PHARM NOTES. Narcolepsy: Why Can t I Stay Awake? A Publication of Neil Medical Group, The Leading Pharmacy Provider in the Southeast

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1 Volume 18, Issue 3 May/June 2015 PHARM NOTES A Publication of Neil Medical Group, The Leading Pharmacy Provider in the Southeast As the face of long-term care changes and medical science becomes better at diagnosis and treatment, we have begun to see conditions in our residents that were not present 10 years ago. One such condition is narcolepsy. This brings to mind the image of someone falling asleep midsentence, but narcolepsy involves much more. Narcolepsy is a complex chronic neurologic disorder that involves a disruption of sleep/wake cycles as well as muscle weakness, and at times, hallucinations and sleep paralysis. This condition affects males and females equally and usually appears during adolescence or young adulthood, but can occur at any age. It is not rare, but is often underdiagnosed or misdiagnosed. There is an average of 15 years between onset of symptoms and correct diagnosis. Narcolepsy with cataplexy is thought to affect 1 in 3,000 Americans, while narcolepsy without cataplexy affects many more. Although the exact cause is unknown, it is believed by most scientists to be due to a genetic mutation. Narcolepsy is not due to mental illness or other psychological problems. Inside this issue: Cover Story: Narcolepsy Sodium Glucose Co-Transporter 2 Inhibitors for Type 2 Diabetes Conclusion: Narcolepsy Trending Now: Vitamin D Controversial Use of Niacin & the Treatment of Cholesterol Neil Medical Contact Information Narcolepsy: Why Can t I Stay Awake? For most adults, an average night s sleep is about 8 hours, which is composed of 4 to 6 sleep cycles. A sleep cycle is defined by a segment of non-rapid eye movement (NREM) sleep followed by a period of rapid eye movement (REM) sleep. NREM sleep can then be divided into deepening stages of sleep. REM sleep involves dreaming and a temporary muscle paralysis. Normally, the first REM sleep begins after about an hour and a half of NREM sleep. For someone with narcolepsy, REM sleep may begin within a few minutes of falling asleep. Therefore, narcoleptics do not receive the amount of restorative NREM sleep that normal adults do. This leads to excessive daytime sleepiness (ESD) and daytime naps that can occur without warning and are sometimes physically irresistible. They are not oversleeping. In fact, narcolepsy causes a constant state of sleep deprivation. The classic symptoms of narcolepsy are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness. Only percent of narcoleptics experience all four symptoms. Excessive day-time sleepiness is the most common symptom and often begins mildly. This leads to misdiagnoses such as insomnia, poor sleep hygiene, drug abuse or even laziness. ESD often has a negative impact on academic and job performance, as well as friendships and other social aspects. Other symptoms may begin to appear months or even years after the onset of the daytime naps. Cataplexy is an episodic sudden loss of muscle tone, ranging from slight weakness (limpness in the neck or knees, sagging facial muscles) to full body collapse. These episodes can last from a few seconds to a few minutes, and the narcoleptic is conscious throughout the entire event. Sometimes cataplexy can resemble See page 4

2 PHARM NOTES PHARM NOTES Sodium-Glucose Co-Transporter 2 Inhibitors for Type 2 Diabetes Sodium-Glucose Co-Transporter 2 Inhibitors, otherwise known as SGLT2 inhibitors or flozins are the first in a new class of oral medications for type 2 diabetes. Sodium-glucose co-transporter 2 is the transporter responsible for reabsorbing most of the glucose filtered by the kidneys (less than 1% of glucose is excreted in the urine). These medications are unique in that they inhibit sodium-glucose co-transporter 2 from getting in the kidneys. This allows for more glucose to be excreted in the urine instead of being reabsorbed into the kidneys; therefore decreasing plasma glucose. The SGLT2 inhibitors should be used along with diet and exercise to lower blood sugar in Type 2 Diabetes. They are not to be used in Type 1 Diabetes or in Diabetic Ketoacidosis (increased ketones in the urine or blood). They usually can reduce the HgbA1c value by 0.7%-1% and rarely cause hypoglycemia. There are currently three US drugs in this class which hit the market in 2013 and 2014: Invokana (canagliflozin), Farxiga (dapagliflozin), and Jardiance (empagliflozin). Invokana (canagliflozin) is the first SGLT2 inhibitor and was FDA approved in the US in March of Invokana (canagliflozin) is available in a 100mg and 300mg tablet. The recommended starting dose is 100mg daily 30 minutes before the first meal of the day. If tolerated, the dose can be increased to 300mg daily as long as the patient does not have moderate to severe renal impairment (defined as a estimated glomerular filtration rate (egfr ) of < 60mL/min/1.73m 2 ). It should not be initiated in patients with a egfr < 45mL/min/1.73m 2 and is not recommended in patients with severe hepatic impairment. Invokana (canagliflozin) could reduce HgbA1c by 1% when used alone. It can also be used as add-on combination therapy with other diabetic medications such as metformin, glimepiride, sitagliptin, thiazolidinediones, and insulin. It may lower blood pressure and cause moderate weight loss. Unfortunately though, the extra glucose in the urine could cause increased genital yeast infections and urinary tract infections. It also has a diuretic effect that could increase urination and lead to dehydration. There may be cardiovascular risks associated with Invokana (canagliflozin) since it could increase the risk of stroke and can increase the LDL (bad cholesterol) by 4-8%. Monitoring for hyperkalemia (high amounts of potassium in the blood) should be done especially in patients with mild renal impairment or concurrently taking medications that can increase potassium (ACE-inhibitors, Angiotensin Receptor Blockers, Potassium Sparing Diuretics, etc.). Drug Interactions: Enzyme inducers such as phenobarbital, rifampin, phenytoin, and ritonavir when used concurrently with Invokana (canagliflozin) may decrease its effectiveness and the 300mg dose (if egfr equal or greater than 60mL/ min/1.73m 2 ) may be needed to reach glycemic control. Invokana (canagliflozin) may increase the concentration of digoxin; therefore digoxin levels should be monitored. The cost of Invokana is around $11 per day. Page 2

3 Neil Medical Group: Pharmacy Services Division (dapagliflozin). Similar to Invokana (canagliflozin), Farxiga (dapagliflozin) costs around $11 a day. Jardiance (empagliflozin) is the third SGLT2 Inhibitor approved in the US in August It is available in a 10mg and 25mg tablet. The recommended starting dose is 10mg once daily in the morning with or without food and can be increased to 25mg once daily if additional glycemic control is needed. Jardiance (empagliflozin) should not be initiated in patients with an egfr <45mL/min/1.73m 2. Jardiance (empagliflozin) can be used as monotherapy or as add-on combination therapy with other diabetic medications such as metformin, sulfonylureas, pioglitazone, and insulin. As with the other two SGLT2 Inhibitors, Jardiance (empagliflozin) could lower blood pressure, increase LDL, increase urination, and cause increased urinary tract infections and genital yeast infections. No significant drug interactions have been reported with Jardiance (empagliflozin). Its cost is estimated to be around $10 a day. Farxiga (dapagliflozin) was FDA approved in the US in January of Farxiga (dapagliflozin) is available in a 5mg and 10mg tablet. The recommended starting dose is 5mg once daily in the morning with or without food and can be increased to 10mg once daily if additional glycemic control is needed. Renal function should be assessed before initiating and it should not be initiated in patients with moderate to severe renal impairment (egfr persistently < 60mL/ min/1.73m 2 ). Farxiga (dapagliflozin) can be used as monotherapy or as add-on combination therapy with other diabetic medications (i.e. metformin, sulfonylureas, thiazolidinediones, and insulin). Like Invokana (canagliflozin), it may reduce HgbA1c by 1%, lower blood pressure, decrease weight (by 4-7 pounds), slightly increase LDL cholesterol, cause increased genital yeast infections and urinary tract infections, and increase urination which could lead to dehydration. One difference with Farxiga (dapagliflozin) is the potential for a small increased risk of bladder cancer and thus should not be used in patients with active bladder cancer. No significant drug interactions have been reported with Farxiga Page 3 Advantages of using an SGLT2 Inhibitor include beneficial effects on blood pressure and weight and when used as monotherapy they have a low incidence of hypoglycemia. Disadvantages include the possible increased LDL, increased rate of yeast infections and urinary tract infections, and possible dehydration from increased urination. These side effects, costs, and the inability to use in renal impairment should be considered before starting SGLT2 Inhibitors as first-line or second-line medications treating Type 2 Diabetes. The elderly may be especially prone to their adverse effects (i.e. falls due to increased urination and lower blood pressure, decreasing the already impaired renal function of elderly, UTI s, etc.). While these agents appear to have similar effects on reducing HgbA1c as other oral agents and until we know more about their long-term safety, consider using SGLT2 Inhibitors as a second- or third-line agent along with gliptins, glitazones, GLP-1 agonists, sulfonylureas, insulin, or metformin. Article by Heather Eaton-Erskine, Pharm D, CGP, FASCP

4 PHARM NOTES Narcolepsy: Why Can t I Stay Awake?...continued from page 1 epileptic seizures. Vision is usually impaired, and speech is slurred. But unlike seizures, hearing and awareness remain normal. Because cataplexy is often triggered by strong emotional responses, it can have a tremendous social impact on the person. Anxiety, fear, and avoidance of people and situations that invoke emotional responses are common in those who suffer from cataplexy. Sleep paralysis is the inability to move during waking up or falling asleep. This is very similar to the paralysis experienced during normal REM sleep. It also can last from seconds to minutes and the person remains conscious. This can be frightening to the person, but it does not result in permanent damage. Hypnagogic hallucinations are vivid, dreamlike experiences that occur when a person is dozing or falling asleep and are often frightening. Hallucinations can also occur when waking. Although any of the senses can be involved, these hallucinations are mostly visual in nature. Other symptoms that can be associated with narcolepsy are extended periods of insomnia and automatic behaviors. This means that a person functions normally during sleep episodes (dressing, talking, putting things away) but later has no memory that these episodes occurred. Narcoleptics can experience any of these symptoms and in varying degrees. Diagnosis is usually difficult because not all patients present with the same symptoms. Three tests are commonly used to diagnose narcolepsy: the polysomnogram, the multiple sleep latency test (MSLT) and the Epworth Sleepiness Scale. These tests are generally administered at a sleep center. The polysomnogram involves recording of sleep brain waves as well as nerve and muscle functions during nighttime sleep. The Epworth Sleepiness Scale is a brief questionnaire used to determine the likelihood of the presence of a sleep disorder. The multiple sleep latency test involves the person being given a chance to sleep every 2 hours during normal wake times. This test measures the amount of time it takes to enter REM sleep as well as heart and respiratory rates and nerve activity in the muscle. Although narcolepsy cannot be cured, the symptoms can be treated with medications and lifestyle modifications. Since each individual case of narcolepsy involves different symptoms, treatment is tailored to the individual. Multiple dose and medication changes are usually needed. Although symptoms can be reduced, the complete control of them is seldom possible. Central nervous stimulants make up the main treatment of excessive day-time sedation. Medications used include amphetamines, methylphenidate, atomoxetine (Straterra), modafinil (Provigil) and armodafinil (Nuvigil). Planned regular short naps can also help improve ESD. Tricyclic antidepressants such as clomipramine and imipramine are often used to treat cataplexy, as well as venlafaxine (Effexor). This is due to the drugs interference with REM sleep. The medication Xyrem (sodium oxybate) is approved by the FDA for the treatment of cataplexy associated with narcolepsy and for ESD associated with narcolepsy. It is a strong sedative that induces sleep and reduces the symptoms of ESD and cataplexy. Due to safety concerns, its distribution is tightly restricted, and the patient must be in the bed prepared for sleep before the medication is administered. Other pharmacological agents that have been tried include histamine agonists, clarithromycin (due to its GABA antagonism), and L-carnitine. There is research being conducted on hypocretin receptor agonists. Low levels of hypocretin, found in the spinal fluid, have been associated with narcolepsy. Although medications are available to help with symptoms, no currently marketed medication corrects the cause of narcolepsy. That is why lifestyle modifications must also be employed by narcoleptics. These changes involve reducing stress, limiting stimulant intake (such as caffeine and nicotine), and more exercise especially for those who are overweight or experience sleep apnea. Scheduling short naps throughout the day can also be beneficial; these naps should not serve as a replacement for nighttime sleep though. Some narcoleptics have a nocturnal body clock. In these individuals, it is often helpful for them to find an occupation that fits this clock, such as working night shift. Since symptoms change over the course of a patient s lifetime, medications and lifestyle changes will also need to change. Open communication between the patient, family and prescriber is a must. Page 4 Article by Lori Poplin, Pharm D

5 Description Vitamin D is a fat-soluble vitamin and has two primary forms: cholecalciferol (Vitamin D3) and ergocalciferol (Vitamin D2). In the skin, under the influence of ultraviolet radiation from sun exposure, vitamin D precursors are converted to vitamin D3, which is metabolized by the liver to 25 -hydroxyvitamin D3 [25 (OH) D3]. In the kidneys, 25 (OH) D3 is then converted to 1,25- hydroxyvitamin D3 [1,25 (OH)D3], or calcitriol, the biologically active form of vitamin D. Vitamin D is responsible for appropriate calcium and phosphate balance. Activated vitamin D increases intestinal absorption of calcium and promotes renal reabsorption of calcium. Indications Vitamin D is approved for the treatment of rickets, vitamin D deficiency, and as a nutritional supplement. Off-label uses include osteoporosis, renal osteo-dystrophy, and hypo-parathyroidism. Sources Sun exposure is the predominant source of vitamin D. Depending on the latitude, minutes of direct daily spring/summer/fall midday sun exposure usually provides sufficient amounts of vitamin D. Food sources of vitamin D include fortified milk and dairy products, fortified cereals, fish liver oils, fatty fish, and eggs. Multivitamin products and some calcium supplements may also provide vitamin D. Neil Medical Group: Pharmacy Services Division Trending Now: Vitamin D Administration Vitamin D may be taken without regard to food but is better absorbed when taken with foods containing fat. The onset of action following oral administration is hours, with maximal effects usually observed in 4 weeks. Recommended Daily Allowance The Food and Nutrition Board of the National Academy of Sciences established adequate daily vitamin D intake levels of 400 international units (IU) for those aged and 600 IU for men and women over age 70. The US recommended dietary allowance (RDA) for adults is 600 IU of vitamin D daily. The RDA goes up to 800 IU a day for those older than age 70. Page 5 Vitamin D deficiency Vitamin D deficiency is defined as 25(OH)D concentrations less than 20 ng/ml and vitamin D insufficiency as 25(OH)D concentrations of ng/ml. The overall incidence of vitamin D deficiency in the United States is reported to be 41.6%. The prevalence is highest in people with dark skin and adults older than age 65. These groups may have limited sunlight exposure and insufficient amounts of vitamin D in their diet and may require supplementation. Symptoms of vitamin D deficiency may include tiredness and general aches and pains. There may be no symptoms at all in some people. Severe vitamin D deficiency can cause rickets in children and osteomalacia in adults, both resulting in soft, thin, and brittle bones. Vitamin D deficiency is an established risk factor for osteoporosis, falls and fractures in the elderly. Vitamin D deficiency has also been linked to other conditions, including cancer, asthma, diabetes, hypertension, depression, Alzheimer s disease and autoimmune diseases like multiple sclerosis and Crohn s disease. Continued on page 6

6 PHARM NOTES Trending Now: Vitamin D. continued from page 5 Dosage for Vitamin D deficiency Patient specific dosing can be determined by measuring 25-hydroxyvitamin D [25(OH)D] serum concentrations, which represent all sources of vitamin D and kidneys. These factors make the elderly especially susceptible to vitamin D deficiency. One study of 824 elderly people older than age 70 revealed that 36% of men and 47% of women had wintertime serum 25-hydroxyvitamin D 3 [25(OH)D 3 ] concentrations less than 30 ng/ml. Other studies suggest the incidence of vitamin D deficiency in the elderly is more than 50 percent. (sunlight, dietary, or supplements). For treatment of vitamin D deficiency, usual doses are 1000 to 2000 IU by mouth once daily. Doses up to 50,000 IU once weekly for 6 to 8 weeks, and then monthly have also been administered. Dosages should be individualized and dependent on the clinical condition of the resident, serum 25(OH)D concentrations, and serum calcium concentrations. Residents with gastrointestinal or liver diseases such as cystic fibrosis, celiac disease, gastric or small bowel resection, may require higher doses. Renal Dosing Patients with renal disease may be at increased risk for vitamin D-induced hypercalcemia. The National Kidney Foundation recommends the use of a vitamin D analog for patients with stage 3 or higher kidney disease. Drug Interactions Phenytoin, phenobarbital, primidone, and rifampin are known to interfere with vitamin D metabolism. Residents receiving these medications may require higher than usual doses of vitamin D. Cholestyramine and Colestipol inhibit vitamin D absorption. If used concurrently, administration of these agents and vitamin D should be separated by the longest interval possible. Falls and Fractures An elderly person over the age of 70 produces less than 30% of the vitamin D of a young person with the same sun exposure, in part due to reduced skin thickness. In addition, the elderly may have decreased dietary intake, impaired intestinal absorption, and decreased metabolism and conversion in the liver Page 6 Studies link low vitamin D levels with an increased risk of fractures in older adults. Vitamin D supplementation may prevent such fractures if given in sufficient dosages. In twelve fracture prevention trials including more than 40,000 elderly people, researchers found that intakes of vitamin D supplements of about 800 IU per day reduced hip and non-spine fractures by 20 percent, while lower intakes (400 IU or less) failed to offer any fracture prevention benefit. Correcting vitamin D deficiency may also increase muscle strength, which in turn helps to prevent falls, a common problem resulting in substantial disability and death in older people. A combined analysis of multiple studies found that taking 700 to 1,000 IU of vitamin D per day lowered the risk of falls by 19 percent. Toxicity In general, the use of vitamin D supplements at recommended dosages is not associated with serious adverse reactions. Vitamin D toxicity is usually associated with long term doses of 10,000 to 40,000 IU per day. Symptoms of vitamin D toxicity can become apparent within 4 weeks of continual excessive ingestion. Reports of vitamin D toxicity are often the result of administration errors when weekly doses of vitamin D are given on a daily basis by mistake. Symptoms of vitamin D toxicity and resultant hypercalcemia may include nausea/vomiting, constipation, loss of appetite, increased thirst, increased urinary frequency, mental/mood changes or irritability, headache, unusual fatigue or tiredness, and arrhythmias. Summary Vitamin D deficiency is extremely prevalent among the elderly and is associated with a higher risk of falls and fractures. Treatment with vitamin D has been demonstrated to reduce these risks and may be beneficial in other disease states as well. Vitamin D is well tolerated with little risk for toxicity at usual doses. Article by Russell Carroll, RPh Consultant Pharmacist, Neil Medical Group

7 Controversial Use of Niacin & the Treatment of Cholesterol Traditionally, the use of niacin has been widely accepted as a treatment option for hyperlipidemia. It is found naturally in several foods that we consume and is included in some multivitamins (vitamin B3), but a much higher dose has been used for the purpose of lowering cholesterol. It works through partially inhibiting the release of free fatty acid from adipose tissue, causing increased lipoprotein lipase activity, and decreasing the amount of triglycerides from the body by about 28%. It helps lower the amount of circulating LDL cholesterol by around 15%, and has been commonly used to help increase levels of HDL cholesterol. The 2013 ACC/AHA Blood Cholesterol guidelines recommend the use of statins for patients with moderate to severe atherothrombotic risk as the first-line treatment for lowering LDL cholesterol and long-term protection for the heart. The use of niacin and other lipid lowering medications are only discussed for patients in whom the statin therapy has not provided enough LDL lowering benefits. The guidelines suggest that options be used which are supported by randomized controlled trials in terms of efficacy and safety. The Coronary Drug Project was the first study to show the effect of niacin on the incidence of myocardial infarction and all-cause mortality compared to placebo. It was seen that niacin lowered the rate of MI by around 27%, but reduction in all-cause mortality was not seen until 9 years after the trial was complete. In this follow-up, niacin was shown to have reduced all-cause mortality by around 11%. This trial was completed between 1966 and From there, an extendedrelease formulation of niacin was introduced, which had fewer side effects such as the flushing that is always associated with niacin use. In 2011, the AIM-HIGH trial evaluated the use of niacin with simvastatin against placebo with simvastatin for outcomes of death from CHD, nonfatal MI, stroke, and hospitalization for acute coronary syndrome. This trial failed to show the benefit of niacin added on to statin therapy for raising HDL levels, and was subsequently stopped early after only 3 years of follow-up because of lack of efficacy. There was no significant difference in the primary outcomes between the patients receiving niacin ( mg daily) and those receiving placebo. The trial also found a higher number of ischemic strokes in the patients who were receiving the niacin. \ Page 7 Neil Medical Group: Pharmacy Services Division Additionally, a study originally intended to be completed in the year 2016, the Heart Protection Study 2 - Treatment of HDL to reduce the incidence of vascular events (HPS2- THRIVE) trial, randomized patients to receive simvastatin with either niacin-laropiprant or placebo. Similar to the AIM- HIGH trial, early results from the HPS2-THRIVE trial showed no significant difference between niacin and placebo for the primary endpoints of nonfatal MI or coronary death, stroke, and revascularization. This trial was recently published in JAMA, and results still showed no clinical benefit of niacin. Furthermore, the patients randomized to receive niacin experienced many more adverse effects such as serious stomach upset, infections, skin problems, and bleeding, making it an unpopular choice for prescribers and patients alike. These two trials show that while niacin may raise HDL cholesterol and be prescribed for this reason, it does not improve overall clinical outcomes for patients already on statin therapy. Similarly, it does not seem to provide additional benefit to a statin medication, but as seen in the first study, the Coronary Drug Project, it can still be used to lower LDL cholesterol. At this time it has been determined that the use of niacin in this goal of therapy will be determined through further studies. The current evidence, however, points to the idea that it does not help improve clinical outcomes and is not useful when combined with a statin, the recommended therapy by the most recent guidelines. Niacin should be considered only in patients who cannot tolerate statins but who could benefit from lowering of LDL cholesterol. Article by Abby Miller, Pharm D Candidate

8 PHARM NOTES Kinston Pharmacy 2545 Jetport Road Kinston, NC Phone Louisville Pharmacy East Gate Parkway Suite 105 Louisville, KY Phone Mooresville Pharmacy 947 N. Main Street Mooresville, NC Phone Pharm Notes is a bimonthly publication by Neil Medical Group Pharmacy Services Division. Articles from all health care disciplines pertinent to long-term care are welcome. References for articles in Pharm Notes are available upon request. Your comments and suggestions are appreciated. Contact: Cathy Fuquay (cathyf@neilmedical.com) Thank you for allowing Neil Medical Group to partner with you in the care of your residents! To all the Pharm Notes Family,...a note from the Editor I was in a facility recently when I heard the nurs- es talking about a newly admitted resident. The family had apparently loaded her up in the car for the 90 minute drive, telling her they were taking her to a carnival. Once at the facility, the soonto-be-resident realized there WAS no carnival...but the family assured her she was only there for a little therapy. The somewhat bewildered resident was becoming increasingly agitated, leaving the staff with a difficult behavior problem and a family that was now hard to reach by phone. The resident approached me, asking if I could possibly give her a ride back to Hillsborough, stating Don t get me wrong honey.this is a really nice place. But I think next year, I ll take me a different vacation! I am sure all of you have a multitude of different family stories that you can share.from the ones that are in your face every day, micro-managing Mama s care, to the ones who won t even show up on a holiday. Just a thought...that while we deal with residents with very complex medical problems...they often come with complex social and family issues as well. Till next time, Cathy Fuquay Pharm Notes Editor