FYDI 2004 Jan/Feb

Therapeutic Consults and Controversies

“Glitazones” and Heart Failure

In April 2002, the US Food and Drug Administration alerted physicians to the possibility of fluid retention associated with the use of either pioglitazone or rosiglitazone, alone or in combination with insulin.^1-2 The fluid retention may lead to exacerbations in congestive heart failure. The package labeling now also includes a warning to discourage their use in New York Heart Failure Class III and IV patients. However, based on two recent cohort studies, thiazolidinediones are routinely prescribed to CHF patients despite the FDA warnings.^3-4

One of the cohort studies evaluated the association between use of the thiazolidinediones and the incidence of CHF. They did find thiazolidinediones may increase the incidence of heart failure by 1.1% annually and may increase the incidence of hospitalization due to heart failure by 0.5% annually.⁴ They did not find a dose to incidence of heart failure relationship. Editorials accompanying the numerous case reports in the literature speculate whether pioglitazone and rosiglitazone truly “cause” heart failure or “exacerbate” subclinical heart failure.^5-8

The debate continues because the “insulin sensitizers” offer much benefit to those patients who have the metabolic syndrome. They improve cardiovascular health by improving glucose control, decreasing plasma insulin levels, improving endothelial function, decreasing vascular inflammation and C-reactive protein levels, and correcting lipid abnormalities. By reducing vascular insulin resistance, patients experience decreased afterload, and improved neurohormonal function, which further improves myocardial function and may lead to left ventricular hypertophy regression.⁷

Even with all these favorable cardiac effects, fluid retention remains a problem in 2-5% of patients who are prescribed thiazolidinediones. The pathogenic mechanism still remains unknown. Some researchers speculate it may be related to increased endothelial cell permeability induced by the thiazolidinediones. Onset of pulmonary edema ranges from 4 to 13 months after the onset of thiazolidinedione therapy or a dosage change. Most of the pulmonary edema experienced by patients resolves within 3 – 6 days of discontinuation of the offending agent. Patients at risk for edema are more likely to develop edema. Concomitant use of dihydropyridine calcium channel blockers (amlodipine, felodipine, nifedipine, and nisoldipine) and high-dose NSAIDs may also increase the risk of peripheral edema, later leading to pulmonary edema.

1. Takeda Pharmaceuticals. Actos Prescribing Information. Available at: http://actos.com/pi/pdf. 2002. Accessed December 17, 2003.

2. GlaxoSmithKline Pharmaceuticals. Avandia Prescribing Inforamtion. Available at: http//us.gsk.com/products/assets/us_avandia.pdf. 2002. Accessed December 17, 2003.

3. Masoudi FA, Want Y, Inzucchi SE, et al. Metformin and thiazolidinedione use in medicare patients with heart failure. JAMA. 2003;290:81-85.

4. Delea TE, Edelsberg JS, Hagiwara M, et al. Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes. Diabetes Care 2003; 26:2983-2989.

5. Kermani A, Garg A. Thiazolinidinedione-associated congestive heart failure and pulmonary edema. Mayo Clin Proc. 2003;78:1088-1091.

6. Kennedy FP. Do Thiazolidinediones cause congestive heart failure? May Clin Proc. 2003:78:1076-1077.

7. Wang C-H, Weisel RD, Liu PP, et al. Glitazones and heart failure: critical appraisal for the clinician. Circulation. 2003;107:1350-1354.

8. Buse JB. Glitazones and heart failure; critical appraisal for the clinican. Circulation. 2003;108:e57.

Drugs in Review

Escitalopram (Lexapro)

Added to formulary November 2003

Similar products on formulary: citalopram, fluoxetine, paroxetine, sertraline, venlafaxine

Escitalopram is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder. Escitalopram is the active S-enantiomer of RS-citalopram. Escitalopram is twice as potent as RS-citalopram. It has a very strong affinity for serotonin reuptake sites with little or no affinity for 5-HT_1-7, dopamine, alpha- and beta-adrenergic, histamine, muscarinic, and benzodiazepine receptors.

Clinical trials demonstrated escitalopram was equivalent to citalopram and better than placebo for the treatment of major depression. Patients on either of the drugs improved their depression rating scales by the end of four weeks when compared to placebo. Initial changes in depression can be noted within 1 week of therapy. An additional study showed no difference in efficacy between escitalopram and venlafaxine XR.

Escitalopram has a similar tolerability profile to that of citalopram. The most common effects reported, when compared to placebo, are nausea, diarrhea, insomnia, dry mouth, and ejaculation disorders (in male patients). The frequency of adverse effects experienced increases with increasing doses.

Escitalopram is N-demthylated through the cytochrome P450 isoenzymes CYP 2C19, CYP 3A4, and CYP2D6. However, unlike its counterpart, citalopram, it does not have an inhibitory effect on any of the CYP isoenzymes. Drug-drug interactions are limited to the potential to exacerbate serotonin syndrome when used concomitantly with other adrenergic or serotonergic compounds.

The recommended starting dose for major depression is 10mg orally once daily. It can be titrated to a maximum dosage of 20mg orally once daily. Ten milligrams of escitalopram is equivalent to 20mg of citalopram.

Ezetimibe (Zetia)

Added to formulary December 2003

Similar products on formulary: none

Ezetimibe is a novel lipid-lowering agent that was approved by the FDA in October 2002. This agent inhibits passage of dietary and biliary cholesterol across the brush border of the small intestine, with minimal or no effect on absorption of other soluble food nutrients. After absorption, the compound is rapidly glucuronidated in the liver. The glucuronide metabolite is the active form of the drug. The relative bioavailability of ezetimibe increases in the presence of food by 25-30% in comparison to a fasting-state.

In phase III clinical trials, ezetimibe monotherpay in combination with NCEP step I diet reduced total cholesterol, LDL, and HDL by -12.4 to -5.6, -17.7 to -16.9, and +1 to +1.3%, respectively when compared to placebo.^1-2 Adding ezetimibe to HMG-CoA inhibitors or fenofibrate also demonstrated statistically and clinically significant reductions in total cholesterol and LDL. Maximum reductions in cholesterol were observed when 10mg ezetimibe and low-dose statins were used in combination. The range of differences in LDL changed between mono- and combination therapy were 19 to 17% in favor of combination therapy.³

To date, adverse effects associated with ezetimibe therapy are few. Viral infections, headache, arthralgia, and upper respiratory tract infections were the most common effects observed; however these effects occurred with similar frequency in study participants receiving placebo. Fat soluble vitamin (A, D, E, and K) levels are not affected by ezetimibe administration. Increase risk of adverse effects is always a concern when the various lipid-lowering agents are used in combination. Ezetimibe does not affect the pharmacokinetic parameters of any of the other antilipemic drugs. Nor do the other compounds affect the pharmacokinetics of ezetimibe. It also does not interact with the P450 isoenzyme system. Concomitant use of exetimibe and HMG-CoA inhibitors is associated with a low-rate of liver dysfunction. A threefold increase in ALT was observed in 1.9% of patients receiving combination “statin”-ezetimibe therapy; when used as monotherapy incidence is 0.6% and 0% respectively. Musculoskeletal events are also higher when statins and ezetimibe are used in combination.

Ezetimibe is available as 10mg tablets. It is dosed orally once daily.

1. Ballantyne CM, Hour J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia. Circulation 2003;107:2409-2415.

2. Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cariol 2002;90:1092-1097.

3. Sudhop T, vonBergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002;62(16): 2333-2347.

Aldurazyme

Orphan Drug

Mucopolysaccharidosis I (MPS I) (Hurler’s syndrome) is a rare, autosomal recessive genetic disease that affects multiple organ systems and tissues. The disease is caused by a defect in the gene coding for the lysosomal enzyme alpha-L-iduronidase. This results in an inability of the lysosome to act in the stepwise degradation of certain glycosaminoglycans (GAG). This process is essential for normal growth and homeostasis of tissues.^1-2These glycosaminoglycans, which are important constituents of the extra cellular matrix, joint fluid, and connective tissue throughout the body, progressively accumulate in the lysosome. Over time, the enzyme deficiency and resulting accumulation of GAG in tissues and cells has progressively debilitating and often fatal effects, usually due to obstructive airway disease, respiratory infection, or cardiac complications. In the most severe cases of MPS I, death usually occurs by age 10 although some patients may have a normal life span.¹

Management of MPS I may now include Aldurazyme, a targeted enzyme replacement therapy that is a polymorphic variant of the human enzyme deficient in MPS I, alpha-L-iduronidase. It is produced by recombinant DNA technology and is indicated for patients with Hurler and Hurler-Scheie forms of MPS I and for patients with the Scheie form who have moderate to severe symptoms. Progressive accumulation of GAG may be stopped, which directly addresses the underlying cause of the disease. Aldurazyme has been shown to improve pulmonary function and walking capacity. Aldurazyme has not been evaluated for effects on the central nervous system manifestations of the disorder.The most common adverse events observed with ALDURAZYME treatment in the clinical studies were upper respiratory tract infection, rash, and injection site reaction. The most common adverse reactions requiring intervention were infusion-related reactions, particularly flushing. Most infusion-related reactions requiring intervention were ameliorated with slowing of the infusion rate, temporarily stopping the infusion, and/or administering additional antipyretics and/or antihistamines. The recommended dosage regimen of Aldurazyme^® is 0.58 mg/kg of body weight administered once weekly as an intravenous infusion. Pretreatment with antipyretics and/or antihistamines is recommended 60 minutes prior to the start of the infusion.³

Reviewed by Julie Kasap, PharmD

1. Clarke LA. Clinical diagnosis of lysosomal storage diseases. In: Organelle Diseases. Clinical Features, Diagnosis, Pathogenesis and Management. Applegarth DA, Dimmick JE, Hall JG, editors. London: Chapman and Hall Medical; 1997. p. 45-8.

2. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, et al, editors. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. 8th ed. New York: McGraw-Hill; 2001. p. 3421-8.

3. Aldurazyme® [package insert]. Novato, CA: BioMarin Pharmaceutical Inc.; 2003 (lines 80-7, 89, 148-58, 192-4, 297).

Medication Safety Notes

Linezolid and Serotonin Syndrome

Although linezolid is a weak, reversible and nonselective monoamine oxidase inhibitor, there is still potential for serotonin syndrome to occur when it is used concomitantly with other adrendergic or serotonergic drugs. In the initial Phase II and Phase III studies, the drug was used in combination with dextromethorphan and no occurrences of serotonin syndrome were noted.¹ Formalized drug-drug interactions studies have not been done.

To date, the association of serotonin syndrome and linezolid use has been published in 4 case reports.^2-4 OSF-SFMC recently reported one case to the ADE Committee. All of these patients were chronically prescribed a SSRI (citalopram, sertraline, paroxetine, fluoxetine) when linezolid was initiated. Mild symptoms began within 3 days of the initation of linezolid. Two of the cases reported required ICU care as a result of the interaction.

Serotonin syndrome is an iatrogenic disorder often provoked by pharmacologic treatments that increase serotonergic activity. It was originally recognized in lab animals in the 1960’s.⁵ Sternbach created diagnostic criteria for serotonin syndrome in 1991 in an effort to distinguish it from neuroleptic malignant syndrome and increase clinician awareness. His diagnostic criteria for the syndrome are listed below.⁶

A. Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following clinical features are present: confusion, hypomania, agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordiantion or fever.

B. Other etiologies (e.g. infectious, metabolic, substance abuse, or withdrawal) have been ruled out.

C. A neuroleptic agent had not been started or increased in dosage prior to the onset of the signs and symptoms listed above.

As scientists discover more about the various serotonin receptors and their role, they theorize that the definition of serotonin syndrome should go beyond an iatrogenic disorder. The pathogenesis of serotonin syndrome should expand to include an endogenous deficit in peripheral 5-HT metabolism, the activation of several 5-HT-receptor subtypes, and a stimulus for release of 5-HT. Therefore, a serotonergic crisis may result from a defect in metabolism combined with a pharmacologic insult.⁷ Disease states that may place patients at higher risk for serotonin syndrome include: liver disease (ethanol induced and hepatitis), pulmonary disease, smokers and cardiovascular disease (hypertension and hyperlipidemia).⁷ To avoid serotonin syndrome in patients at higher risk for the syndrome, the psychiatric literature suggests a wash-out period of two weeks (5 weeks for fluoxetine) from the serotonergic agent and then initiate the new serotonergic compound.^5-7 Given that all the available antidepressants possess serotonergic and/or adrenergic activity in varying degrees, treating depression in a patient who is also on linezolid can be a clinical challenge. One recent case report, clinicians had success with the combination of citalopram and linezolid.⁸ They theorized that mirtazapine, although a SSRI, also antagonizes the 5-HT₂ and 5-HT₃ receptors. However since then, mirtazapine has been implicated as the causal additive agent in other serotonin syndrome case reports, not involving linezolid. Due to the potential severity and lethal complications of serotonin syndrome, risks and benefits must be weighed for the individual patients involved until more clinical experience with these combinations is available.

1. Pharmacia & Upjohn. Prescribing Information. January 2001.

2. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis 2002;34:1651-2.

3. Bernard L, Stern R, Hoffmeyer P. Serotonin synerom after concomitant treatment with linezolid and citalopram. Clin Infect Dis 2003;35:1197.

4. Hachem RY, Hicks K, Huen A, Raad I. Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clin Infect Dis 2003;37:e8-11.

5. Ener RA, Meglathery SB, Van Decker WA, et al. Serotonin syndrome and other serotonergic disorders. Pain Medicine. 2003;4(1):63-74.

6. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148(6):705-713.

7. Brown TM, Skop BP, Mareth TR. Pathophysiology and management of the serotonin syndrome. Ann Pharmacother 1996;30:527-33.

8. Aga VM, Barklage NE, Jefferson JW. Linezolid, a monoamine oxidase inhibiting antibiotic, and antidepressants. J Clin Psychiatry 2003;64(5):609-611.

9. Gillman PK. Serotonin syndrome: history and risk. Fundam Clin Pharmacol 1998;12:482-91.

Compounds associated with serotonin syndrome⁹

Serotonin reuptake inhibitors	Serotonin Agonists	Acute serotonin releasers	Monoamine oxidase inhibitors	Reversible inhibitors of monoamine oxidase A	Other drugs
Paroxetine	Sumatriptan	p-chloramphetamine	Tranylcypromine	linezolid	Chlorpheniramine
Sertraline	Dihydroergotamine	methamphetamine	Phenelzine		Brompheniramine
fluoxetine	Buspirone		Isoniazid		Cocaine
fluvoxamine			Isocarboxazid		Dextromethorphan
citalopram			Pargyline		Meperidine
venlafaxine			Selegiline		Tramadol
clomipramine			Clorgyline		Bromocriptine
imipramine			procarbazine		Levodopa
nefazodone					lithium
trazodone					Ginseng
St. John’s Wort

Drugs in italics have been implicated in fatalities.