David Bai, PharmD

In February 2018, the FDA approved amantadine (Osmolex ER, Osmotica Pharmaceuticals) for the treatment of Parkinson disease and drug-induced extrapyramidal reactions in adults.

Parkinson disease is a neurological disorder where patients have a lack of dopaminergic neurons in the substantia nigra. The affected population is estimated to extend toward 10 million worldwide.

 Drug-induced extrapyramidal reactions, mainly caused by antipsychotics, has led to many problematic symptoms such as dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia. Anticholinergics, such as amantadine have been used to treat extrapyramidal symptoms caused by antipsychotics for many years now.

Amantadine is taken in a dose of 129 mg orally in the morning. The dose can be increased in weekly intervals, to 322 mg (129-mg and 193-mg tablet) in the morning. Do not interchange amantadine with other amantadine products. Amantadine is an extended-release product and should be swallowed whole (do not chew, crush, split tablets), and can be taken with or without food.

Titration interval and dosing frequency will need to be adjusted in patients with moderate to severe renal impairment.

The exact mechanism of amantadine is unknown. Amantadine is a weak N-methyl-D-aspartate uncompetitive antagonist and exhibits dopaminergic effects.

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This guide includes everything you need to know about amantadine (Osmolex ER, Osmotica Pharmaceuticals) for the treatment of Parkinson disease and drug-induced extrapyramidal reactions in adults.

What You Need to Know About Amantadine for Parkinson Disease

In June 2018, the FDA approved cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) for 2 rare types of epilepsy, Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS).

LGS is a form of epilepsy characterized by frequent seizures in early childhood that can cause a multitude of symptoms, from uncontrollable muscle contracts to complete loss of consciousness. LGS is estimated to affect 1 out of every 50,000 to 100,000 children, leading to a prevalence of 4% of all childhood epilepsies.

DS is another rare form of epilepsy associated with frequent and prolonged seizures. DS is estimated to affect 1 out of every 75,000 individuals, 80% of whom have an 

CBD is initially administered at 2.5 mg/kg orally twice a day. After the first week, the dose of CBD can be increased to 5 mg/kg twice a day. Additional dose increases can be made to a maximum of 10 mg/kg twice a day to reduce seizure frequencies. Dose increases should be done at weekly increments of 2.5 mg/kg. Dosage increases can be done every other day for patients who need more rapid titration.

High-fat and high-calorie meals increase CBD’s maximum concentration and bioavailability compared with no food. CBD needs to be taken consistently with or without food. Measure out the dose with the calibrated oral syringe (1 ml or 5 ml) provided with CBD. Do not use a household teaspoon or tablespoon.

Serum transaminases (ALT and AST) and total bilirubin levels must be obtained prior to treatment because of the risk of hepatocellular injury.

Moderate and severe hepatic impairment require dose adjustments (Child-Pugh B or C). Mild hepatic impairment does not require dose adjustments (Child-Pugh A).

Table 1. Dose Adjustments for Moderate and Severe Hepatic Impairment

Discontinuation of seizure medications, including CBD must be tapered gradually to avoid increased seizure frequency and status epilepticus.

CBD does not exert its anticonvulsant effects through the cannabinoid receptors. The exact mechanism is unknown.

CBD is a colorless to yellow solution supplied in an amber glass bottle containing 100 ml of oral solution. Each ml of solution contains 100 mg of cannabidiol. CBD comes with two 5-

ml calibrated oral dosing syringes and a bottle adapter. The pharmacy can provide 1 ml calibrated oral dosing syringes, if required.

Store CBD at 20-25°C (68-77°F) with a permitted range between 15-30°C (59-86°F). Do not refrigerate or freeze the medication and keep the cap tightly closed. CBD must be used within 12 weeks for opening the bottle. Discard any medication remaining past 12 weeks.

CBD is metabolized by CYP3A4 and CYP2C19. Co-administration with moderate or strong CYP3A4 or CYP2C19 inhibitors can increase CBD concentration and may require a dose reduction. Co-administration with a strong CYP3A4 or CYP2C19 inducer decreases CBD concentration and may require a dose increase.

CBD also may increase concentrations of CYP2C19 substrates (diazepam). Clobazam, when co-administered with CBD, had a 3-fold increase in plasma concentrations of its active metabolite. Dose reductions for CYP2C19 substrates may be needed when administered together with CBD.

In vitro data suggests that CBD might have drug-drug interactions with CYP1A2 substrates (eg, theophylline, caffeine), CYP2B6 substrates (eg, bupropion, efavirez), UGT1A9 substrates (eg, diflunisal, fenofibrate, propofol), UGT2B7 substrates (eg, gemfibrozil, lamotrigine, lorazepam, morphine), CYP2C8 and CYP2C9 substrates (phenytoin). A reduction in the dose of UGT1A9, UGT2B7, CYP2C8, and CYP2C9 may be required to avoid adverse reactions. Dose adjustments for CYP1A2 and CYP2B6 substrates may also be required.

Valproate taken with CBD increase liver enzyme elevations and may increase hepatotoxicity. Discontinuation or reduction of CBD or valproate should be considered. There is no data on other hepatotoxic drugs.

Increased risk of sedation was observed when CBD was used with central nervous system (CNS) depressants or alcohol.

CBD is contraindicated in any patient with an allergic reaction to CBD or any of its components.

CBD can cause elevated liver transaminase (ALT/AST) that can result in hospitalization. In one-third of cases, transaminase elevations returned to normal without therapy changes. In two-thirds of cases transaminase elevations resolved upon discontinuation of CBD, reduction in dose of CBD and/or valproate. The risk of elevated liver transaminase is higher in patients also taking valproate or clobazam; dose adjustments may be needed. The risk is also higher with higher doses of CBD (20 mg/kg/day vs 10 mg/kg/day) and patients with higher than normal baseline transaminase levels.

Serum transaminase levels and total bilirubin levels should be obtained prior to initiation of therapy, at 1 month, 3 months, 6 months, and when clinically indicated after initiation of treatment. Serum transaminase levels and total bilirubin levels should also be obtained within 1 month of dosage changes of CBD or other medications known to affect the liver. More frequent monitoring may be needed in patients with elevated liver enzymes at baseline, taking valproate, or experiencing clinical signs or symptoms of liver dysfunction (dark urine, jaundice).

Discontinue CBD in patients with elevated transaminase levels 3 times the upper limit of normal (ULN) and bilirubin levels 2 times the ULN, or if there is sustained transaminase levels 5 times the ULN.

A dose-related incidence of sedation or somnolence was observed in patients on CBD, with higher rates in patients also taking clobazam or other CNS depressants, including alcohol. Sedation/somnolence usually occurs early in therapy and lessens after continued use. Patients should be advised not to operate machinery or drive until they have enough time to know if CBD will cause drowsiness.

CBD can cause suicidal thoughts or behavior, hypersensitivity reactions, and increased risk of seizure frequency and status epilepticus if not gradually withdrawn. Rapid discontinuation should only be considered in the case of a serious adverse event.

Common adverse reactions, regarded as an incidence rate of ≥10%, are listed in the table below.

Table 2. Adverse Reactions From Placebo-Controlled Clinical Trials

This guide includes everything you need to know about cannabidiol (Epidiolex, GW Pharmaceuticals) for the treatment of 2 rare types of epilepsy: Lennox-Gastaut syndrome and Dravet syndrome.

What You Need to Know About Cannabidiol for Rare Forms of Epilepsy

In April 2016, pimavanserin (Nuplazid, Acadia Pharmaceuticals) became the first FDA-approved drug to treat delusions and hallucinations associated with Parkinson disease psychosis.

Hallucination is defined as seeing or hearing things that are not there, while delusions are defined as having false beliefs. Around 50,000 Americans are diagnosed with Parkinson disease every year, with about half of them developing hallucinations or delusions throughout the course of the disease.

Pimavanserin is taking at 34 mg orally, every day with or without food. If patients are taking a strong CYP3A4 inhibitor (eg, ketoconazole, clarithromycin, lopinavir), the dose of pimavanserin will need to be reduced to 10 mg once daily (tablet formulation). Patients taking a strong CYP3A4 inducer (eg, rifampin, carbamazepine) may need higher doses of pimavanserin.

Pimavanserin is thought to exert its effect by being a 5-HT

 receptor inverse agonist and antagonist. High-fat meals did not have a significant effect on pimavanserin. Age, sex, ethnicity, and weight were not factors relevant to the effects of pimavanserin. Patients with mild to moderate renal impairment had similar effects as patients with normal renal function. Severe renal impairments (CrCl <30ml/min) may result in increased exposure to pimavanserin but also does not require an initial dose adjustment. Patients with hepatic impairment had similar effects as patients with normal hepatic function.

Pimavanserin is formulated and supplied under two dosage forms and two different strengths: 10-mg tablet and 34-mg capsule according to the package insert. A 17-mg tablet formulation is also available.

Pimavanserin capsules and tablets should be stored at room temperature 20

C (68°F-77°F), with a permitted temperature range of 15 to 30

C (59°F-86°F). Capsules should be stored away from light, as light will cause the capsule’s color to fade.

Drugs that can prolong the QT interval may increase the risk of cardiac arrhythmias when used together with pimavanserin. Drugs that have documented risk of QT prolongation are antiarrhythmics (quinidine, amiodarone, sotalol, procainamide, disopyramide), antipsychotics (ziprasidone, thioridazine, chlorpromazine), and antibiotics (gatifloxacin, moxifloxacin). Avoid using any drug that may cause QT prolongation with pimavanserin.

Pimavanserin is a known substrate of CYP3A4 and other enzymes. CYP3A4 inhibitors will increase pimavanserin concentrations, while CYP3A4 inducers will decrease pimavanserin concentrations. Reduced doses of pimavanserin to 10 mg daily will be needed when used in combination with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, or indinavir. Increased doses of pimavanserin may be needed with strong CYP3A4 inducers such as rifampin, St. John’s Wort, phenytoin, or carbamazepine. 

Carbidopa/levodopa does not require a dosage adjustment when used together with pimavanserin.

Pimavanserin is contraindicated in any patient with an allergic reaction to pimavanserin or any of its components.

Pimavanserin has a black box warning of increased all-cause deaths associated with dementia-related psychosis in elderly patients. In a clinical trial, the rate of death in this population was 4.5% in patients taking pimavanserin compared with 2.6% in patients taking placebo. The reasons for death vary but are most likely to be associated with cardiovascular and infections. A diagnosis of Parkinson disease psychosis is paramount when deciding whether to use pimavanserin.

Pimavanserin prolongs QT interval. It should not be used with drugs that can also cause QT prolongation or in patients who already have a history of cardiac arrhythmias.

Common adverse reactions, regarded as an incidence rate of ≥5%, are listed in the table below. Hallucinations, urinary tract infections, and fatigue are some adverse events (AEs) more commonly seen in patients taking pimavanserin than placebo that led to discontinuation of pimavanserin. Other relevant AEs included constipation (4%) and gait disturbance (2%).

There are no data on pregnancy and lactation in pregnant women. pimavanserin was evaluated for teratogenicity in animal studies. In rats, there was maternal toxicity at 2 times the maximum recommended human dose (MRHD; 34 mg/day), including mortality, dehydration, and decreases in body weight and food consumption. There was also decreased pup survival, litter size, pup weight, and food consumption. In rabbits, pimavanserin was not teratogenic at 12 times the MRHD. Maternal toxicity had the same clinical signs as rats did, but only at doses 12 times the MRHD.

There are no dose adjustments required for elderly patients or in patients with less/more severe cognitive impairment.

The efficacy of pimavanserin was demonstrated in one placebo-controlled clinical study. In this trial, a Parkinson Disease-Adapted Scale Assessment of Positive Symptoms (SAPS-PD) was used to assess hallucinations and delusions. After a period of 6 weeks, pimavanserin showed significant superiority compared with placebo in terms of SAPS-PD hallucinations and delusions. SAPS-PD hallucination had a mean score difference of 2.01 compared with placebo. SAPS-PD delusions had a mean score difference of 0.94 compared with placebo.

Notably, pimavanserin did not exhibit an effect on motor function improvements in patients with Parkinson disease, as measured through the United Parkinson Disease Rating Scale Part II and III, compared to placebo.

Before the approval of pimavanserin, there were no FDA-approved treatments of Parkinson disease psychosis. Instead, many clinicians would use second-generation antipsychotics off label to help reduce these symptoms for their patients. Clozapine was the agent that has shown to be the most effective in treating Parkinson disease psychosis. The issue with clozapine is its safety profile. Clozapine has numerous AEs, including agranulocytosis. Patients are required to have blood drawn at certain intervals prior to clozapine being dispensed at a pharmacy. This can make it rather inconvenient to prescribe clozapine.

Quetiapine is another drug that is used for Parkinson disease psychosis. Unlike clozapine, there are not many clinical trials that prove quetiapine’s efficacy. However, quetiapine has a better safety profile than clozapine, with most of its AEs from metabolic syndromes.

 In studies comparing clozapine to quetiapine head-on, clozapine was shown to have an advantage in controlling hallucinations and reducing delusions. The approval of pimavanserin is a significant practical implication as it allows clinicians to select another drug for usage in these patients. There have been no trials comparing clozapine or quetiapine to pimavanserin.

Pimavanserin is covered by all Medicare Part D programs, with 90% of the programs not charging a copay higher than $25. Patients with commercial insurance may qualify for $0 copay card. Patients with no insurance may qualify for financial assistance and may also require no payment. Clinicians can request a 14-day free supply of medications by going to www.nuplazidhcp.com and filling out the form.

Table 3. Costs of Pimavanserin from Red Book Online

This guide includes everything you need to know about pimavanserin (Nuplazid, Acadia Pharmaceuticals) for the treatment of delusions and hallucinations associated with Parkinson disease psychosis.

What You Need to Know About Pimavanserin for Parkinson Disease Psychosis

In May 2018, erenumab-aooe (Aimovig, Amgen/Novartis) was approved by the FDA for the preventive treatment of migraine in adults.

Migraines are ranked the third most prevalent illness and sixth most disabling illness in the world according to Migraine Research Foundation. They are severe throbbing, recurring pain, usually on one side of the head. Patients with migraines do not only have headaches, but also other debilitating symptoms such as nausea, vomiting, dizziness, sensitivity to light, touch and sound. Migraines usually last anywhere between 4 to 72 hours. They affect quality of life, leading to early disability, depression, anxiety, and sleep disturbances.

Erenumab is administered subcutaneously at a dosage of either 70 mg or 140 mg once monthly in the abdomen, thigh, or upper arm.

 It is self-administered by the patient. Before administering, keep erenumab at room temperature for at least 30 minutes, protected from direct sunlight. Let it warm up naturally, without using other heat sources. Do not shake the solution.

Visually inspect the solution for any discoloration or particulate matters before administering. Do not use if the solution is cloudy or contains particles.

One administration of either the autoinjector or syringe will deliver the entire dose of 70 mg. Two prefilled syringes or autoinjectors will be needed for a 140 mg dose. See instructions for use for full administration directions.

Erenumab is human monoclonal antibody that is a calcitonin gene-related peptide (CGRP) antagonist.

Erenumab injection comes as a clear and colorless to light yellow solution. The needle shield from the autoinjector and the needle cap of the syringe contains dry natural rubber, a type of latex.

			Pack of 2 autoinjectors 140 mg/ml (2 x 70 mg/ml)

			Pack of 2 syringes 140 mg/ml (2 x 70 mg/ml)

Erenumab is to be refrigerated at 2°C to 8°C (36°F-46°F) in its original container and protected from light. erenumab must be used within 7 days if kept at room temperature, 25°C (77°F), in its original container. Do not store in the freezer and do not shake.

There are no drug interactions or contraindications reported on the packaging label of erenumab. Of note, erenumab is not metabolized by CYP450 enzymes, and does not affect oral contraceptive or sumatriptan pharmacokinetics.

Belimumab should be not used together with erenumab because erenumab will increase the toxicity of belimumab.

Adverse reactions listed below were observed from placebo-controlled clinical trials from both doses of erenumab (70 mg and 140 mg).

Table 2. Adverse Reactions Observed From Placebo-controlled Clinical Trials

Injection site reactions (pain, erythema, pruritus)

There are no data on the effect that erenumab has on human pregnancy or lactation.

 Erenumab did not have any adverse effects on female monkey’s offspring. Studies have shown that women with migraine may be predisposed to an increased risk of preeclampsia during pregnancy.

Erenumab has not been tested in pediatrics. Patients 65 years and older should start erenumab treatment at the lower dose (70 mg).

Erenumab was evaluated in 3 different clinical studies, 2 studies in patients with episodic migraine and 1 study in patients with chronic migraine. In the first study evaluating patients with episodic migraine, erenumab 70 mg and 140 mg had significantly lower mean monthly migraine days (3-4 migraine day difference from baseline), increased the proportion of patients with a ≥50% reduction from baseline in mean monthly migraine days (43.3% to 50% responders in erenumab), lowered monthly acute migraine-specific medication days (1-2 day difference from baseline), and saw improvements in migraine physical function impact diary (MPFID), a measurement of the impacts that migraine has on everyday activities and physical impairment.   

Similarly, in the second study conducted on patients with episodic migraine, erenumab 70 mg was shown to significantly lower monthly migraine days, increased the proportion of patients with ≥50% reduction from baseline in mean monthly migraine days, and lowered monthly acute migraine-specific medication days. MFPID improvements in scores of at least a 5-point reduction, as a predetermined outcome, was not achieved by erenumab compared to placebo.

The third study on erenumab efficacy was assessed in patients with chronic migraine. erenumab 70 mg and 140 mg had significantly lower mean monthly migraine days (6.6 migraine day difference from baseline), increased proportion of patients with ≥50% reduction from baseline in mean monthly migraine days (39.9% to 41.2% responders in erenumab), and lower monthly acute migraine-specific medication days (approximately 4-day difference from baseline).

Classification of migraine preventative therapies are done through medications with established efficacy in trials. Level A medications with established efficacy (≥2 Class I trials) include antiepileptic drugs (valproate, topiramate), β-blockers (metoprolol, propranolol, timolol) and frovatriptan. Level B medications with probable efficacy (1 class I or 2 class II studies) include amitriptyline, venlafaxine, β-blockers (atenolol, nadolol) and triptans (naratriptan, zolmitriptan). Level C medications with possible efficacy (1 class II study) include lisinopril, candesartan, α-agonists (clonidine, guanfacine), carbamazepine, β-blockers (nebivolol, pindolol) and cyproheptadine. Selective serotonin reuptake inhibitors, calcium channel blockers and other drugs in the same drug class as the ones listed in Level A to C either have inadequate data to support use or are ineffective.

The most recent update for the prevention of episodic migraines was the 2012 guidelines from the American Headache Society. Because erenumab was just approved in 2018, it does not have a recommendation on usage in this guideline.

The cost for erenumab 70-mg and 140-mg autoinjectors are listed below (see 

). There is a co-pay card that commercially insured patients may be eligible for. There is also a service request form that can be submitted by the clinician to help cover the cost of the drug. Both are available online at www.aimovig.com/co-pay-and-support.

Table 3. Costs of Erenumab from Red Book Online

This guide includes everything you need to know about erenumab-aooe (Aimovig, Amgen/Novartis) for the preventive treatment of migraine in adults.

Author | David Bai, PharmD

Articles

What You Need to Know About Amantadine for Parkinson Disease

What You Need to Know About Cannabidiol for Rare Forms of Epilepsy

What You Need to Know About Pimavanserin for Parkinson Disease Psychosis

What You Need to Know About Erenumab for Preventive Treatment of Migraine