Strategies for Enhancing Adherence in the Management of Parkinson’s Disease

Supported by an educational grant from Teva Neuroscience.

FACULTY:

Stephen M. Setter, PharmD, CDE, CGP, FASCP
Associate Professor of Pharmacotherapy
Washington State University
Spokane, WA

FACULTY DISCLOSURE STATEMENTS:

Dr. Setter reports to be a member of the Speakers’ Bureau for Teva Neuroscience.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Program No.: 430-000-08-004-H01-P and 430- 000-08-004-H01-T
Credits: 2.0 hours (0.20 ceu)

TARGET AUDIENCE:

This accredited program is targeted to pharmacists and pharmacy technicians. Estimated time to complete this monograph and posttest is 90 to 120 minutes.

METHOD OF PARTICIPATION:

There are no fees for participating and receiving CE credit for this activity. During the period March 1, 2008 through Month 31, 2010, participants must:

1. read the learning objectives and faculty disclosure;
2. study the educational activity;
3. complete the posttest by recording the best answer to each question in the answer key on the evaluation form;
4. complete the evaluation form; and
5. mail or fax the evaluation form with answer key to the address listed on the form. For faster service, enter your answers on the Internet at www.uspharmacist.com. A statement of credit will be issued upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better.

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To provide pharmacists with an update on the management of PD, guidelines for appropriate selection of therapy, and strategies for enhancing patient adherence.

OBJECTIVES:

After completing this program, participants will be able to:

1. Describe the prevalence and diagnosis of PD.*
2. Recount the implications of non-adherence to pharmacological therapy.*
3. Outline the efficacy and safety of current agents for the management of PD.*
4. Review guidelines for appropriate selection of therapy.*
5. Describe strategies for enhancing patient adherence.

*Also applies to pharmacy technicians.

Parkinson’s disease (PD) afflicts approximately 1 to 1.5 million people in the United States.¹ Men tend to be more affected than women, with a higher prevalence among Caucasians.¹ PD tends to affect people aged 60 and older; however, up to 5% of those with PD are diagnosed at age 40 or younger.¹ Risk factors for the development of PD include age, genetics, a history of significant head trauma, and environmental toxin exposure. Even though the genetic aspect of PD is not completely understood, one fifth of all patients with PD possess at least one relative with PD.² It has been postulated that possessing a certain genetic make-up may more likely predispose one to other risk factors associated with the development of PD, such as exposure to environmental toxins and a history of head trauma.²

Although the underlying root cause of PD is incompletely understood, the underlying pathology is well characterized. Dopaminergic neurons in the substantia nigra communicate with the striatum and other regions of the brain to coordinate muscle movements within the body. Degeneration of these neurons (with the concomitant loss of dopamine) substantially impairs patients’ motor capabilities. The initial symptoms associated with PD generally surface when dopamine levels decline to 60% to 80% of normal.³ The four cardinal motor symptoms associated with PD include bradykinesia (slow movement), muscle rigidity or stiffness, resting tremor, and postural instability (which results in poor balance). These four cardinal symptoms have in the past been identified by the common acronym TRAP, representing Tremor, Rigidity, Akinesia (total lack of movement), and Postural instability. Today, it is more common to refer to the symptoms associated with PD as a triad: rigidity, bradykinesia, and rest tremor.⁴ Postural instability is less frequently regarded as a cardinal symptom since it is less likely present at the time of diagnosis. Only about 70% to 80% of patients with PD experience tremor, whereas it is generally recognized that 100% of patients with PD experience muscle rigidity.⁵

Examples of the cardinal motor symptoms previously discussed include, but are not limited to, bradykinesia, micrographia (small handwriting), hypophonia (soft speech), shuffling gait, reduced eye blinking that can result in xerophthalmia (dry eye), and dysphagia.⁴ It is very important for pharmacists and other health care professionals to recognize and address these symptoms. For example, if a patient experiences dysphagia, a smaller dosage form of medication or one that is taken less frequently may be more ideal. Also, a liquid formulation or transdermal patch formulation of a medication may be appropriate in certain patients, particularly those unable to take oral therapies or those with dysphagia due to advanced disease.

DISEASE PROGRESSION

Each patient with PD is unique, in that the types and severity of symptoms presented vary. Additionally, the symptoms experienced over time may change. No one patient stays the same. For many patients with PD, muscle rigidity and a mild tremor may be the first symptoms to surface. As time goes on, these symptoms may progress and others may occur. It should be noted that as the symptoms associated with PD progress or occur, patients may require aides to maintain medication adherence.

IMPLICATIONS OF NONADHERENCE

The effective management of PD most often involves the consumption of orally administered medications that must be taken anywhere from one to five or more times daily depending on the drug regimen. In general, patients with PD quickly learn that their clinical response is critically associated and closely tied to their level of medication adherence. Unfortunately, drug absorption associated with many agents is variable and the short half-life of some agents necessitates the consumption of multiple doses per day. Furthermore, as PD progresses, patients often require multiple categories of medications to control their symptoms and, therefore, medication nonadherence with PD therapies is common.⁶ On the flip side, medication overuse can contribute to the development of psychiatric disturbances such as psychosis that may include hallucinations and delusions, and increased incidence of motor symptomatology (e.g., dyskinesia).

In general, clinicians prescribing PD therapies realize that medication adherence is a primary element of patients obtaining symptomatic benefit. PD is perhaps one of the best examples in which the level and degree of medication adherence is a prime motivator for gaining relief from the motor complications associated with it. Fortunately, for many patients with PD, clinical response is highly correlated to, and noticeable, when therapies are taken as prescribed. On the downside, poor motor control is clearly exhibited when medications are missed. It should be noted that patients’ level of tremor or rigidity may be a contributing factor to the level of medication adherence. Pharmacists and other health care professionals can play a critical role in counseling patients and providing tools to enable patients to achieve optimal medication adherence.

Despite the therapeutic and educational initiatives to gain acceptable to superior symptomatic relief from the motor disorders associated with PD, studies on PD have identified less than ideal medication adherence.⁷ As previously mentioned, in most medical practitioners’ clinical experience, patients with PD are highly motivated to gain symptomatic relief of their primary symptoms. However, comorbid conditions such as depression, anxiety, or cognitive impairment can complicate efforts toward symptomatic relief and, thus, hinder or sabotage patients’ attempts at medication adherence. Indeed, patients with depression are three times more likely to be nonadherent.⁸ Another factor that may lead to suboptimal adherence is medication-associated side effects. Some categories of PD medications, particularly carbidopa/levodopa and the dopamine agonists, are associated with a high rate of nausea and/or hypotension and, therefore, alternative therapies or strategies to attenuate these side effects are often needed.

In summary, nonadherence with medical therapies among patients with PD leads to lack of efficacy, impaired function, and a decline in quality of life. In general, patients with PD who delay therapy or are not adherent to their regimens experience poor motor control, which negatively impacts their quality of life. Approaches and strategies that can be recommended to patients to improve medication adherence are worthwhile and examples of these strategies will be discussed in an upcoming section.

OVERVIEW OF SELECT AGENTS/CATEGORIES OF AGENTS

Since the most noticeable and readily treated symptoms associated with patients with PD are motor in nature and are caused by the lack of dopamine in the nigrostriatal system, the majority of pharmacotherapies used to treat PD attempt to replenish, mimic, or augment dopamine in the affected brain regions. In this section, the four drug/drug categories that are most often used to treat the motor symptoms associated with PD (levodopa, COMT inhibitors, dopamine agonists, and MAO-B inhibitors) will be reviewed. Note that this section only will review the most commonly prescribed agents used to treat PD and will not be an exhaustive review of all currently available therapies (Figure 1).

Carbidopa/Levodopa

Levodopa was approved by the FDA in 1967 and was heralded as a “miracle drug.”⁹ Fortunately, it was quickly realized that levodopa is peripherally metabolized to dopamine, thereby diminishing its ability to cross the blood brain barrier (BBB). This peripheral conversion also negatively affects its side-effect profile. Therefore, levodopa is currently combined with carbidopa or carbidopa and entacapone to prevent peripheral conversion to non-active metabolites. Without inhibiting the aromatic amino acid decarboxylase (AADC), the enzyme blocked by carbidopa, roughly only 1% of levodopa would enter the brain (where it is then converted to dopamine).¹⁰ Combining levodopa with carbidopa allows more levodopa to cross through the BBB, where upon conversion to dopamine it can have its intended clinical action. Therefore, carbidopa prevents the peripheral conversion of levodopa prematurely to dopamine in the peripheral circulation. This lessens the severity of side effects and also increases the likelihood that levodopa will enter the brain, where it is converted to the deficient neurotransmitter dopamine.⁹

Carbidopa/levodopa is approved for use in early or moderate-to-advanced PD.³ Symptoms most likely to respond to carbidopa/levodopa therapy include rigidity, bradykinesia, hypomimia (masked facies), and micrographia. Note that carbidopa/levodopa therapy is less likely to be efficacious for postural instability, speech problems, constipation, depression, or dementia. Unfortunately, this miracle drug was soon associated with untoward movement derangements such as dyskinesia and “wearing off.”

Wearing off describes the often abrupt loss in efficacy of medications (in this case, levodopa), which particularly occurs prior to the next scheduled dose. This is in contrast to the “on-off phenomenon,” in which there is a rapid fluctuation of akinetic (off) and choreoathetotic (on) movements.

COMT Inhibitors

Catechol-O-methyl transferase (COMT) is an enzyme in the body that converts levodopa into 3-O-methyldopa. 3-O-methyldopa has no benefit in treating patients with PD and may in fact compete for levodopa transfer through the BBB.

There are currently two approved COMT inhibitors: entacapone and tolcapone. Entacapone is used in the treatment of PD as an adjunct to carbidopa/levodopa therapy in patients who experience wearing off. Keep in mind that by itself entacapone has no intrinsic benefit in treating patients with PD and should only be given in combination with carbidopa/levodopa. Tolcapone is indicated as an adjunct to carbidopa/levodopa therapy for the treatment of the signs and symptoms of PD. The frequency of use of tolcapone among clinicians is adversely affected due to its association with liver toxicity and, thus, the need for frequent liver function testing.³ An important distinction between entacapone and tolcapone is that since tolcapone crosses the BBB and entacapone does not, tolcapone may be dosed independently of carbidopa/levodopa, whereas entacapone may not.

Dopamine Agonists

There are five known subtypes of dopamine receptors identified as D1, D2, D3, D4, and D5. The D1 and D5 receptors are members of the D1-like family of dopamine receptors, whereas the D2, D3 and D4 receptors are members of the D2-like family.¹¹ Unlike levodopa, a dopamine agonist is not converted into dopamine, but its activity mimics that of dopamine. Dopamine agonists need to be administered multiple times per day and require slow dose titration to decrease the incidence and severity of side effects (more on this later). When used alone in early PD, dopamine agonists may reduce symptoms of the disease, especially those that affect motor function, such as stiffness and slowness. Although they are not as effective as levodopa in controlling symptoms, they have the benefit of postponing the need for levodopa therapy, which in turn may help delay the onset of levodopa-related motor fluctuations.¹²

Currently available dopamine agonists include apomorphine, bromocriptine, pramipexole, ropinirole, and rotigotine. Pergolide, another dopamine agonist, was voluntarily withdrawn from the US market due to its propensity to cause valvulopathy (heart valve damage).

Apomorphine is an injectable, rapid-acting dopamine agonist. Because apomorphine is rapid acting, it is usually effective within 10 minutes from the time of injection. Its effectiveness lasts approximately 60 to 90 minutes.¹³

Bromocriptine does not seem to be as effective as the other dopamine agonists early in PD.¹⁴ It also is not useful late in the disease to reduce motor fluctuations caused by levodopa. Bromocriptine is prescribed infrequently for patients with PD due to its increased risk of causing pleural and pulmonary fibrosis as well as retroperitoneal fibrosis.¹⁴

Pramipexole and ropinirole show good results in controlling PD symptoms in patients still in the initial stages of the disease and not yet treated with carbidopa/levodopa, thus postponing the need of carbidopa/levodopa therapy to a later phase. They work as well in those patients with advanced PD symptoms already receiving carbidopa/levodopa therapy.^15,16

Rotigotine is a D2/D3 nonergot dopamine agonist available as a transdermal delivery system (TDS). Rotigotine is approved as monotherapy for patients with newly diagnosed PD.¹⁷

MAO-B Inhibitors

Monoamine oxidase type B (MAO-B) inhibitors prevent the breakdown of dopamine in the nigrostriatal region of the brain.¹⁸ Additionally, MAO-B inhibitors prevent the oxidative deamination of norepinephrine (NE) and serotonin as well as the biogenic amine tyramine. Currently, there are two MAO-B inhibitors available: rasagiline and selegiline.

Rasagiline was approved by the FDA in May 2006 for early-stage and moderate-to-advanced-stage PD. Clinical data indicate that patients on rasagiline as initial monotherapy have less progression of their movement disability, and patients with moderate-to-advanced-stage PD experience less “off” time. Another interesting aspect that is currently under investigation is whether or not rasagiline delays the progression of PD.¹⁹ Rasagiline is metabolized to 1 R-aminoindan, which in some experimental animal models has demonstrated neuroprotective properties, but as of yet there is no evidence that this holds true for patients with PD.¹⁹

Selegiline was initially thought to be neuroprotective; however, this is as yet unproven.²⁰ In animal models, selegiline has been shown to prevent the development of symptoms associated with PD by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a substance that when converted to MPP+ (ion) [1-methyl-4-phenylpyridium] is known to destroy dopaminergic neurons. In a large double-blind US study, patients with early PD were administered placebo, vitamin E, selegiline, or a combination of these therapies. Although the onset of disability was initially delayed, this positive clinical effect experienced by those taking selegiline was not sustained.²⁰ Selegiline is approved as an adjunctive therapy to treat patients on carbidopa/levodopa therapy. Selegiline is not approved for initial therapy for patients with PD.²¹

Other Therapies

Other agents used to treat patients with PD include amantadine and drugs that possess anticholinergic activity.³ Amantadine has long been prescribed for PD and has recently been found useful in controlling carbidopa/levodopa-associated dyskinesia. Anticholinergics were originally prescribed for patients with PD because of their effectiveness in managing tremor, but are less often prescribed today due to their bothersome side effects (including xerostomia, constipation, blurred vision, and drowsiness) and their propensity to contribute to cognitive impairment, particularly in older patients.³

PHARMACOKINETICS OF SELECT AGENTS/CATEGORIES OF AGENTS

Even though health care providers do not often realize it, pharmacokinetics may play a role in their prescribing habits. The pharmacokinetic profile may determine the frequency of drug administration and, therefore, may contribute to the eventual adherence achieved by patients.

Carbidopa/levodopa and carbidopa/levodopa/entacapone preparations often need to be consumed three to four times daily in order to achieve clinical benefit. The immediate-release (IR) formulation of carbidopa/levodopa has an onset of 20 to 40 minutes with an average duration of action of two to four hours.⁹ The controlled-release (CR) formulation of carbidopa/levodopa has an onset of 30 to 60 minutes with an average duration of action of three to six hours. Note that CR formulations of carbidopa/levodopa may be split once, but crushing will alter this dosage form’s pharmacokinetics and, therefore, is not recommended. Some patients may require both IR and CR formulations of carbidopa/levodopa. When entacapone is added to carbidopa/levodopa therapy, each dose of entacapone needs to be given along with the carbidopa/levodopa-containing medication. The other option is to administer the single dosage form that contains carbidopa/levodopa and entacapone.

Since rotigotine TDS is available as a 24-hour dosage formulation, it may be more convenient for some patients.²² Benefits associated with the rotigotine TDS include its provision of relatively stable levels of the medication in the bloodstream for 24 hours and pulsatile stimulation of the dopamine receptors (often associated with the development of motor fluctuations and dyskinesia) is avoided.²³ The rotigotine TDS may be particularly well accepted by those patients with dysphagia or those intolerant to the gastrointestinal side effects commonly associated with oral dopamine agonist therapy.

Selegiline for the treatment of PD is available as a twice-a-day oral product or as a once-daily orally disintegrating tablet (ODT).²¹ Of particular clinical interest is that selegiline is metabolized to L-methamphetamine and L-amphetamine, which may contribute to its propensity to contribute to insomnia.²⁴ Rasagiline, regardless of whether it is being used as initial treatment or more late-stage treatment, is given once daily. Data from the medical literature indicate that up to 40 days are required to completely restore brain MAO-B activity after discontinuation of either selegiline or rasagiline.²⁵ Implications associated with this include duration of effect and drug interaction potential.

SIDE EFFECTS ASSOCIATED WITH SELECT AGENTS/CATEGORIES OF AGENTS

Side effects are one of the primary reasons why patients with PD may achieve less than optimal adherence with their drug regimen. If side effects do arise, patients should be instructed to always work closely with their health care professional. Patients with PD need to be adequately counseled on side effects and be given strategies to manage them. For example, to manage hypotension, a higher salt diet may be recommended or agents such as indomethacin, fludrocortisone, or midodrine may be co-prescribed. Nausea can often be managed by taking the dose with food or with the addition of domperidone, a drug available in Canada. Additionally, extra doses of carbidopa may often be used to treat carbidopa/levodopa-associated nausea.²⁶ Managing hallucinations may require a dosage reduction and/or the addition of an atypical antipsychotic such as quetiapine.²⁷ The development of wearing-off often requires an increase in the frequency of administration or the addition of a dopamine agonist, an MAO-B inhibitor, or the addition of entacapone to the carbidopa/levodopa regimen.

In this section, side effects will be briefly discussed with the discussion focused on the more frequently prescribed therapies (Table 1).

Carbidopa/Levodopa

Carbidopa/levodopa products are associated with a multitude of side effects that are generally well known due to this drug combination being available since the 1970s. Common side effects include hypotension, nausea, confusion, dizziness, fatigue, hallucinations, and dyskinesia, which is perhaps the most debilitating and bothersome side effect.²⁸ Long-term CNS adverse effects that may occur include akathisia, depression, delirium, agitation, paranoia, delusions, and hallucinations. It should be noted that the aforementioned adverse effects may occur regardless of the type of therapy being used.

COMT Inhibitors

In general, entacapone is associated with few side effects. Side effects experienced are more likely due to the increase in levodopa entering the brain and, therefore, contributing to dopaminergic side effects. In double-blind, placebo-controlled trials entacapone-treated patients experienced nausea, urine discoloration, diarrhea, and abdominal pain more frequently than placebo-treated patients.^29,30

Tolcapone is associated with side effects such as dyskinesia, nausea, sleep disorder, dystonia, anorexia, muscle cramps, somnolence, and diarrhea.³

Dopamine Agonists

Generally, dopamine agonists are less likely to be associated with the development of wearing off or dyskinesia compared with carbidopa/levodopa.³ However, the development of nausea, postural hypotension, edema, drowsiness/somnolence, unsteadiness, and confusion are quite common. As well, with the oral dopamine agonists delusions, hallucinations, and compulsive behavior are not uncommon. The development of edema often requires a reduction in dosage or the consideration of another drug from another class in its place. The rotigotine TDS, in addition to application site reactions, is associated with nausea, vomiting, dizziness, headache, somnolence and insomnia above that experienced with patients receiving placebo in clinical trials.^22,23

Uniformly, side effects involving the rotigotine TDS tend to occur more commonly in the 6-mg/24-hour group than with the lower dosages of 2 and 4 mg/24 hours.^17,31 Additionally, and as for all therapies that affect central dopamine activity, sudden sleep attacks can occur.¹²

MAO-B Inhibitors

MAO-B inhibitors in general are associated with fewer side effects than the levodopa-containing formulations and the dopamine agonists. Selegiline, because it is metabolized to L-methamphetamine and L-amphetamine, is associated with insomnia and, therefore, when given twice a day, patients should take the second dose early in the afternoon. Other commonly reported side effects associated with selegiline include nausea and dizziness. Specifically for the selegiline ODT, the most commonly observed side effects, which were greater than placebo, reported in double-blind placebo-controlled trials during treatment were dizziness, nausea, pain, headache, insomnia, rhinitis, dyskinesia, back pain, stomatitis, and dyspepsia.²¹ At doses of ≤10 mg/day of selegiline and up to 2.5 mg/day of selegiline ODT, a tyramine pressor response is rare and serious adverse effects associated with selegiline and tyramine-containing foods are rarely seen.³² This tyramine pressor response commonly known as the “cheese effect” is so named because foods such as aged, hard cheeses (e.g., cheddar, roquefort, and swiss), cured meats, and broad bean pods contain tyramine that, when ingested, places the patient at risk for an adverse pressor effect that contributes to the development of hypertension, headache, nausea, palpitations, and tachycardia.³³ Selective MAO-B inhibitors are for the most part free of risk for a tyramine interaction unless supratherapeutic doses of MAO-B inhibitors are ingested.

Rasagiline is associated with mild side effects, with the most common being headache.³³ In clinical trials dizziness, postural hypotension, confusion, hallucination, and somnolence did not differ from placebo.³⁴ Rasagiline at therapeutic and recommended doses of 1 mg or less has not been associated with a tyramine pressor response.

CONTRAINDICATIONS AND WARNINGS

Contraindications and warnings are factors that may also influence medication adherence. Often, these terms may appear to be confusing to pharmacists and other health care professionals, and this confusion may affect how agents are prescribed and administered. There are two categories of contraindications. An absolute contraindication is a situation that makes a particular treatment or procedure absolutely inadvisable. A relative contraindication is a condition that makes a particular treatment or procedure somewhat inadvisable but does not rule it out.

Warnings are also expressed in two categories: warnings and those contained within a black box, known as black box warnings (BBWs). The BBW is the FDA’s strongest labeling requirement for high-risk medicines. The BBW alerts the prescriber and others to the potential serious risk that may accompany the use of a drug. Non-BBWs are important to understand and heed but are there to inform the prescriber that a risk may be involved. Currently, no BBWs exist for carbidopa/levodopa, COMT inhibitors, dopamine agonists, or MAO-B inhibitors.

Absolute Contraindications

Absolute contraindications for carbidopa/levodopa include abrupt discontinuation, breastfeeding, closed-angle glaucoma, and melanoma. Sporadic reports of a neuroleptic malignant syndrome-like syndrome have been reported with the abrupt discontinuation of carbidopa/levodopa.³⁵

The absolute contraindication for carbidopa/levodopa in women who are breastfeeding is due to levodopa’s ability to inhibit lactation by blocking prolactin release. Even though carbidopa/levodopa is contraindicated in closed-angle glaucoma, it can be safely administered to those patients with open-angle disease. Since levodopa has been reported to activate melanoma, it is contraindicated in patients with a history of melanoma.³⁵

The absolute contraindication to entacapone therapy is concomitant use with nonselective MAOIs such as isocarboxazid, phenelzine, and tranylcypromine.²⁹ Since these agents are infrequently prescribed, this is of limited concern for those administering to patients with PD.

There are no absolute contraindications for pramipexole or ropinirole. Absolute contraindications for the rotigotine TDS include patients undergoing cardioversion and magnetic resonance imaging (MRI). Patients must remove their rotigotine patch prior to MRI studies and cardioversion to avoid dermal burns.¹⁷

Absolute contraindications for the MAO-B inhibitors include MAOI therapy or breastfeeding, the latter being an absolute indication only for selegiline. Additional absolute contraindications for rasagiline include acute myocardial infarction, alcoholism, patients younger than 18 years of age, migraine, and pheochromocytoma.³⁶

Warnings

Warnings for carbidopa/levodopa have been in place for many years and include the development of dyskinesia and psychosis and the need to use cautiously in patients with severe cardiovascular, pulmonary, renal, hepatic or endocrine disease.³⁵ Additionally, the likelihood of carbidopa/levodopa therapy to increase the risk of upper gastrointestinal hemorrhage or the rare development of neuroleptic malignant-like syndrome when the drug is abruptly discontinued or tapered too rapidly is noted.

The sole warning for entacapone is in regard to the statement that entacapone should not be coprescribed with a nonselective MAO inhibitor (e.g., phenelzine or tranylcypromine).²⁹ The reasoning for this is that the majority of catecholamine metabolism and breakdown is via the COMT and MAO pathways and by blocking both of these catabolic pathways, deleterious catecholamine-associated adverse events may occur. Note that carbidopa/levodopa +/-entacapone can be safely co-administered with selegiline or rasagiline.

Warnings for ropinirole and pramipexole include falling asleep during activities of daily living, also known as sleep attacks. Prodromal signs may not be evident and in some instances severe motor vehicle accidents have occurred.³⁷ Syncope with or without bradycardia can occur as well as symptomatic orthostatic hypotension. The dopamine agonists also carry a warning regarding the development of hallucinations.^15,16

Warnings for the MAO-B inhibitors include the necessity not to exceed dosing limits due to the risk of losing selectivity. Dosing for the oral formulation of selegiline should not exceed 10 mg/day.³⁸ In addition, there is a warning that the ODT formulation of selegiline (2.5 mg/day) should not be consumed, although this may be solely relevant to the efficacy of the administered drug.²¹

Rasagiline’s upper dosing limit is 1 mg/day.³⁶ Carried over from the warnings issued with nonselective MAOIs, the MAO-B inhibitors carry a warning about coadministration with antidepressants (SSRIs, SNRIs, and TCAs), although with the prevalence of depression in patients with PD it is not reasonable to expect that these drugs will not be used concomitantly.^36,38 Additionally, a warning regarding the risk of developing orthostatic hypotension is included.

GUIDELINES FOR INITIATION OF APPROPRIATE THERAPY

Many patients when first diagnosed with PD may still be working and enjoying active lives. Initiation of symptomatic therapy should be individualized and the decision should include factors such as the impact the disease is having on their lives at home and at work, their life expectancy, age, their quality of life, and any comorbidities that may be present. Currently, the average life expectancy from diagnosis to death is 17 years, with more and more patients living 30 years or more.³⁹ It is well accepted in clinical practice that the longer patients are on carbidopa/levodopa therapy, the more likely they will develop dyskinesia. Thus, taking a long-term approach and delaying carbidopa/levodopa therapy for as long as possible may be beneficial for some patients. Therefore, a long-term treatment strategy is imperative and initial therapy needs to take into account the propensity to cause side effects and cost.

Historically, treatment has been withheld until movement disorder symptoms (tremor, rigidity, or bradykinesia) significantly impair performance or draw unneeded attention at work, at home, or in social situations. A new paradigm is emerging that addresses the benefit of early therapy that is instituted prior to the development of significant impairment or awareness.³ It is also important for pharmacists and other health care professionals to be aware of which agents are indicated for initial therapy and which are indicated for advanced stages, for example, rasagiline is indicated for initial therapy and advanced therapy but selegiline is only indicated for advanced therapy.^36,38

The three drug/drug classes available for consideration as initial therapy include levodopa, dopamine agonists, and the MAO-B inhibitors (Figure 1). Levodopa is very effective in treating bradykinesia, rigidity, and tremor.⁴⁰ Patients often respond most robustly to levodopa, at least initially. An important factor that enters into whether or not levodopa is used is the age of the patient due to levodopa’s propensity to induce motor complications such as wearing off and, more importantly, dyskinesia. In young patients motor complications can affect up to 70% of patients after three years whereas older patients tend to develop these motor complications at a rate of approximately 10% per year.⁴¹ Therefore, the age of a patient is critical when deciding if or when to initiate levodopa therapy.

Dopamine agonists are also effective therapies. Age may be a factor in determining when to initiate therapy. In general, patients under the age of 70 tolerate the dopamine agonists better than those over the age of 70.³ Additionally, since the majority of dopamine agonists (as well as levodopa) need to be administered three times daily, the willingness of the patient to comply should be addressed prior to initiation of therapy.

Rasagiline is approved as monotherapy in patients with PD and it is generally well tolerated. Rasagiline has demonstrated good efficacy in movement disorder response. In one trial comparing the response of starting therapy early or later in the disease, a group taking rasagiline early on demonstrated significant symptomatic improvement compared with the cohort that was started six-months post-diagnosis.³⁴ Thus, many clinicians may likely begin rasagiline therapy even before symptoms start to impair patients’ quality of life. Another factor favoring early and initial treatment with rasagiline is its favorable side-effect profile: data demonstrate that fewer side effects were seen in patients under 70 years of age compared with patients over 70 years of age.¹⁹ Therefore, it is important that clinicians understand the value of tailoring the drug regimen to specific patient factors.

STRATEGIES FOR ENHANCING PATIENT ADHERENCE

Pharmacists and other health care professionals should be keenly aware that the complexity of any drug regimen is inversely related to adherence. A systematic review by Claxton and colleagues on adherence in relationship to dosing schedule showed an average adherence rate of 79% for patients on a once-daily drug regimen versus 51% for a four-times-daily drug regimen.⁴²

It makes intuitive and rational sense that simplifying dosing frequency can improve adherence, patient quality of life, and patient satisfaction. Although numerous approaches to improving adherence have proved unsuccessful or mildly successful in the past, it is even more important that pharmacists and other health care professionals continue to strive to identify strategies to enhance patient adherence, especially patients with PD. These strategies should include an understanding of patients’ personal beliefs, involvement of patients in therapy decisions, and encouraging patients to assess their treatment plan. Regimen simplification with longer-acting preparations such as rasagiline or the rotigotine TDS may ease the process of medicine-taking.⁷ The bottom line is that providing easily consumed medicines and simplifying drug regimens improve adherence.

Another issue that is often overlooked in relation to medication adherence is the importance of building rapport and open communication with patients. In fact it has been demonstrated that one-on-one educational interventions have the potential to improve drug regimen adherence and health outcomes.⁴³

When counseling patients with PD, denial is something that needs to be addressed. Newly diagnosed patients may not want to admit that they have a progressive neurodegenerative disorder. Taking medications to treat PD is admitting that they do have PD. With proper handling and counseling, patients can be eased into accepting their diagnosis. Additionally, having to take fewer doses per day, at least initially, may ease their transition into acceptance.

Medication side effects can alter a patient’s best intention to maintain adherence. Adverse effects are a widely recognized reason for nonadherence.⁴⁴ Side effects associated with PD medications may lead to suboptimal PD therapy adherence, with nausea and light-headedness frequently encountered early in therapy. Tolerability can definitely impact patients’ levels of adherence. In a review of multiple clinical trials involving PD therapies, discontinuation rates associated with an active drug varied from 7.7% to 23%, whereas discontinuation rates associated with placebo varied from 0% to 14%.⁴⁴ Therefore, adverse effects or compromised tolerability can contribute to a high degree of nonadherence.

It is essential when communicating with patients about potential adverse drug effects that tact and sensitivity are incorporated. The key word here is “potential” adverse drug effects. All patients with PD are unique and their propensity to experience no or many side effects is difficult to predict. The key is to provide the side effect information in a straightforward manner and inform patients that there are a multitude of strategies to manage these effects. Patients must be “coached” that the solution is not to “jump ship” prematurely and that given time most patients tolerate their drugs exceptionally well. Certainly, if side effects do arise, patients need to contact their pharmacist or other health care professionals to help them understand and strategize on how best to attenuate drug side effects.

In regard to patient adherence, it is extremely valuable for pharmacists or other health care professionals to evaluate patients’ levels of adherence in a non-threatening, non-judgmental manner. Asking simple questions such as “I see you are on a few medications that need to be taken multiple times daily, and it’s only human to miss a dose now and then. Do you miss doses often?” If a “yes” is solicited, then add, “Is there anything I can do to help you gain the most benefit from your therapy?” Fortunately, many pharmacies carry medication boxes and travel containers, and are able to customize medication calendars and medication lists. Certainly, if patients express the need for a more detailed assessment of their adherence, arrangements can be made. Strategies would include simplifying the medication regimen and choosing medicines with fewer side effects. Finally, it is always good to keep in mind some very practical and common reasons why patients with PD might miss doses of medications. A study by Leopold and colleagues identified the common reasons for missed doses (Tables 2 and 3).⁷

Assessing Comorbidities

Neurologists and others diagnosing and prescribing for patients with PD are often expert at assessing medical comorbidities that may complicate treatment. Agents such as dopamine agonists and anticholinergics should be cautiously prescribed for patients with cognitive impairment. Additionally, patients with hypotension or dysphagia often need special consideration when prescribed therapies for PD.

Education and Counseling

The following are some brief points to consider in educating and counseling patients regarding specific agents used to treat patients with PD.

Carbidopa/Levodopa and Entacapone: The oral carbidopa/levodopa tablet therapies should be administered with 6 to 8 ounces of water and ideally be taken 30 to 60 minutes prior to eating or one hour after consumption of food, since administration with protein-rich foods may decrease absorption. However, early in the disease course the coadministration with food will decrease nausea and in most patients will not appreciably affect the clinical response. As the disease progresses, it is more critical to eliminate coadministration with protein-rich foods.

CR formulations of carbidopa/levodopa may be of benefit in some patients and the tablets can be halved (although not be crushed or chewed). The orally dissolving tablet of carbidopa/levodopa is mint flavored and should be gently removed from the bottle with dry hands, placed on the tongue, and then allowed to dissolve and be swallowed. Administration with liquid is not necessary. A liquid formulation of carbidopa/levodopa can be prepared that may be particularly well accepted by patients with dysphagia; however, patients may abandon this dosage form due to inconvenience.²⁰

For added convenience there is formulation of carbidopa/levodopa/entacapone that is available in film-coated tablets in four different strengths. This combination drug should be taken with water with the same instructions regarding meal and protein consumption as other carbidopa/levodopa products. The product should not be crushed or split and should be swallowed whole.

As previously mentioned, entacapone is used as an adjunct to carbidopa/levodopa for the treatment of PD for patients experiencing end-of-dose “wearing off.” Patients need to understand that this medication is administered with every dose of carbidopa/levodopa, IR or CR, up to four times daily. For many patients, taking an additional pill can be an added activity and for these patients the combination agent of carbidopa/levodopa/entacapone may be considered. Additionally, when initiating entacapone therapy, the dose of carbidopa/levodopa may need to be decreased. Thus, patients should be counseled to work closely with their health care professional when adding or discontinuing entacapone therapy.

Dopamine Agonists: The oral dopamine agonists are available as tablets and/or capsules. Ropinirole is a small non-scored tablet that is given three times a day with or without food. Dose titrations are recommended every seven days until the desired response is achieved. Pramipexole, also taken three times a day, is a small oral tablet with the larger dosages scored. As with ropinirole, pramipexole needs gradual dose titration (every five to seven days) and can be given with or without food. Note that administration with food tends to decrease the degree of nausea associated with dopamine agonists. For both ropinirole and pramipexole, slow titration is a must; even slower titration than is routinely recommended can often ease the degree of side effects experienced, particularly by older patients.

As previously noted, the rotigotine TDS is available in three sizes: 2 mg/24 hours, 4 mg/24 hours, and 6 mg/24 hours.¹⁷ Titration occurs weekly and is based on tolerability and clinical response. In clinical studies, the TDS was rotated daily (abdomen, thigh, hip, flank, shoulder, or upper arm).¹⁷ Food does not affect absorption and therefore can be applied without regard to meals. The rotigotine TDS should not be applied to the same application site more than once every 14 days and should not be placed on skin that is oily, irritated, or damaged, or where it will be rubbed by tight clothing. Skin irritation is common. Areas on the body with excessive hair should be shaved at least three days prior to application.

Selegiline: Patients with PD receiving carbidopa/levodopa therapy who demonstrate a diminishing response to treatment are candidates for selegiline therapy. The conventional form of selegiline (5 mg capsule or tablet) should be taken twice daily (5 mg BID with breakfast and lunch) or 10 mg QAM.³⁸ Most patients can easily swallow the tablet or capsule form of selegiline.

The ODT formulation of selegiline should be taken once daily prior to breakfast without any liquid.²¹ The tablet is not meant to be pushed through the foil, since that may damage the dosage form. The tablet is to be dissolved in the mouth without chewing or swallowing. Patients should specifically be instructed that nothing should be consumed orally for five minutes before or after administration.

Selegiline can be dispensed without elaborate restrictions placed on diet and concomitant drug use. However, consideration of patients’ intake of large amounts of tyramine, tryptophan, and/or caffeine should be monitored.³⁸ Hypertensive crisis has been reported with the swallowed use of selegiline, even at its recommended dose.³⁸ Selegiline should not be prescribed at doses greater than 10 mg/day or at doses greater than 2.5 mg/day for the ODT formulation due to the risks associated with nonselective inhibition of MAO.²¹

Rasagiline: Is offered as a small oral tablet that is consumed once daily. Labeling does include information on the tyramine reaction as well as CNS toxicity that may occur with concomitant use of tricyclic anti-depressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs).³⁶ These potential issues should be addressed in an informative manner without “scaring” patients. Being a once-daily dosage form does contribute to its convenience and contribute to enhanced adherence. All patients should be instructed not to exceed the recommended dosing limit.

CONCLUSION

As with any therapy it is critically important that patients are able to confidently and competently use/administer the prescribed medicine. Patients with PD often experience profound rigidity, manual dexterity challenges, and tremor that may complicate medication adherence. Therefore, when dispensing therapies it is paramount that patients are assessed to determine that they can realistically self-administer the prescribed therapy or at the very least that a caregiver is able to routinely provide this function for the patient.

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