5 just prior to taking the dose. The ERTM contains a chart with equiva- mg per day no sooner than once tablet should be taken immediately lent doses. Any other amphetamine weekly with a maximum dose of 50 and not stored for future use. It is formulations are not interchange- able on a milligram per milligram hours as needed for pain. Product tions with the CYP3A4 medica- basis, and patients should be labeling specifies that this drug tions. Strong CYP3A4 inducers, counseled to discontinue the other should be used for the management such as rifampin, can decrease product before starting the new of pain severe enough to require naldemedine concentrations, while one. an opioid analgesic and for which moderate to strong CYP3A4 in- Adzenys ERTM carries the same alternative treatments are inade- hibitors, such as itraconazole, can warnings and patient counsel- quate. Pharmacists should counsel increase naldemedine concentra- ing advice as other amphetamine patients on the use and potential tions. Symproic® also interacts with ADHD medications. misuse of this product. drugs that affect P-glycoprotein Adzenys ERTM should be stored RoxyBondTM is available as inhibitors, such as cyclosporine. at room temperature. Patients and 5 mg, 15 mg and 30 mg tablets. It crosses the placenta and can caregivers should be counseled to cause opioid withdrawal in a fetus shake the suspension prior to use, Naldemedine (Symproic®, exposed to opioid drugs. FDA and administer with a clean oral Shionogi Incorporated with partner requires a Medication Guide be syringe. Pharmacists are key in Purdue Pharma) was approved dispensed with this product. assuring patients and caregivers March 23, 2017 for the treatment use an accurate oral syringe and of opioid-induced constipation (Xadago®, Newron administer the correct volume. (OIC). It is a peripherally-acting Pharmaceuticals) is a new mono- The recommended starting mu-opioid receptor antagonist amine oxidase type B (MAO-B) dose of Adzenys ERTM for patients (PAMORA) specifically indicated inhibitor indicated as adjunctive six to 17 years of age is 6.3 mg (5 for OIC. treatment to levodopa/carbidopa in mL) once daily in the morning. Symproic® is classified as a patients with Parkinson’s disease Increases in dosing can be done in CII controlled substance since it experiencing “off”’ episodes. It was increments of 3.1 mg (2.5 mL) or is structurally similar to naltrex- approved in March of 2017. It joins 6.3 mg (5 mL) at weekly intervals. one. At the time of writing, the other MAO-B inhibitors currently The maximum dose is 18.8 mg (15 manufacturer was petitioning the on the market for managing Par- mL) daily for patients six to 12 Drug Enforcement Administration kinson’s disease. These products years, and 12.5 mg (10 mL) daily (DEA) to overturn that ruling since include rasagiline (Azilect®) and for patients 13 to 17 years. it is a peripherally-acting drug selegiline. Efficacy of Adzenys ERTM is and has not been shown to have The clinical trials submitted also affected by changes in gas- abuse potential in clinical trials. It for approval of the drug were all tric pH, and pharmacists should is estimated that 40-50 percent of placebo-controlled and none were provide similar counseling about patients on opioid medications suf- comparator studies to MAO-B in- GI products as recommended with fer from OIC. hibitors currently on the market. Cotempla XR-ODTTM. FDA approval was based on Xadago® is labeled for use only Adzenys XR-ODTTM is available data from the COMPOSE program, in combination with levodopa/ in 3.1 mg, 6.3 mg, 9.4 mg. 12.5 mg, a global comprehensive develop- carbidopa. It is essential that 15.7 mg, and 18.8 mg strengths, ment program comprised of clinical patients continue on both medica- while the ER suspension is 1.25 studies conducted in adult patients tions. Xadago® is dosed at 50 mg mg/mL. The orange-flavored sus- with OIC and chronic non-cancer once daily, and increased after two pension is available as a 450 mL pain. COMPOSE I and II were weeks to 100 mg once daily. The bottle. 12-week, multicenter, randomized, maximum dose for patients with double-blind, placebo-controlled, liver dysfunction (Child-Pugh class Oxycodone Hydrochloride parallel-group studies, while COM- B) is 50 mg per day. Safinamide (RoxyBondTM, Inspirion Delivery POSE III was a 52-week efficacy should be avoided in patients with Sciences) received FDA approval and long-term safety study. severe liver disease. April 20, 2017. This CII controlled Symproic® is available as a 0.2 Xadago® is available in 50 mg substance is an immediate-release, mg tablet and is dosed as 0.2 mg and 100 mg tablets. It is important abuse-deterrent formulation of daily. Pharmacists should counsel to take it at the same time each oxycodone for the management patients to discontinue Symproic® day, but the medication can be of severe pain. RoxyBondTM uses when the patient is no longer tak- given without regards to meals. physical and chemical barriers to ing opioid medications. Xadago® carries some of the deter abuse rather than aversive Although rare, Symproic® can same drug-drug interactions and agents or opioid antagonists. It cause gastrointestinal perforation. drug-food interactions as other meets FDA’s 2015 Guidance for Patients should be counseled to MAO-B inhibitors, but safinamide Industry standards for abuse deter- seek emergency treatment for se- is a selective inhibitor when dosed rent opioids. vere GI pain and discomfort. at 100 mg or less per day. Although Initial dosing of RoxyBondTM Symproic® has the potential to the potential interactions are less is 5 mg to 15 mg every four to six have significant drug-drug interac- in recommended doses, patients should be made aware of the inter- The manufacturer enrolled ing influenza. Patients should re- actions. Foods that contain high over 280 patients in three different ceive live vaccines prior to starting concentrations of tyramine could placebo-controlled trials to evalu- therapy, and therapy should not be cause severe hypertension, espe- ate effectiveness. In the clinical tri- initiated until patients have had cially if the patient is taking high als, the dose was 340 mg (274 mg time to seroconvert with the vac- doses of the drug. The food-MAO-B equivalent base) daily cine. Inactivated influenza vaccine interaction can result in hyperten- at bedtime. This extended-release would be the preferred choice in sive crisis which is an emergency product was dosed at bedtime so these patients. situation. Pharmacists should the resulting blood levels were GocovriTM is available in 68.5 provide the patient or caregiver higher upon awakening when the mg and 137 mg (expressed as the with a list of foods that are high in dyskinesia can be the most difficult amantadine base) extended-release tyramine. for patients. capsules. Abrupt discontinuation or The initial dose is 137 mg daily interruption of antiparkinsonian at bedtime, and then increased Summary therapy has been associated with after one week to 274 mg as the This lesson includes a broad over- a discontinuation syndrome, which recommended maximum daily view of drugs approved in 2017 for may resemble neuroleptic malig- dose. The lower 137 mg daily dose central nervous system disorders. nant syndrome. Symptoms may should be recommended to patients Pharmacists should consult the include elevated temperature, with moderate or severe kidney patient package insert and other muscular rigidity, altered con- impairment. GocovriTM can be references for more detailed infor- sciousness and autonomic instabil- given without regard to meals. It mation. ity. Pharmacists should counsel should be swallowed whole, or the Many pharmacists will not be patients on not discontinuing contents can be sprinkled on soft exposed to some of these newer Xadago® abruptly. food but swallowed whole without medications in their practices, but Drug-drug interactions can chewing. should stay current with new drug occur with concomitant use of other Patients should not be abruptly and formulation approvals, as well monoamine oxidase inhibitors or withdrawn from GocovriTM. Aman- as updates to treatment guide- other drugs that are potent inhibi- tadine can cause anticholinergic lines that could include these new tors of monoamine oxidase (line- side effects and these can be exag- agents. zolid); opioids (meperidine, metha- gerated when combined with other done, propoxyphene, ); drugs with the same effect. serotonin- reuptake Alcohol should be avoided inhibitors; tricyclic, tetracyclic, or since it is known to cause a dose triazolopyridine antidepressants, dumping effect which destroys the The author, the Ohio Pharmacists Founda- tion and the Ohio Pharmacists Association , methylphenidate, extended-release feature and the disclaim any liability to you or your patients amphetamine and their deriva- entire dose would be released at resulting from reliance solely upon the infor- tives; St. John’s wort; and dextro- one time. mation contained herein. Bibliography for . Safinamide is contra- Urine pH has been reported additional reading and inquiry is available upon request. indicated with any of these drugs. to influence the rate of Adverse events with Xadago® amantadine. The pH of the urine This lesson is a knowledge-based CPE can include dyskinesia, hyperten- can be affected by diet, drugs such activity and is targeted to pharmacists in sion, impulse control disorder, and as carbonic anhydrase inhibitors, all practice settings. Disclosure: The OPF trustees and other individuals responsible serotonin syndrome. When discon- sodium bicarbonate and clinical for planning OPF continuing pharmacy edu- tinuing therapy, it is recommended disease states such as urinary tract cation activities have no relevant financial to have patients taking the 100 mg infections. Acidifying the urine relationships to disclose. dose taper off by decreasing the can cause amantadine to be elimi- dose by half for one week. nated faster, while increasing the The 50 mg and 100 mg tablets alkalinity of the urine can increase are film-coated and not intended to blood levels and increase the risk of be split. This product became avail- adverse events. able to the market in July 2017. The most common side effects Program 0129-0000-18-001-H01-P include hallucination, dizziness, Amantadine Hydrochloride dry mouth, swelling of legs and Release date: 1-15-18 (GocovriTM, Adamas Pharmaceuti- feet, constipation, and falls. Expiration date: 1-15-21 cals) received FDA approval on Au- Immunizing pharmacists CPE Hours: 1.5 (0.15 CEU) gust 24, 2017 for the treatment of should be aware that the antiviral levodopa-induced dyskinesia. This properties of amantadine could po- The Ohio Pharmacists Foundation Inc. is follows its April 2015 FDA orphan tentially interfere with the efficacy accredited by the Accreditation Council for Pharmacy Education as a provider of drug status. of live attenuated vaccines includ- continuing pharmacy education. Please print. Program 0129-0000-18-001-H01-P continuing education quiz 0.15 CEU Name______

New Drugs 2017: Central Nervous System Address______

City, State, Zip______1. Valbenazine is used in the treatment of tardive dyskinesia by acting as a(n): Email______a. VMAT1 inhibitor. c. interleukin-2 receptor blocker. b. VMAT2 inhibitor. d. opioid agonist. NABP e-Profile ID______Birthdate______(MMDD) Return quiz and payment (check or money order) to 2. Which of the following drugs should be taken on an Correspondence Course, OPA, empty stomach for better absorption? 2674 Federated Blvd, Columbus, OH 43235-4990 a. Valbenazine c. Methylphenidate b. Deutetrabenazine d. Safinamide 8. NoctivaTM carries a Boxed Warning for: a. cardiovascular events. c. hyponatremia. 3. Deutetrabenazine has a Boxed Warning for: b. liver failure. d. depression. a. cardiovacular events. c. hyponatremia. b. liver failure. d. depression. 9. MydayisTM is not interchangeable with other amphet- amine mixed salt forms. 4. The starting dose for deutetrabenazine for Huntington’s a. True b. False disease is: a. 6 mg once daily x 1 week. 10. All of the following are true for Cotempla XR-ODTTM b. 6 mg twice daily x 1 week. EXCEPT: c. 12 mg once daily x 1 week. a. it is approved for ages 18 years and older. d. 12 mg twice daily x 1 week. b. the oral disintegration tablet does not lose its extend- ed- release properties. 5. The first drug indicated for both primary progressive c. it can be taken with or without food, but consistently and relapsing forms of multiple sclerosis is: with or without. a. valbenazine. c. ocrelizumab. d. it is important to peel the foil from the blister pack b. deutetrabenazine. d. edaravone. rather than pushing the tablet through the foil.

6. For the treatment of ALS, edaravone acts as a: 11. The maximum daily dose of Adzenys ERTM for patients a. VMAT2 inhibitor. c. sympathomimetic amine. 6-12 years old is: b. free radical scavenger. d. MAO-B inhibitor. a. 3.1 mg. c. 12.5 mg. b. 6.3 mg. d. 18.8 mg. 7. FDA approved NoctivaTM for the treatment of: a. diabetes insipidus. c. von Willebrand disease. 12. RoxyBondTM uses opioid antagonists to deter abuse. b. hemophilia A. d. nocturnal polyuria. a. True b. False

13. An important counseling point for naldemedine is: a. it can cause a hypertensive crisis if taken with tyra- mine. Completely fill in the lettered box corresponding to b. it should be discontinued if the opioid medication is your answer. discontinued. 1. [a] [b] [c] [d] 6. [a] [b] [c] [d] 11. [a] [b] [c] [d] c. it should be taken as needed when the patient is consti- 2. [a] [b] [c] [d] 7. [a] [b] [c] [d] 12. [a] [b] pated. 3. [a] [b] [c] [d] 8. [a] [b] [c] [d] 13. [a] [b] [c] [d] d. if severe GI pain occurs, it should be discontinued and 4. [a] [b] [c] [d] 9. [a] [b] 14. [a] [b] [c] [d] an antacid started immediately. 5. [a] [b] [c] [d] 10. [a] [b] [c] [d] 15. [a] [b] [c] [d] 14. Which of the following is true for safinamide?  I am enclosing $5 for this quiz made payable to: Ohio a. It should not be used with levodopa/carbidopa. Pharmacists Association. b. It must be given with meals. c. It is important to take it at the same time each day. 1. Rate this lesson: (Excellent) 5 4 3 2 1 (Poor) d. It can be discontinued abruptly. 2. Did it meet each of its objectives?  yes  no If no, list any unmet______3. Was the content balanced and without commercial bias? 15. All of the following should be avoided with amantadine  yes  no If no, why?______EXCEPT: 4. Did the program meet your educational/practice needs? a. live attenuated vaccines. c. inactivated vaccines.  yes  no b. alcohol. d. alkaline urine. 5. How long did it take you to read this lesson and complete the quiz? ______To receive CPE credit, your quiz must be received no later than January 15, 2021. A passing grade of 80% must be attained. CPE credit for successfully completed quizzes will be uploaded to the CPE Monitor. CPE statements of credit can be printed from the CPE Moni- tor website. Send inquiries to [email protected]. january 2018