The Omnicare HealthLine Page 1 of 7 References for all content available upon request ©2017 Omnicare

The Omnicare HealthLineMarch 2017

Focus on Seizure Disorder in Older Adults: Part 1 - by Carrie Allen

This focus article is part 1 of 2 dedicated to seizure disorder/epilepsy (SDE) in older adults. Part 1 will focus on the background information and general concepts related to SDE, while part 2 will focus on selected medications used to treat SDE, including side effects and monitoring. SDE is the 3rd most common neurologic disorder in older adults. While the incidence of having a first seizure is highest in infants and people ≥ 60-65 years old, the rate of SDE is 2-3 times greater in older adults compared to younger adults. For people over 80 years old, the rate is 3 times that of children. Given the rapid growth of the older adult population, the impact and burden of SDE will only increase. Therefore, awareness and understanding of the problem are important, especially in the long-term care (LTC) setting. While the estimates of SDE prevalence in LTC varies, as of the 4th quarter of 2016, the national total of nursing home residents (NHR) with SDE was reported as 11.7% by the Centers for Medicare and Medicaid Services (CMS).

However, SDE may go unrecognized due to the fact that older adults are more likely to have focal seizures (also known as partial seizures) and may display more subtle symptoms vs. overt convulsions. Older adults may present with confusion, memory loss, periods of staring, lack of awareness of their surroundings, syncope, visual or audio hallucinations, and anxiety. These symptoms can be mistaken for dementia, depression, or part of normal aging. Older adults often have multiple comorbid conditions, which can complicate identification of SDE. Once a resident is correctly diagnosed with SDE, it is important to become aware of how seizures typically display themselves in each resident (if known) and educate staff to monitor appropriately to avoid negative sequelae, such as falls. Common causes of SDE in older adults are listed in Table 1, below.

Table 1. Common Causes of SDE in Older Adults

• Prior stroke (most common cause)

• Metabolic disturbances (e.g., hyperglycemia, hypoglycemia*, hyponatremia*)

• Dementia

• Trauma (especially head injury)

• Medications (See Table 3)

• Infection (especially central nervous system infections)

• Tumors

• Uremia• Hepatic encephalopathyRed font, italics = most common causes of SDE in older adults*hypoglycemia and hyponatremia are of particular concern

Cerebrovascular events account for more than half of new-onset SDE in older adults. The risk varies by the type of stroke, but even transient ischemic attacks have been associated with an increased risk of SDE. Pre-existing dementia also increases the risk of

Inside This Issue1-3 Focus on Seizure

Disorder in Older Adults: Part 1

4 Entresto is Contraindicated with ACE Inhibitors

4 Increased Risk of Bladder Cancer with Pioglitazone-Containing Medications

5 Clinical Capsule: Considerations of Selected Herbal Supplements and Foods in Epilepsy

5 Regulatory Recap

6 New Drug Trulance™

6 New Generic Medications

7 HealthLine Quiz

“Cerebrovascular events account for more than half of new-onset SDE in

older adults.”

The Omnicare HealthLine 2

The Omnicare HealthLine Page 2 of 7 References for all content available upon request ©2017 Omnicare

post-stroke SDE. Though a prior stroke is the most common cause of new-onset SDE in older adults, a history of seizure activity is also associated with an increased risk of strokes in older adults. The risk of stroke is approximately 3 times higher in older adults who experience new-onset seizures. These patients should be assessed for cerebrovascular risk factors and receive appropriate stroke prevention therapy, as warranted.

Additionally, certain prescription medications (Table 3) and herbal supplements (Clinical Capsule, page 5) can lower the seizure threshold; meaning that these agents put people at increased risk for having a seizure with minimal stimulation to the brain. Risk factors for medication induced/provoked seizures are listed in Table 2.

Table 2. Risk Factors for Medication-Induced/Provoked Seizures Include:

• A history of seizures

• Head injury/falls

• Recent stroke

• Excessively high drug dosages or serum drug concentrations

• Concomitant use of agents that lower the threshold for seizures

• Increased pharmacodynamic sensitivity

• Pharmacokinetic changes

• Alcohol use/abuse

In addition, seizures, and other adverse events can be caused when there are abrupt dosage increases, decreases, and/or rapid discontinuation of antiepileptic drugs (AED). Withdrawal from alcohol, benzodiazepines and barbiturates may also result in seizures.

Table 3. Medications that May Increase the Risk of Seizures *†

Analgesics e.g., fentanyl, meperidine, tramadol

Antidepressants e.g., bupropion, tricyclic antidepressants, selective serotonin reuptake inhibitors, venlafaxine

Anti-infective agents e.g., carbapenems (e.g., imipenem), ß-lactams (i.e., high-dose penicillin, cephalosporins), fluoroquinolones, metronidazole, isoniazid, antifungals

Antineoplastic agents e.g., fluorouracil

Antipsychotics e.g., chlorpromazine, clozapine, fluphenazine, perphenazine, loxapine, olanzapine, thiothixene, thioridazine, quetiapine

Miscellaneous amphetamines, baclofen, contrast media, immunosuppressants (e.g., cyclosporine), lithium overdose, local anesthetics (e.g., lidocaine), theophylline, vaccines

*Table is not all-inclusive; † Via lowering the seizure threshold

The Omnicare HealthLine 3

The Omnicare HealthLine Page 3 of 7 References for all content available upon request ©2017 Omnicare

SDE in the Nursing Home

Research indicates that older adults with SDE in nursing homes may require a more careful evaluation of their care, with special consideration of the complexities that exist in this population.

NHR with SDE:

• have a higher risk of polypharmacy, increasing the risk of drug-drug and drug-disease interactions as well as changes in serum drug concentrations of certain AED.

• are more likely to be treated with older AED (e.g., phenytoin, phenobarbital, valproic acid).

• are less likely to have adequate serum drug concentration monitoring (a 2006 study found that only 42% of NHR were monitored correctly).

• are often simultaneously treated with more than one AED, without adequate rationale

These issues are echoed in findings of the 2014 Report by the Office of the Inspector General (OIG) “Adverse events in skilled nursing facilities: national incidence among Medicare beneficiaries”, and the subsequent recommendations by CMS and the OIG to surveyors in the Adverse Event Trigger Tool. In particular, the risks associated with phenytoin and valproic acid are highlighted in these documents. See the Regulatory Recap for excerpts from the Adverse Event Trigger Tool regarding phenytoin (page 5), and the November 2016 Regulatory Recap for information on valproic acid.

Additionally, studies in NHR have frequently found that AED listed on the medication record lack an indication for use, and that residents have no documented history of epilepsy or seizures witnessed by nursing staff. These studies typically excluded AED used for other indications, such as neuropathic pain or mood stabilization. Therefore, authors of these studies have recommended better documentation of the need to use AED and discontinuation of treatment, where possible.

Duration of Therapy

Many individuals with SDE require life-long therapy; however, some can safely discontinue treatment through a slow tapering process guided by their prescriber. Factors that influence AED discontinuation include the cause and type of SDE, medication tolerance, quality of life, response to medication, and seizure-free duration. When an AED is discontinued, it should generally be tapered off (over 2 - 6 months) to lower the risk of precipitating seizures.

Good prognostic indicators for considering AED discontinuation are:

Poor prognostic indicators for considering AED discontinuation are:

• A seizure free period of ≥ 2 years

• Successful treatment after the first seizure

• A normalized electroencephalogram (EEG)

• Partial seizures or multiple seizure types in the same patient

• Family history of seizures

• History of status epilepticus

• Multiple, concomitant AED required for seizure control

• Traumatic brain lesion visible on imaging

The Omnicare HealthLine 4

The Omnicare HealthLine Page 4 of 7 References for all content available upon request ©2017 Omnicare

Medication Safety by Yamini Shah

Entresto (sacubitril and valsartan) is Contraindicated with ACE Inhibitors A January 2017 Institute for Safe Medication Practices (ISMP) medication safety alert states that the US Food and Drug Administration (FDA) has received 55 cases reporting concomitant use of Entresto and an angiotensin-converting enzyme inhibitor (ACEI) with several cases describing serious outcomes. Eleven patients were hospitalized. Common adverse events reported from this drug interaction were angioedema, hyperkalemia, acute kidney injury, and hypotension.

Entresto is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB), indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction. Entresto is usually administered in conjunction with other heart failure therapies, in place of an ACEI (e.g., lisinopril, enalapril) or other ARB (e.g., losartan, valsartan).

Entresto is contraindicated with concomitant use of an ACE inhibitor because of increased risk of angioedema. Furthermore, the dual renin-angiotensin-aldosterone system (RAAS) blockade that occurs when valsartan is combined with ACE inhibitors increases the risk of hypotension, acute kidney injury, and hyperkalemia. Entresto should also be avoided with other ARBs to avoid duplicate ARB therapy. In general, also avoid combined use of Entresto and aliskiren (e.g., Tekturna, a medication for hypertension) because of the potential for adverse events resulting from dual blockade of the RAAS.

Conduct a thorough medication reconciliation, particularly during transitions of care, to ensure that patients who are prescribed Entresto have discontinued ACE inhibitors or ARBs and are not inadvertently re-started on these medications. If switching from an ACE inhibitor to Entresto (or from Entresto to an ACE inhibitor), allow a washout period of 36 hours between administration of the two drugs to decrease the risk of angioedema.

Entresto is contraindicated in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy. It should also be noted that Entresto has been associated with a higher rate of angioedema in Black patients compared with non-Black patients. The FDA is requiring the manufacturer to conduct an postmarketing study to evaluate the incidence of angioedema in Black patients treated with Entresto compared with a control drug.

Increased Risk of Bladder Cancer with Pioglitazone-Containing Medications by Allen Lefkovitz

Pioglitazone is approved for the treatment of type 2 diabetes in conjunction with diet and exercise. In December 2016 the FDA informed healthcare professionals that an updated review concluded that pioglitazone-containing products may be linked to an increased risk of bladder cancer. Initial alerts from the FDA occurred in both September 2010 and June 2011, which resulted in labeling changes to warn about the potential risk and required the manufacturer to continue long-term studies. Although further research produced inconsistent results, some data suggested that higher doses and/or longer duration of pioglitazone therapy was more common in those who developed bladder cancer.

As a result of the latest findings, healthcare professionals are advised to not use pioglitazone in patients with active bladder cancer, and to carefully consider the benefits versus the risks of therapy in those with a history of bladder cancer.

Pioglitazone-containing products include Actos (pioglitazone), Actoplus Met or Actoplus Met XR (pioglitazone / metformin), Duetact (pioglitazone / glimepiride), and Oseni (pioglitazone / alogliptin).Additional information is available at: http://www.fda.gov/Drugs/DrugSafety/ucm519616.htm.

Any patient using pioglitazone should be monitored closely for:• Blood or red color in

the urine;• New or worsening urge

to urinate; OR• Pain when urinating

If any of these signs or symptoms are detected, their prescriber should be notified immediately.

The Omnicare HealthLine 5

The Omnicare HealthLine Page 5 of 7 References for all content available upon request ©2017 Omnicare

The Clinical Capsule by Kori Hauersperger

Considerations of Selected Herbal Supplements and Foods in Epilepsy*

Antiepileptic Drug (AED) Increased risk of seizure†Increased risk of adverse

effects from AED‡Food and Enteral Feeding (EF)

Considerations

Carbamazepine (Tegretol) Danshen, St. John’s wort Chamomile, dong quai, echinacea, ginkgo, grapefruit, goldenseal, kava

EF slows absorption, hold EF at least 15 minutes before and after administration

Phenytoin (Dilantin) Ginkgo, St. John’s wort Cranberry, devil’s claw, dong quai, echinacea, ginkgo, milk thistle, soya

EF decreases (up to 80%) absorption, hold EF at least 1 hour before and after administration

Valproic Acid (Depakene)/Divalproex (Depakote)

Ginkgo, St. John’s wort Cranberry, devil’s claw, dong quai, echinacea, ginkgo, milk thistle, soya

Oxcarbazepine (Trileptal) Kava Take extended-release tablet (Oxtellar XR) on an empty stomach

Herbal supplements that may increase seizure risk

Borage, black cohosh, ephedra (Ma Huang), evening primrose oil, ginkgo, ginseng, green tea, kava, star anise, wormwood.

*Table not all inclusive, † via decreased AED concentration, ‡ via increased AED concentration

Regulatory Recap: CMS Adverse Event Trigger Tool: Toxicity Related to Phenytoin- by Carrie Allen

Phenytoin is a narrow therapeutic index medication, and is recognized by CMS as a common source of adverse drug events (ADE). The table* below is information on selected risk factors, signs and symptoms and specific documentation that surveyors look for in the facility related to phenytoin use.

Risk Factors for ADE¥ Signs and Symptoms Documentation

• Advanced age• Liver impairment• Kidney impairment

• Severe mental status or mood changes • Changes in gait, balance or coordination • Drowsiness • Loss of consciousness • Uncontrollable eye movements• Uncontrollable shaking/jerking motions • Slow/slurred speech • Nausea/vomiting • Decreased respirations

Is there evidence of a system to ensure: • therapeutic drug levels are drawn

routinely?• lab results are appropriately

communicated to the physician including when panic values are obtained?

• changes in condition are identified and assessed promptly, including an assessment of medications?

• extended-release formulations are delivered correctly (e.g., medications not crushed)?

Is there evidence in the medical record for clinical indication?

For residents with risk factors for drug toxicity, does the care plan reflect interdisciplinary monitoring for signs/symptoms of adverse drug reactions?

* This table is not all-inclusive; refer to the CMS Adverse Event Trigger Tool and relevant clinical references for more information. ¥ Multiple risk factors increase the risk of an ADE occurring.

The Omnicare HealthLine 6

The Omnicare HealthLine Page 6 of 7 References for all content available upon request ©2017 Omnicare

NEW Drug by Dave Pregizer

Trulance™ Tablets

Brand Name (Generic Name)

Trulance™ [troo’ lans]; (plecanatide) [ple KAN a tide]

How Supplied 3 mg tablets in bottles of 30 and aluminum foil unit dose blister pack of 30 tablets

Therapeutic Class Guanylate cyclase-C agonist

Approved Indication Treatment of chronic idiopathic constipation in adults

Usual Dosing 3 mg taken orally once daily with or without food

Select Drug Interactions None expected

Most Common Side Effects Diarrhea

Miscellaneous Boxed warning for risk of serious dehydration in pediatric patients. Contraindicated in patients < 6 years of age. May crush tablets and administer in either applesauce or with water. May administer with water via a nasogastric or gastric feeding tube.

Website http://www.trulance.com

NEW Generic Medications

Generic Name Brand Name Date Generic Available

No new generics since last month’s issue n/a n/a

The Omnicare HealthLine 7

The Omnicare HealthLine Page 7 of 7 References for all content available upon request ©2017 Omnicare

HealthLine Quiz- by Steve Law

1. Which statement about seizure disorder/epilepsy (SDE) in older adults is FALSE?a. SDE is the 3rd most common neurologic disorder

in older adults b. The rate of SDE is 2-3 times greater in older adults

compared to younger adultsc. Older adults are more likely to have grand mal

seizures than focal seizuresd. The symptoms of SDE in older adults may present

as confusion and/or memory loss

2. A common cause of SDE in older adults include:a. Dementiab. Post strokec. Trauma to the headd. Hypoglycemiae. All of the above

3. Which medication would LEAST likely increase the risk of seizures?a. Quetiapineb. Bupropionc. Tramadold. Acetaminophen

4. Which is considered a good prognostic indicator for considering antiepileptic drug (AED) discontinuation?a. Family history of of seizuresb. A normalized EEGc. Multiple, concomitant AEDs required for seizure

controld. A seizure free period of > 6 months

5. There is an increased risk of pancreatic cancer with pioglitazone-containing medications:a. True b. False

6. Echinacea may decrease the risk of adverse effects from phenytoin:a. True b. False

7. Which is FALSE about the new medication Trulance™ (plecanatide)?a. It is indicated for the treatment of chronic

idiopathic constipationb. It is contraindicated in patients less than 6 years

of agec. The most common side effect is diarrhead. It is only to be taken as needed for constipation

*Please note, the HealthLine Quiz is designed to help readers retain information that is relevant to their care setting. It is not an approved source of continuing education credits for healthcare professionals.

Editorial BoardAllen L. Lefkovitz, PharmD, BCGP, FASCP – Senior Editor

Carrie Allen, PharmD, BCGP, BCPS, BCPP, CCHP – Assistant Editor

Kori Hauersperger, PharmD, BCGP

Steve Law, PharmD, BCGP

Terry O’Shea, PharmD, BCGP

David Pregizer, RPh

Yamini Shah, PharmD

Contributing Authors for This IssueAllen L. Lefkovitz, PharmD, BCGP, FASCP Senior Manager, Clinical Education - LTC, CVS Health

Yamini Shah, PharmD Clinical Pharmacist, Clinical Development, CVS/caremark

Kori Hauersperger, PharmD, BCGP OSC2OR Clinical and Drug Information Analyst, CVS Health

Carrie Allen, PharmD, BCGP, BCPS, BCPP, CCHP Clinical Advisor, CVS Health

David Pregizer, RPh, Consultant Pharmacist, HCR-Manorcare

Steve Law, PharmD, BCGP Clinical Services Manager for Indiana; Omnicare Pharmacies in Indiana

Answers to the HealthLine Quiz: 1) C 2) E 3) D 4) B 5) B 6) B 7) D