Clinical Pharmacology III Week 3 (3).pdf

CLINICAL PHARMACOLOGY III Dr. Lessard-Chaudoin Week 3 Franklin Pierce University Physician Assistant Program TOPICS Drugs used for Parkinson’s Disease Drugs used for Huntington Disease Drugs for Tourette Syndrome Antiseizure Drugs ASSOCIATED READINGS th Basic & Clinical Pharmacology 15 Ed. Ch 24, 28...

CLINICAL PHARMACOLOGY III Dr. Lessard-Chaudoin Week 3 Franklin Pierce University Physician Assistant Program TOPICS Drugs used for Parkinson’s Disease Drugs used for Huntington Disease Drugs for Tourette Syndrome Antiseizure Drugs ASSOCIATED READINGS th Basic & Clinical Pharmacology 15 Ed. Ch 24, 28 Supplemental Resources: Access Pharmacy: Drug Monographs UpToDate Lamotrigine Pronunciation: (la MOE tri jeen) Brand Names: US: LaMICtal Pharmacologic Category: Anticonvulsant, Miscellaneous Mechanism of Action: A triazine derivative which inhibits release of glutamate (an excitatory amino acid) and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membranes. Lamotrigine has weak inhibitory effect on the 5-HT3 receptor; in vitro inhibits dihydrofolate reductase. Pharmacodynamics/Kinetics: Absorption: Immediate release: Rapid and complete, 97.6% absorbed; Note: Orally disintegrating tablets (either swallowed whole with water or disintegrated in the mouth) are equivalent to regular tablets (swallowed whole with water) in terms of rate and extent of absorption. Lamotrigine Use: Labeled Indications Bipolar disorder: Maintenance treatment of bipolar disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes), as monotherapy or adjunctive therapy. Focal (partial) onset seizures and generalized onset seizures: Treatment of Lennox-Gastaut syndrome (adjunctive therapy only), primary generalized tonic-clonic seizures (adjunctive therapy only), and focal onset seizures (monotherapy or adjunctive therapy). May be used off-label for other seizure types. Contraindications Hypersensitivity (eg, rash, angioedema, acute urticaria, extensive pruritus, mucosal ulceration) to lamotrigine or any component of the formulation Lamotrigine ALERT: US Boxed Warning Serious skin rashes:Lamotrigine can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens-Johnson syndrome, is approximately 0.3% to 0.8% in pediatric patients (2 to 17 years of age) and 0.08% to 0.3% in adults receiving lamotrigine. One rash-related death was reported in a prospectively followed cohort of 1,983 pediatric patients (2 to 16 years of age) with epilepsy taking lamotrigine immediate-release as adjunctive therapy. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adults and pediatric patients, but those numbers are too few to permit a precise estimate of the rate. The risk of serious rash caused by treatment with lamotrigine ER is not expected to differ from that with the immediate-release formulation of lamotrigine. Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by lamotrigine. There are suggestions, yet to be proven, that the risk of rash may also be increased by coadministration of lamotrigine with valproate (includes valproic acid and divalproex sodium), exceeding the recommended initial dose of lamotrigine, or exceeding the recommended dose escalation for lamotrigine. However, cases have been reported in the absence of these factors. Lamotrigine Special populations:Pediatric: Children are at increased risk for developing serious skin rashes during therapy; lower starting doses and slower dose escalations may decrease the risk of rash. Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment may be required. Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be required. Other warnings/precautions: Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Taper over at least 2 weeks if possible. Lamotrigine Pregnancy Considerations Lamotrigine crosses the human placenta and can be measured in the plasma of exposed newborns (Harden and Pennell 2009; Ohman 2000). An overall increase in the risk for major congenital malformations has not been observed in available studies; however, an increased risk for cleft lip or cleft palate has not been ruled out (Cunnington 2011; Hernández-Díaz 2012; Holmes 2012). An increased risk of malformations following maternal lamotrigine use may be associated with larger doses (Cunnington 2007; Tomson 2011). Polytherapy may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended (Harden and Meader 2009). Due to pregnancy-induced physiologic changes, women who are pregnant may require dose adjustments of lamotrigine in order to maintain clinical response; monitoring during pregnancy should be considered (Harden and Pennell 2009). For women with epilepsy who are planning a pregnancy in advance, baseline serum concentrations should be measured once or twice prior to pregnancy during a period when seizure control is optimal. Monitoring can then be continued up to once a month during pregnancy and every second day during the first week postpartum (Patsalos 2008; Patsalos 2018). Potentially significant interactions may exist with hormone-containing contraceptives. Pregnancy registries are available for women who have been exposed to lamotrigine. Patients may enroll themselves in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling (888) 233-2334. Additional information is available at www.aedpregnancyregistry.org. Lamotrigine Adverse Reactions Percentages reported in adults on monotherapy for epilepsy or bipolar disorder. >10%: Gastrointestinal: Nausea (7% to 14%) Administration: Oral Doses should be rounded down to the nearest whole tablet. Lamictal chewable/dispersible tablets: May be chewed, dispersed in water or diluted fruit juice, or swallowed whole. To disperse tablets, add to a small amount of liquid (just enough to cover tablet); let sit ~1 minute until dispersed; swirl solution and consume immediately. Do not administer partial amounts of liquid. If tablets are chewed, a small amount of water or diluted fruit juice should be used to aid in swallowing. Lamictal ODT: Place tablets on tongue and move around in the mouth. Tablets will dissolve rapidly and can be swallowed with or without food or water. Lamictal XR: Administer without regard to meals. Swallow whole; do not chew, crush, or cut. Lamotrigine Breast-Feeding Considerations Lamotrigine can be detected in the serum of breastfed infants; the manufacturer reports that infant lamotrigine plasma concentrations may be as high as 50% of the maternal serum concentration. Neonates and young infants are at an increased risk for high serum concentrations due to a decreased capacity for glucuronidation needed for drug clearance, especially if the maternal lamotrigine dose is not returned to the prepregnancy dosage (maternal doses are often increased during pregnancy). Adverse events observed in breastfed infants include apnea, drowsiness, poor sucking, thrombocytosis, and rash (Newport 2008; Nordmo 2009; Soussan 2014; Wakil 2009). Symptoms of withdrawal may occur if breastfeeding is abruptly discontinued (Popescu 2005). Lamotrigine Monitoring Obtain liver function, renal function tests, serum levels of concurrent anticonvulsants. Assess for signs of hypersensitivity, especially for skin rash. Discontinue at the first sign of rash, unless clearly not drug-related. Assess for suicide ideation, depression, unusual behavior changes, or signs of aseptic meningitis. Observe and teach seizure/safety precautions. Assess for therapeutic response. Reference Range Timing of serum samples: Draw trough just before next dose. Laboratory alert level: 20 mcg/mL (SI: 78 mcmol/L) Therapeutic reference range: Note: Dosing should be based on therapeutic response as opposed to serum concentrations (Hiemke 2018). Bipolar disorder: 1 to 6 mcg/mL (SI: 3.9 to 23.4 mcmol/L) Epilepsy: 3 to 15 mcg/mL (SI: 11.7 to 58.5 mcmol/L) Valproic Acid Pronunciation: (val PROE ik AS id) Brand Names: US Depacon [DSC] Depakene [DSC] Depakote Depakote ER Depakote Sprinkles Pharmacologic Category Anticonvulsant, Miscellaneous Antimanic Agent Histone Deacetylase Inhibitor Valproic Acid Mechanism of Action Causes increased availability of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, to brain neurons or may enhance the action of GABA or mimic its action at postsynaptic receptor sites. Also blocks voltage-dependent sodium channels, which results in suppression of highfrequency repetitive neuronal firing (Bourin 2009). Divalproex sodium is a compound of sodium valproate and valproic acid; divalproex dissociates to valproate in the GI tract. Pharmacodynamics/Kinetics Distribution: Distributes into CSF at concentrations similar to unbound concentration in plasma (ie, ~10% of total plasma concentration) Protein binding (concentration dependent): 80% to 90%; free fraction: ~10% at 40 mcg/mL and ~18.5% at 130 mcg/mL; protein binding decreased in neonates, the elderly and patients with hepatic or renal impairment Valproic Acid Use: Labeled Indications Bipolar disorder: Treatment of manic episodes (delayed release) or acute manic or mixed episodes with or without psychotic features (24-hour extended release) associated with bipolar disorder, as monotherapy or in combination with atypical antipsychotics (BAP [Goodwin 2016]) Focal (partial) onset and generalized onset seizures: Monotherapy and adjunctive therapy in the treatment of patients with focal onset seizures with impairment of consciousness or awareness (complex partial) and generalized onset nonmotor seizures (absence), and as adjunctive therapy for multiple seizure types. May be used off-label as monotherapy for other seizure types. Migraine prophylaxis (excluding IV formulation): Prophylaxis of migraine headaches Limitation of use: Do not administer to pregnant women, women who plan to become pregnant, or women of childbearing potential for the treatment of epilepsy or bipolar disorder unless essential for the management of her condition. Valproic Acid Contraindications Hypersensitivity to valproic acid, divalproex, derivatives, or any component of the formulation; hepatic disease or significant impairment; urea cycle disorders; prevention of migraine in pregnant women and women of childbearing potential who are not using effective contraception; known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase gamma (POLG; eg, Alpers-Huttenlocher syndrome [AHS]) or children 1% to 15%), pain (oral: 11%; intravenous: 1%), nervousness (oral: 7% to 11%; intravenous: 1% to 24%) Gastrointestinal: Nausea (oral: 15% to 48%; intravenous: 3% to 6%), vomiting (oral: 7% to 27%; intravenous: 1%), abdominal pain (oral: 7% to 23%; intravenous: 1%), diarrhea (oral: 7% to 23%; intravenous: 1% to 12%) Hematologic & oncologic: Thrombocytopenia (1% to 27%; dose related) Infection: Infection (≤20%) Neuromuscular & skeletal: Tremor (≤57%), asthenia (6% to 27%; intravenous: 7%) Ophthalmic: Diplopia (>1% to 16%), visual disturbance (amblyopia, blurred vision ≤1% to 12%) Respiratory: Flu-like symptoms (>1% to 12%) Miscellaneous: Accidental injury (>1% to 11%) Valproic Acid Administration: IV IV: For IV use only. Seizures: Following dilution to final concentration, manufacturer's labeling recommends administering over 60 minutes at a rate ≤20 mg/minute. Status epilepticus: Loading dose: 3 to 6 mg/kg/minute (NCS [Brophy 2012]); however, evidence suggest rates of 10 mg/kg/minute may be safely used with doses up to 30 mg/kg (Limdi 2007). Administration: Oral Oral valproate products may cause GI upset; taking with food or slowly increasing the dose may decrease GI upset should it occur. Divalproex sodium tablets (delayed release, 24-hour extended release and enteric coated [Canadian product]) and valproic acid capsules (immediate release): Swallow whole; do not crush or chew. Divalproex sodium delayed release sprinkle capsules: May be swallowed whole or capsule opened and sprinkled on small amount (1 teaspoonful) of soft food (eg, pudding, applesauce) to be used immediately (do not store or chew). Valproic Acid Breast-Feeding Considerations Valproate is present in breast milk. A study presented information from 30 lactating women with epilepsy on monotherapy (51%), combination therapy with one additional agent (46%), or triple therapy (3%). In all cases, breast milk was collected between 6 and 32 days postpartum (median 7 days) and sampling occurred prior to the morning dose. Using information from all women in the study, values for maternal dose (3.6 to 20.6 mg/kg), maternal serum (5.4 to 69 mg/L), breast milk (10%: Central nervous system: Dizziness (immediate release, adolescents and adults: 17% to 28%; extended release, adults: 11%; immediate release, children: 3%), drowsiness (immediate release, adolescents and adults: 19% to 21%; immediate release, children: 8%; extended release, adults: 5%), ataxia (immediate release, adolescents and adults: 1% to 13%), fatigue (immediate release, adolescents and adults: 11%; immediate release, children: 3%) Infection: Viral infection (immediate release, children: 11%) Food Interactions Tablet, solution (immediate release): No significant effect on rate or extent of absorption; extended release tablet: Increases rate and extent of absorption. Management: Administer immediate release products without regard to food. Administer extended release with food. Test Interactions False positives have been reported with the Ames N-Multistix SG® dipstick test for urine protein Gabapentin Administration: Oral Immediate release: May administer without regards to meals. Administer first dose on first day at bedtime to avoid somnolence and dizziness. Dosage must be adjusted for renal function; when given 3 times daily, the maximum time between doses should not exceed 12 hours. Capsules may be opened and sprinkled on food (eg, applesauce, orange juice, pudding) for patients unable to swallow capsules (Gidal 1998). Extended release: Administer with evening meal. Swallow whole; do not chew, crush, or split. Monitoring Obtain periodic renal function tests; dosage adjustment may be needed. Assess patients for history of substance abuse; potential for drug dependency. Assess for multiorgan sensitivity. Taper dose prior to discontinuation. Gabapentin Breast-Feeding Considerations Gabapentin is present in breast milk. The relative infant dose (RID) of gabapentin is 8.7% to 13% when calculated using the highest breast milk concentration located and compared to an infant therapeutic dose of 10 to 15 mg/kg/day. In general, breastfeeding is considered acceptable when the RID is 25% breastfeeding should generally be avoided (Anderson 2016; Ito 2000). The RID of gabapentin was calculated using a milk concentration of 8.7 mcg/mL, providing an estimated daily infant dose via breast milk of 1.3 mg/kg/day. This milk concentration was obtained following maternal administration of oral gabapentin 2,100 mg/day. Gabapentin was detected in the serum of two breastfeeding infants 2 to 3 weeks after delivery and in one infant after 3 months of breastfeeding. Adverse events were not reported in the breastfed infants (Ohman 2005). Manufacturer recommendations may vary; the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Based on limited information, gabapentin is considered relatively compatible with breastfeeding; infants should be monitored for drowsiness, adequate weight gain, and developmental milestones (Davanzo 2013; Veiby 2015). Available guidelines state gabapentin may be considered for the treatment of refractory restless leg syndrome in breastfeeding women (Picchietti 2015). Pharmacological agents should not be used for the treatment of alcohol use disorder in breastfeeding women unless needed for the treatment of acute alcohol withdrawal or a coexisting disorder (APA [Reus 2018]). Topiramate Pronunciation: (toe PYRE a mate) Brand Names: US Qudexy XR Topamax Topamax Sprinkle Trokendi XR Pharmacologic Category Anticonvulsant, Miscellaneous Topiramate Mechanism of Action Anticonvulsant activity may be due to a combination of potential mechanisms: Blocks neuronal voltage-dependent sodium channels, enhances GABA(A) activity, antagonizes AMPA/kainate glutamate receptors, and weakly inhibits carbonic anhydrase. Pharmacodynamics/Kinetics Metabolism: Not extensively metabolized. Minor amounts metabolized in liver via hydroxylation, hydrolysis, and glucuronidation; there is evidence of renal tubular reabsorption; percentage of dose metabolized in liver and clearance are increased in patients receiving enzyme inducers (eg, carbamazepine, phenytoin) Topiramate Use: Labeled Indications Migraine (prevention): Prophylaxis of migraine headache in patients ≥12 years of age Seizures: Monotherapy or adjunctive therapy in patients ≥2 years of age (immediate release and Qudexy XR) or ≥6 years of age (Trokendi XR) with focal (partial) onset or primary generalized tonic-clonic seizures; adjunctive therapy in patients ≥2 years of age (immediate release and Qudexy XR) or ≥6 years of age (Trokendi XR only) with seizures associated with Lennox-Gastaut syndrome Contraindications Extended release: Recent alcohol use (ie, within 6 hours prior to and 6 hours after administration) (Trokendi XR only); patients with metabolic acidosis who are taking concomitant metformin (Qudexy XR only). Immediate release: There are no contraindications listed in the manufacturer's labeling. Topiramate Warnings/Precautions Concerns related to adverse effects: CNS effects: Cognitive dysfunction (confusion, psychomotor slowing, difficulty with concentration/attention, difficulty with memory, speech or language problems), psychiatric disturbances (depression or mood disorders), and sedation (somnolence or fatigue) may occur with use; incidence may be related to rapid titration and higher doses; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). May also cause paresthesia, dizziness, and ataxia. Hyperammonemia/encephalopathy: Hyperammonemia with or without encephalopathy may occur with monotherapy or in combination with valproic acid and has been documented in patients who have tolerated each drug alone; incidence may be dose-related. Risk may be increased in patients with inborn errors of metabolism or decreased hepatic mitochondrial activity. May be asymptomatic; monitor for lethargy, vomiting, or unexplained changes in mental status. Metabolic acidosis: May be associated with hyperchloremic nonanion gap metabolic acidosis due to inhibition of carbonic anhydrase and increased renal bicarbonate loss. Decreases in serum bicarbonate are relatively common (up to 67% of epilepsy patients and 77% of migraine patients) but usually mild-to-moderate (average decrease of 4 mEq/L at dose of 400 mg/day in adults and 6 mg/kg/day in children). However, risk may be increased in patients with a predisposing condition (renal, respiratory and/or hepatic impairment), diarrhea, ketogenic diet, status epilepticus, or concurrent treatment with other drugs which may cause acidosis. Metabolic acidosis may occur at dosages as low as 50 mg/day. Serum bicarbonate should be monitored, as well as potential complications of chronic acidosis (nephrolithiasis, nephrocalcinosis, osteomalacia/osteoporosis, and reduced growth rates and/or reduced weight in children). Dose reduction or discontinuation (by tapering dose) should be considered in patients with persistent or severe metabolic acidosis. If treatment is continued, alkali supplementation should be considered. Topiramate Warnings/Precautions Concerns related to adverse effects: Oligohidrosis/hyperthermia: May be associated with oligohidrosis and hyperthermia, most frequently in children; use caution and monitor closely during strenuous exercise, during exposure to high environmental temperature, or in patients receiving other carbonic anhydrase inhibitors and drugs with anticholinergic activity. Ophthalmic effects: Has been associated with acute myopia and secondary angle-closure glaucoma in adults and children, typically within 1 month of initiation; discontinue in patients with acute onset of decreased visual acuity and/or ocular pain. Renal calculus: Topiramate exhibits weak carbonic anhydrase inhibitory properties and may increase the risk of kidney stones about 2 to 4 times that of the untreated population. Kidney stones have been reported in children and adults (incidence higher in males). Consider avoiding use in patients on a ketogenic diet. The risk of kidney stones may be reduced by increasing fluid intake. Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur. Visual field defects: Has been reported independent of increased intraocular pressure; generally reversible upon discontinuation. Consider discontinuation if visual problems occur at any time during treatment. Topiramate Special populations: Elderly: Use with caution; dosage adjustment may be necessary. Weight loss, cognitive impairment, sedation, and gait/balance disturbances may be more pronounced in the older adult cohort (Sommer 2010). Other warnings/precautions: Withdrawal: Do not discontinue abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Doses were also gradually withdrawn in migraine prophylaxis studies (decreased in weekly intervals by 25-50 mg/day). Topiramate Pregnancy Considerations Based on limited data (n=5), topiramate was found to cross the placenta and could be detected in neonatal serum (Ohman 2002). Topiramate may cause fetal harm if administered to a pregnant woman. An increased risk of oral clefts (cleft lip and/or palate) and for being small for gestational age (SGA) has been observed following in utero exposure. Data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that the prevalence of oral clefts was 1.1% for infants exposed to topiramate during the first trimester of pregnancy, versus 0.36% for infants exposed to a reference antiepileptic drug, and 0.12% for infants with no exposure born to mothers without epilepsy; the relative risk of oral clefts in infants exposed to topiramate was calculated to be 9.6 (95% CI: 4 to 23). Data from the NAAED Pregnancy Registry reported that the prevalence of small for gestational age newborns was 19.7% for newborns exposed to topiramate in utero, versus 7.9% for newborns exposed to a reference antiepileptic drug, and 5.4% for newborns with no exposure born to mothers without epilepsy. Although not evaluated during pregnancy, metabolic acidosis may be induced by topiramate. Metabolic acidosis during pregnancy may result in adverse effects and fetal death. Pregnant women and their newborns should be monitored for metabolic acidosis. In general, maternal polytherapy with antiepileptic drugs may increase the risk of congenital malformations; monotherapy with the lowest effective dose is recommended. Newborns of women taking antiepileptic medications may be at an increased risk of a 1 minute Apgar score 10%: Central nervous system: Paresthesia (adolescents and adults: 19% to 51%; children and adolescents: 3% to 12%), fatigue (8% to 15%), drowsiness (adolescents and adults: 6% to 15%), dizziness (adolescents and adults: 6% to 14%), memory impairment (1% to 11%) Endocrine & metabolic: Decreased serum bicarbonate (adolescents and adults: 14% to 77%; children and adolescents: 9% to 25%; >5 mEq/L to 50 mg/day). Assess other medicines patient may be taking; alternate therapy or dosage adjustments may be needed. Valbenazine Pronunciation: (val BEN a zeen) Brand Names: US Ingrezza Pharmacologic Category Central Monoamine-Depleting Agent Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor Valbenazine Mechanism of Action The mechanism of action of valbenazine in the treatment of tardive dyskinesia is unknown, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. Valbenazine and its active metabolite have no appreciable binding affinity for VMAT1 or dopaminergic, serotonergic, adrenergic, histaminergic or muscarinic receptors. Pharmacodynamics/Kinetics Absorption: High-fat meals decrease Cmax by 47% and AUC by 13%. Excretion: Urine (~60%, primarily as inactive metabolites); feces (~30%, primarily as inactive metabolites) Use: Labeled Indications Tardive dyskinesia: Treatment of adults with tardive dyskinesia Valbenazine Contraindications Hypersensitivity to valbenazine or any component of the formulation Warnings/Precautions Concerns related to adverse effects: CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). Depression/Suicidal ideation: Vesicular monoamine transport inhibitors have been associated with depression and suicidal thoughts and behavior. In a pooled analysis of two 6-week trials and a 42-week extension trial, 96.5% (N=113) of patients who reported no suicidal ideation at baseline continued to have no suicidal ideation at any time during the study; however, 4 patients (2 on placebo, 2 on valbenazine) reported a shift in their Columbia-Suicide Severity Rating Scale score to suicidal thoughts/ideation (McIntyre 2019). Parkinsonism: Cases of parkinson-like symptoms (eg, falls, gait disturbances, tremor, drooling, hypokinesia), some severe requiring hospitalization, have been reported. Onset of severe symptoms occurs most commonly within 2 weeks of the start of therapy or a dose increase; may resolve with discontinuation of therapy. Reduce dose or discontinue treatment in patients who develop clinically significant parkinson-like signs or symptoms. QT prolongation: May prolong the QT interval; use caution when used concomitantly with a strong CYP2D6 or CYP3A4 inhibitor or in a poor CYP2D6 metabolizer, dose reduction may be necessary. Avoid use in patients with congenital long QT syndrome or arrhythmias associated with prolonged QT interval. For patients at risk of prolonged QT interval, perform EKG before increasing the dosage. Valbenazine Disease-related concerns: Hepatic impairment: Use with caution in patients with moderate or severe hepatic impairment; use reduced dose. Renal impairment: Use is not recommended in patients with severe renal impairment. Pregnancy Considerations Adverse events were observed in some animal reproduction studies Valbenazine Adverse Reactions >10%: Central nervous system: Drowsiness (≤11%), fatigue (≤11%), sedation (≤11%) 1% to 10%: Central nervous system: Abnormal gait (≤4%), dizziness (≤4%), equilibrium disturbance (≤4%), falling (≤4%), akathisia (≤3%), restlessness (≤3%), anxiety (1% to