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The contents of this blog contain topics relevant to end of life care written by our own hospice clinical pharmacists. Continue to check this site regularly for the newest post or subscribe to the RSS feed below.
Delta Campus Pharmacy Student

Management of Pruritus from a Hepatic Etiology

Pruritus is a common symptom experienced by many patients in palliative and hospice care which can dramatically affect a patient’s comfort and quality of life even though it is not the most prevalent symptom such as pain or dyspnea. While the complete pathology of all causes of pruritus is not yet completely understood, the itching sensation is best relieved by properly treating the underlying etiology if it is known.1

Pruritus has been associated with both malignant disease as well as nonmalignant chronic diseases such as renal, thyroid, and hepatic disease. A Cochrane Review found that about one third of all patients with end stage renal disease not on hemodialysis and 70%-80% of patients receiving hemodialysis experience significant pruritus. The same review found that nearly 100% of patients with biliary cirrhosis had a cholestatic pruritus.1 According to the guidelines from the American Association for the Study of Liver Diseases, cholestatic pruritus is often times the initial symptom in half of the patients with biliary cirrhosis.1,2

There exist many therapies that could be used to treat pruritus in general such as antihistamines like hydroxyzine, opioid receptor antagonists similar to naloxone, direct serotonergic agents such as ondansetron, selective serotonin reuptake inhibitors (SSRI’s) such as paroxetine and sertraline, antiepileptics such as gabapentin, and the antibiotic rifampicin. Most of these agents have different mechanisms against pruritus which may be more or less effective given certain patient factors. The American Association for the Study of Liver Diseases guidelines for primary biliary cirrhosis recommend several agents for the treatment of cholestatic pruritus:1,2

Bile Acid Sequestrants: The first line therapy recommendation is to use a bile acid sequestrant agent. Bile acid sequestrants are approved for the treatment of dyslipidemias by functioning as a resin that traps cholesterol and other acids from bile in the GI tract which can allow passing of these substances out through the GI tract instead of being systemically reabsorbed. It is believed that forcing the elimination of these bile acids will also relieve cholestatic pruritus. The bile acid sequestrant of choice is cholestyramine dosed at 4 grams per dose with a maximum dose of 16 grams daily. [The other currently available bile acid sequestrants, colesevelam, and colestipol, have not been studied and currently contain no recommendations for the treatment of pruritis.2] Complications of bile acid sequestrant therapy include gastrointestinal disturbances (constipation, loose stool, cramping, excessive flatus, etc.) and the prevention of drug absorption in the GI tract since acidic drugs will also be trapped by the resin.1,2 It is recommended to separate the administration of a bile acid sequestrant from other medications by 2-4 hours.

Antidepressants: It is believed that serotoninergic activity contributes to signal transduction of pruritus. Several antidepressants have been tested including paroxetine, doxepin, and sertraline. Sertraline 75 mg to 100 mg is the preferred therapy for cholestatic pruritus according to the guidelines by the American Association for the Study of Liver Disease.2 General pruritus relief has been noticed with paroxetine 5 mg to 10 mg at night for multiple etiologies including hepatic and renal disease.1 Doxepin appears to be effective at doses of 25 mg daily, however tricyclic antidepressants tend to have anticholinergic activity which can cause adverse effects in older patients and should be avoided unless necessary.1,3 Relief of pruritus by antidepressants is usually seen in 24 to 48 hours, much sooner than the antidepressant effects of these agents.1 Ondansetron has been studied as a direct acting serotonergic agent, however it has only shown mild to no benefit in clinical trials.1,2

Rifampicin: Rifampicin is an antibiotic and hepatic enzyme inducer shown in several trials and meta-analyses to relieve hepatic pruritus. Recommended dose is 150-300 mg twice daily depending on serum bilirubin (300 mg for bilirubin less than 3 mg/dL and 150 mg for bilirubin 3 mg/dL or higher). Complications of therapy include drug induced hepatotoxicity or renal impairment and hepatic ennzyme induction which could decrease the efficacy of other medication therapies.1,2 Due to the risks for hepatotoxicity and nephrotoxicity, liver and renal function tests will need to be continually monitored suggesting that therapy with rifampicin should be held in reserve for when benefit outweighs risk in end-of-life care.

Opioid Antagonists: While there is strong evidence for the use of the opioid antagonists naloxone or naltrexone, these therapies are usually inappropriate in hospice care since these agents will counter the analgesic activity of other opioids used in the treatment of chronic pain and could also induce opiate withdrawal.1,2 In addition, naltrexone has a rare potential for causing hepatotoxicity which will require monitoring liver function. The recommended dose of naltrexone is 50 mg by mouth daily, however naltrexone is hepatically eliminated and will accumulate in decompensated and end-stage liver disease requiring that the dose of naltrexone be decreased.2 Due to the monitoring burden and the risk of counteracting chronic opiate activity, it is recommended only to use naltrexone when the patient is not taking opioid analgesics and benefit outweighs risk of decreasing liver function.

Antihistamines: The mechanism of antihistaminergic compounds is reliant on non-specific antipruritic effects with little treatment to the direct etiology of hepatic pruritus.2 Complications that occur are the risk of confusion, sedation, exacerbation of dementias, and increase in fall potential for patients that are still ambulatory from the anticholinergic activity of the antihistamine agents similar to diphenhydramine and hydroxyzine.3 It is recommended to use these only when other systemic therapies have failed or are inappropriate.

Phenobarbital: Phenobarbital was once utilized as a therapy for hepatic pruritus, however its use is limited in modern practice due to risks of severe sedation and hepatic enzyme induction.2,3

There is a large variety of medication therapies that can be used to treat pruritus from a hepatic etiology. Topical therapies such as the counter-irritants capsacin or menthol have some limited efficacy1 but the application area may become so large in advanced disease that their use becomes impractical. While conventional therapies of systemic antihistamines may be moderately effective, they have the potential for undesirable adverse events and may be less effective or efficient than an etiology specific agent. Cholestyramine or sertraline may not be the first agent that comes to mind when a patient complains of an itch, however these less conventional therapies have become a mainstay for the treatment of pruritus in advanced hepatic disease. In addition, the use of these alternate therapies broadens the spectrum of drugs that could be used for multiple pharmacological effects and can afford a patient specific drug selection.


Submitted by: James R. Thomas, PharmD., BS Hospice Clinical Pharmacist and Pharmacy Resident at Delta Care Rx


References:

1. Xander, C., Meerpohl, J. J., Galandi, D., Buroh, S., Schwarzer, G., Antes, G., & Becker, G. (2013). Pharmacological interventions for pruritus in adult palliative care patients. The Cochrane Database of Systematic Reviews, 6(6), CD008320. doi:10.1002/14651858.CD008320.pub2

2. Lindor, K. D., Gershwin, M. E., Poupon, R., Kaplan, M., Bergasa, N. V., & Heathcote, E. J. (2009). Primary biliary cirrhosis. Hepatology. doi:10.1002/hep.22906

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Lori Osso-Connor, PharmD, CGP

Role of Warfarin in Hospice and Palliative Care

Patients who make the hospice choice have opted for comfort measures and are no longer seeking life sustaining treatment. However, as hospice professionals encounter daily, many patients are admitted on medications that are considered treatment and are used for curative measures and not palliative measures.

The risk for thromboembolism in hospice and palliative care patients increases due to advanced age and diagnoses such as cancer or cardiomyopathy. Warfarin (Coumadin®) is indicated as treatment to prevent clotting in atrial fibrillation, thromboembolic disease, and artificial heart valves. It is a medication that poses a clinical challenge on whether to continue or discontinue when the patient becomes hospice appropriate. Warfarin’s mechanism of action is to inhibit Vitamin K epoxide reductase which decreases the Vitamin K in the body and decreases clotting. While warfarin is typically indicated as treatment, it could be argued that it is used in hospice and palliative care to provide comfort by reducing the risk of pain and swelling in the extremities due to DVT, unilateral weakness, or paralysis related to stroke.

However, there are several arguments that can be made to support the discontinuation of warfarin in hospice and palliative care. Some issues to consider include:

• The use of warfarin requires PT/INR lab work to ensure therapeutic efficacy. Studies have shown that hospice and palliative care patients require more frequent INR monitoring. These blood draws may be undesirable to the patient and or caregivers at this point in care. Additionally, poor venous access may make obtaining the blood difficult.

• Warfarin is a medication that has many drug-drug interactions including many antibiotics and drug-dietary interactions which could pose unnecessary complications to the patient. Some examples of drug–drug interactions with warfarin in which the anticoagulant effect is increased include levofloxacin (Levaquin ®), sulfamethoxazole/ trimethoprim (Bactrim ®), prednisone, and NSAIDS. In addition, Vitamin K rich foods may decrease the effects of warfarin. Therefore, it is most important to keep a consistent type diet.

• As intake declines or is erratic, the dietary vitamin K may fluctuate which could increase the risk of a bleed or clot.

• Nausea and vomiting could impact the medication adherence which may alter INR due to drug interactions.

• When a dose is changed, it takes 5-6 days to take full effect. If the PT/INR is not carefully managed, it leads to additional increases or decreases in the dose and a myriad of additional blood draws.

• The risk of an intracranial hemorrhage in a debilitated ambulatory patient who may fall is greater than the benefit in preventing a stroke.3

• The risk of a GI hemorrhage is about 8%.1

• The 1-year risk of stroke in atrial fibrillation is 2% in patients treated with warfarin and 4% in those untreated.1

Do the benefits of continuing outweigh the risks? Some factors to consider when facing this decision include: indication, prognosis, bleeding risk, thrombosis risk, nutritional status, appropriate monitoring, medication adherence, medication changes, and patient/family preferences. It is also important to consider whether a new clot will impair the patient’s function or quality of life. As one can see, the choice to discontinue warfarin is a difficult one and is not always clear cut. The risks verse the benefits in each patient must be assessed in accordance with the family and patient’s goals. This individualized approach will help the hospice care professional determine whether the benefits outweigh the risks to the patient and make an appropriate choice.


References:

1. Allen, Richard. “10 Drugs to Reconsider When a Patient Enrolls in Hospice.” NHPCO Newsline(2014): 5.

2. Hill, Robin, Kerri Martinez, Thomas Delate, and Daniel Witt. “A Descriptive Evaluation of Warfarin Use in Patients Receiving Hospice or Palliative Care Services.” Journal of Thrombosis and Thrombolysis 27.3 (2008): 334-39.

3. Von Gunten, Charles, David Weissman, and Janet Abraham. “Fast Fact #278 Warfarin and Palliative Care.” #278 Warfarin And Palliative Care. Web. 26 Feb. 2015

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Char Cole, PharmD, CGP

Impact of Bariatric Surgery on End of Life Care Symptom Management

Obesity is a growing concern in the United States. There are three major types of bariatric surgery done in the United States to combat the obesity problem.

1. Vertical Banded (Stapled) Gastroplasty

2. Adjustable Gastric Banding

3. Roux-en-Y Gastric Bypass

Weight loss occurs by causing malabsorption or by restricting gastric volume or a combination of both. Banding procedures limit the amount of intake, whereas the Roux-en-Y procedure not only reduces the stomach size, it also changes the site of attachment of the small intestine. The Roux-en-Y procedure bypasses the lower portion of the stomach and a much smaller stomach pouch (15-30 mL capacity) is created, then the small intestine (the entire duodenum and part of the proximal jejunum) is removed from the lower stomach and attached to the newly formed stomach pouch. This procedure reduces the surface area that is available for absorption of nutrients and medications.

Different medications have different requirements for absorption and ultimately effectiveness. Medications in aqueous solution are more rapidly absorbed then those in oily solutions. Medications are soluble at different pH levels. Different medications that are more soluble at acidic pH are absorbed in the stomach, whereas medications that are more soluble at alkaline pH are absorbed in the small intestine. Intestinal enzymes are also necessary for the absorption of some medications. The Roux-en-Y Gastric Bypass can alter medication absorption.

Reducing the amount of time needed for absorption of the medication is essential for safe and effective use of medications. The formulation of the medication can be sufficient to reduce the amount of time needed in the stomach/small intestine for absorption. When possible the use of pills that can be crushed should be considered, as well as liquids, subcutaneous, intravenous, rectal, vaginal, intranasal and transdermal formulation and/or routes of administration should be considered. Avoid or use with caution any medication that has a long stomach absorptive phase.

Oral non-steroidal anti-inflammatory drugs (NSAIDs), salicylates and bisphosphonates should be avoided. These medications can cause or increase the potential of the patient to develop ulcers in the new much smaller stomach and/or reduced small intestines in all types of bariatric surgery. If the use of these medications are essential, then consider alternative routes of administration such as topical or injectable. Delayed release preparations of all medications such as CR, SR, XR, LA, EC, etc. should be avoided in Roux-en-Y Gastric Bypass.

Pain management in end of life care is essential. The use of MS Contin or morphine ER should be avoided in patients that have had a Roux-en-Y Gastric Bypass. Due to the reduced surface area of the gastrointestinal tract, the use of immediate release formulations would be a better alternative to extended release preparations. The use of immediate release formulations or non-extended release formulations may require a more frequent dosing schedule; however the Roux-en-Y bypass patient will be more apt to achieve more consistent pain management.

It is important to inform all healthcare providers of a patient’s bariatric surgical history if it exists as this will alter the medication therapy chosen for the patient. The length of time the patient is status post bariatric surgery has no impact to the medication therapy consideration. Once a patient has had bariatric surgery, medications will always need to be adjusted to take into account the changes made to the gastrointestinal tract through the bariatric surgery and how this will alter the absorption of medications. All medication therapies chosen for a bariatric surgery patient should be evaluated for effectiveness and for the increased potential for side effects if the proper monitoring is not done.


References:

1. Vanhoose K. Medication Absorption after Gastric Bypass. Advance Healthcare Network for NPs and PAs. www.ADVANCEforNPs\&Pas\_PrinterFriendly.htm

2. Rogula T, Schauer P. Medications after Bariatric Surgery. www.Medicationsafterbariatricsurgery.htm

3. Miller AD, Smith KM. Medication and Nutrient Administration Considerations after Bariatric Surgery. AM J Health Syst Pharm.2006;63(19):1852-1857.

4. Lawrecki T. How is drug absorption altered by bariatric surgery? University of Illinois Chicago College of Pharmacy

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Delta Campus Pharmacy Student

Tramadol Induced Hypoglycemia: The Latest Consideration for Tramadol in Pain Therapy

Tramadol, a weak opioid analgesic, is primarily popular for its two separate and distinct mechanisms associated with pain management. As an opioid, it inherently binds to the mu-opioid receptor to induce analgesia. But its additional effect results in inhibition of the serotonin and norepinephrine receptors. The latter is believed to play a role in the treatment of neuropathic pain, as this type of pain is believed to be associated with a malfunction of the peripheral or central nervous system.1 Because of this dual mechanism and a general perception that tramadol is safer than most existing opioids, prescribing has grown significantly in recent years.

Like most other therapeutic alternatives in pain treatment, however, it is not free of potentially life-threatening adverse effects. Tramadol carries a risk for the development of serotonin syndrome, a condition characteristic of hyperthermia, irregular heartbeat, organ failure, and death, due to the potential for accumulation of serotonin in the body, as well as a notable risk of seizures, both possible even at therapeutic doses.2 These risks are greatly increased when co-administered with serotonin modulators, such as selective-serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, and antimigraine medications, among others.3

Additionally, tramadol still maintains a similar profile of abuse potential compared to other opioid analgesics. The reclassification of tramadol to schedule IV under the US Controlled Substances act in August of 2014 echoes the emerging association of abuse witnessed from the increased use in practice.2

As of recent, a group of researchers based in Canada and France have now raised a new concern for the use of tramadol in pain therapy. Tramadol has been identified with an increased chance of hospitalization for hypoglycemic episodes, according to researchers. Tramadol administration resulted in a 52% increase in risk of hospitalization for hypoglycemia. The recent study published in December 2014 by Fournier, et al., investigated the growing trend in tramadol-induced hypoglycemia.

A trial conducted within the United Kingdom Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics (HES) database with an enlisted cohort of 334,034 patients compared the risk of hypoglycemia in patients treated with tramadol versus codeine for non-cancer pain from 1998 to 2012. Selected patients were at least 18 years of age with at least one year of baseline medical history in the CPRD and HES, which covers 13 million patients and over 680 practices in the United Kingdom. Included patients were limited to those newly initiating single opioid therapy with tramadol or codeine.

Typical pain treatment in this population included headache, neuralgia, abdominal and pelvic pain, musculoskeletal pain, injury and/or trauma, and surgery. Additionally, all cases of pain related to cancer were preclusive to inclusion. Within this cohort, 1,105 patients were hospitalized for hypoglycemia at follow-up intervals during the study period. All hospitalized patients were compared to 11,019 controls based on 10 controls on age, sex, and duration of follow-up. The resulting analysis identified an association between tramadol administration and increased risk of hospitalization for hypoglycemia versus the use of codeine (OR 1.52, 95% CI 1.09-2.10). Additional findings of the study noted a trend towards increased risk of hospitalization within the first 30 days of therapy in tramadol versus codeine use (OR 2.61, 95% CI 1.61-4.23).1 This casual relationship identified in early initiation of therapy warrants increased awareness of patient monitoring to avoid potentially life-threatening episodes of hypoglycemia.

It is evident that these findings create a conversation piece regarding the therapeutic use of tramadol, particularly in the growing prevalence of the need to treat diabetic neuropathy. In addition to the concern for opioid-induced adverse reactions, seizures, and a number of drug interactions, the risk for hypoglycemic episodes suggests much more consideration from the prescriber when selecting analgesic therapy, especially when initiating therapy for the first time. Serotonin syndrome poses an additional concern due to the highly prevalent use of serotonin-regulating medications in the (i.e. duloxetine, TCAs, trazodone, etc.), especially in the hospice setting. This, coupled with the risk for hypoglycemia, may lead to unintended consequences in the already vulnerable hospice population. The use of tramadol in hospice still remains less than what is observed in practice of other populations. Nonetheless, as time passes the hospice industry will likely notice increased use due to the pressure of opioid use reform in the United States.

While the authors advised that further research is needed to determine a stronger link, the sheer prevalence of use in practice warrants extra patient consideration. As stated by Nelson L, and Juurlink D, “If we replace conventional opioids with tramadol, as some guidelines have suggested, we may be left with more unintended consequences of the opioid epidemic to worry about.”2


Submitted by: Christopher Smurthwaite, PharmD Candidate at Duquesne University and Mary Mihalyo, B.S., PharmD, CGP, BCPS, CEO at Delta Care Rx


REFERENCES:

1. Fournier J, Azoulay L, Yin H, Montastruc J, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. Published online 8 December 2014. doi:10.1001/jamainternmed.2014.6512. Accessed 24 January 2015.

2. Nelson LS, Juurlink DN. Tramadol and hypoglycemia: one more thing to worry about. JAMA Intern Med. Published online December 08, 2014. doi:10.1001/jamainternmed.2014.5260. Accessed 24 January 2015.

3. Sindrup SH, Ott M, Finnerup MO, et al. Antidepressents in the treatment of neuropathic pain. Basic & Clinical Pharmacology & Toxicology. Published online 9 August, 2005. Accessed 24 January 2015

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Delta Campus Pharmacy Student

Comparison of Insulin Therapies

BACKGROUND: Insulin is a common therapy in the treatment of diabetes mellitus type 1 and 2. With the advent of intermediate-acting and long-acting insulin products, basal insulin therapy has become a common practice usually utilized to reduce the number of injections needed to administer or in combination with a short-acting insulin product in the basal–bolus insulin regimens.

The original insulins created to have longer durations of action were the NPH insulins which utilized a crystalline complex between the insulin and protamine.2 In more recent years, newer basal insulins such as Levemir and Lantus have come onto the market which do not rely on the use of protamine-insulin complexes and also claim to last longer (possibly up to single dose a day administration) with no peak activity. The lack of peak activity promises to reduce hypoglycemia risk and to provide a more basal-like dosing.1,3 The original insulins used as bolus insulin therapy were isolated from either animal or human sources. Today, the standard of isolated insulin therapies is regular human insulin. Like the long acting insulin products, recent years have seen the emergence of rapid acting insulin analogues. These rapid insulins promise to have higher efficacy and safety due to rapid onset (for meal time administration) and shorter duration of action.1,4,5

While the newer insulin products claim to have benefits of duration of action and less risk of hypoglycemia, they come at a higher cost than the regular human insulin and NPH insulin products. The average patient admitted to hospice care usually does not have insulin therapy related to the terminal diagnosis — with some obvious exceptions such as pancreatic cancer. The following is an analysis of the benefits and claimed convenience of the newer designer insulin analogues and how they could be substituted with regular human insulin and NPH insulin.

COMPARATIVE ANALYSIS: All three insulins (glarginine, detemir, and NPH) appear to have an onset of 1 to 2 hours. Peak efficacy of Levemir is at a narrow range of 6 to 8 hours (in graphic data in package insert; the analysis section states that there is “no pronounced peak”) versus a more unpredictable reported peak between 3 and 12 hours of Humulin N. Lantus appears to have the most data to support the assertion that there is no pronounced peak of activity with full onset occurring around 4-5 hours after administration and remaining constant throughout the duration of the trials. Duration of action appears to be similar between NPH and Levemir treatments which officially list their durations of action in package inserts as “up to 24 hours.”2,3 Lantus claims to have a constant level up to 24 hours as well, however all data collection ended at 24 hours demonstrating that it could have a greater than 24 hours duration.15

The variable ranges of duration of action and time to peak pharmacodynamic response could be affected by multiple factors such as patient metabolism, site of administration, administration technique, storage conditions of the product, etc. It appears that the NPH insulin (Humulin N) would be more prone to administration technique errors due to the necessity to remember to resuspend the crystalline suspension dosage form by rolling the vials prior to administration. While Lantus has no particularly documented half-life, Levemir has a similar but slightly greater half-life than NPH which could be the result of its being albumin bound which protects some of the insulin from clearance.6,7 There does not appear to be data readily available on the effects of insulin detemir in patients with hypoalbuminemia which is a common condition as a patient's nutritional status declines in end-of life care.

For hypoglycemia risk, the current American Diabetes Association guidelines state that NPH insulin has a higher risk of hypoglycemia over the newer basal insulins Levemir and Lantus. However, in comparative trials, only one case of severe hypoglycemia will be prevented for every thirty-seven patients treated with Levemir than if all thirty-seven patients were to receive NPH. In the case of non-severe hypoglycemia, the risk was similar between Levemir and NPH.3 In trials of Lantus vs NPH both combined with regular human insulin as a bolus, Lantus would need to be used in 97 patients than if they were treated with NPH in order to prevent only one case of severe hypoglycemia.15

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RESULTS: Given the similar onset, peak, and duration, Humulin N properly dosed twice daily could be used as a treatment alternative to Levemir or Lantus as a basal insulin alternative. While the newer insulins have a significantly less pronounced peak than NPH insulin,2,3,15 Humulin N has a long enough duration of action to be utilized as a longer acting insulin replacement therapy. It appears that hypoglycemia risk is similar between all three insulin therapies. However, it should be noted that Levemir and Lantus have been shown to have a more predictable pharmacodynamic profile over NPH insulin — not more effective6 — and that NPH insulin has the potential for hypersensitivity to the protamine. Regardless, all three insulin therapies can be considered equiefficacious (not equipotent) and can be utilized as basal insulin supplementation.

CONCLUSIONS: The choice between any of the available insulin products appears to be mostly based on clinical safety instead of clinical efficacy. The data suggests that any basal-bolus regimen can be considered equiefficacious if properly managed. The selection on which agents to use for outpatient therapy may need to take into account some of those minute differences in safety or dosing depending on individual patient factors. While true, once a day dosing of Lantus or Levemir may seem appealing since it reduces the number of invasive injections during palliative care, the need for basal insulin therapy decreases as nutritional intake declines. In addition, the existence of mixed human insulin products (Novolin 70/30 and Humulin 70/30) may increase convenience since they can provide both bolus coverage and basal insulin in only one or two administrations a day and can be more easily adjusted for changes in intake than the pure basal therapies. Utilization of the older human insulin products can be beneficial from a cost-effectiveness potential especially in the hospice industry since regular human and NPH insulin are available as a lower cost alternative. The cost-effectiveness of human insulin products can be significant since most hospices will not usually have sufficient insulin utilization for purchasing power as some larger health care institutions.


References:

1. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014;37 Suppl 1:S14-80.

2. Eli Lilly . Humulin N [package insert] 2013.

3. Novo Nordisk. Levemir [package insert] 2013.

4. Novo Nordisk. Novolog [package insert] 2014.

5. Sanofi-Aventis. Apidra [package insert] 2014.

6. Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to nph insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614-20.

7. Brunner GA, Sendhofer G, Wutte A, et al. Pharmacokinetic and pharmacodynamic properties of long-acting insulin analogue nn304 in comparison to nph insulin in humans. Exp Clin Endocrinol Diabetes. 2000;108:100-5.

8. American Diabetes Association . Insulin administration. Diabetes Care. 2004;27 Suppl 1:S106-9.

9. Goldman-Levine JD, Lee KW. Insulin detemir–a new basal insulin analog. Ann Pharmacother. 2005;39:502-7.

10. Eli Lilly . Humulin R [package insert] 2013.

11. Novo Nordisk. Novolin R [package insert] 2013.

12. Ratner R, Wynne A, Nakhle S, Brusco O, Vlajnic A, Rendell M. Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basalbolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (nct00135096). Diabetes Obes Metab. 2011;13:1142-8.

13. Meyer C, Boron A, Plummer E, Voltchenok M, Vedda R. Glulisine versus human regular insulin in combination with glargine in noncritically ill hospitalized patients with type 2 diabetes: a randomized double-blind study. Diabetes Care. 2010;33:2496-501.

14. Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab. 2009;94:564-9.

15. Sanofi . Lantus [package insert] 2013.

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