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Microsoft word - 12 08 newsletter1212.doc

The following actions were taken at the November/December 2008 Therapeutics Committee Meeting
- Janine Barnaby, R.Ph., Robert Begliomini, Pharm.D., Jenny Boucher, Pharm. D., Christina Foley,
Pharm.D., Jarrod Kile, R.Ph., Leroy Kromis, Pharm.D., Jason Laskosky, Pharm.D., Shannon Lenner,
Pharm.D., Joseph Ottinger, R.Ph., MS, MBA, Krina Patel, Pharm.D., Jessica Price, Pharm.D., Kathleen
Wesser, Pharm.D., Health Spectrum Pharmacy – Jay Needle, R.Ph.
Information contained herein is confidential and proprietary to Lehigh Valley Hospital. It is intended solely for the
internal use of Lehigh Valley Hospital. Any unauthorized use will be prosecuted to the fullest extent of the law.


Cimzia® (certolizumab)
Cimzia® (certolizumab) is a new TNFα blocker indicated for reducing the signs and symptoms of
Crohn’s disease and maintaining clinical response in adult patients with moderate to severe
active disease that have had an inadequate response to conventional therapy. Cimzia appears to
be just as safe as other TNF blockers with all agents implicated in the risk of infection,
malignancy, hematological effects, heart failure and hypersensitivity reactions. There are no
head-to-head studies with which to compare Cimzia’s efficacy with other TNF blockers or
conventional Crohn’s disease therapy. Infliximab (Remicade®) is the current formulary TNFα
blocker, has the most data to support its use, and has FDA approved indications for other disease
states. The only benefit Cimzia offers over infliximab is its subcutaneous administration as
compared to a 2-hour IV infusion. Overall, there appears to be no safety, efficacy or cost benefit
for Cimzia when compared to infliximab. Given the vast amount of literature and experience with
infliximab and a lack of additional benefits for Cimzia, infliximab will remain the TNFα blocker on
formulary for inpatient use. Cimzia will be made available for outpatient use only.
Clevidipine butyrate injectable emulsion (Cleviprex, The
Medicines Company)
Is indicated for the reduction of blood pressure when oral therapy is not feasible or desirable.

Other agents used for the acute intravenous (IV) management of hypertension include sodium
nitroprusside, nitroglycerin, fenoldopam, hydralazine, esmolol, labetalol, and nicardipine.
Clevidipine is an ultrashort-acting dihydropyridine L-type calcium channel antagonist. Clevidipine
is structurally related to felodipine, with the inclusion of an ester group in the structure that causes
it to undergo rapid hydrolysis by esterases in the blood and extravascular tissue to an inactive
metabolite. Clevidipine is poorly soluble in water and has been formulated in a 20% lipid emulsion
with the same constituents as Intralipid (2kcal per ml= 200mg fat/ml)
The new drug application (NDA) submission contained data from 6 clinical trials with clevidipine butyrate injectable emulsion. The manufacturer has reported that all 6 studies met their primary end point; however, not all 6 studies have been published at this time. The package insert summarizes 3 open-label studies (ECLIPSE) enrolling a total of 1,506 patients randomized to receive clevidipine, nitroglycerin (perioperative hypertension), sodium nitroprusside (perioperative hypertension), or nicardipine (postoperative hypertension) for the treatment of hypertension in cardiac surgery. Blood pressure control was reported to be similar
with each of the 4 regimens. The primary outcomes in the post-operative cardiac surgery
population with hypertension receiving clevidipine or nicardipine cited no difference in Death,
Stroke, Myocardial Infarction or Renal Dysfunction at 30 days.

Currently, our institution uses little nitroprusside, and primarily utilizes the longer-acting
nicardipine infusion to maintain systolic pressures in a wide-range of surgical and non-surgical
scenarios. Nicardipine has a half-life of 2-4 hours is primarily metabolized by metabolic pathways
with an onset of 10 minutes and a duration of approximately 4-8 hours after therapy is stopped.
The infusion rate is 5-15 mg/hr with a maintenance rate of 3mg/hr. To date, only the ECLIPSE
trial published comparative data between nicardipine and clevidipine.
The Medicines Company is in the process of enrolling for a larger trial comparing clevidipine and
nicardipine to provide a more direct comparison. The Therapeutics Meeting would like to review
these data when they become available to more fully evaluate this product prior to making a final
Formulary decision. Until this time, the Committee recommended that no use of this product be
attempted, as several major issues were preliminarily identified that could impact patient care and
safety. A substantial educational effort would be needed, if subsequent data suggests that
clevidipine has clinical advantages vs. nicardipine.

Nefazodone (formerly Serzone) is indicated for major depressive disorder. It is a
serotonin/norepinephrine reuptake inhibitor antidepressant. Nefazodone was removed from the
LVHHN drug formulary in June of 2004 as a result of reported cases of life-threatening hepatic
failure and subsequent discontinuation by the brand drug manufacturer. At that time, LVHHN
prescribers were requested to select alternative antidepressant treatment for these nefazodone-
treated patients, despite continued availability of the generic formulations.
Initiation of new nefazodone therapy is not recommended at LVHHN due to the aforementioned
warning for hepatic risk. Nefazodone may cause severe and possibly irreversible liver failure,
leading to transplant or death. According to the black box warning, the risk of life threatening liver
failure is reported as one case of liver failure resulting in death or transplant per 250,000-300,000
patient years of nefazodone treatment. The total patient years is a summation of each patient’s
duration of exposure expressed in years. This statistic is likely an underestimate due to under
Treatment with nefazodone should not be initiated in patients that have active liver disease or
elevated baseline serum transaminases. Nefazodone should be discontinued if clinical signs or
symptoms suggest evidence of hepatic injury or failure. Patients who develop increased serum
AST or ALT levels ≥ 3 times the upper limit of normal while taking nefazodone should be
withdrawn from the drug. Subsequent re-treatment in patients that experience nefazodone-
induced hepatic failure is contraindicated. Routine monitoring is essential for maintaining safe
treatment with nefazodone.
In order to better monitor patients who require nefazodone therapy, nefazodone has been
reinstated onto the drug formulary, with restriction to patients requiring continuation of
maintenance therapy only.
Ramelteon (Rozerem)

THERAPEUTIC CLASS: Sleep hypnotic, Nonbenzodiazepine
INDICATIONS : Ramelteon is indicated for the treatment of insomnia characterized by difficulty
with sleep onset.
CLINICAL PHARMACOLOGY : Melatonin receptor agonist with affinity for melatonin MT1 and
MT2 receptors. The activity at these sites are thought to contribute to the sleep-promoting PHARMACOKINETICS : Ramelteon is rapidly absorbed with peak concentrations at 45 minutes
after oral administration of 4 to 64 mg. Seventy percent of the drug is bound to human serum
albumin and has substantial tissue distribution. Ramelteon is metabolized primarily by the
CYP1A2 hepatic enzyme. Eighty-four percent is excreted in the urine and approximately 4% in
the feces. Elimination half-life of ramelteon is approximately 1 to 2.6 hours. The major active
metabolite, M-II, has a half-life of 2 to 5 hours.
CLINICAL TRIALS: Placebo-controlled studies show moderate efficacy over placebo for
treatment of chronic insomnia and transient insomnia.2-21 There are limited randomized
controlled trials with objective data in adults.2-21 Many studies are published in abstract form only
and some are post-hoc analyses of previous trials.2-21 Ramelteon significantly shortens the time
to onset of sleep and may increase sleep duration.1-21
CONTRAINDICATIONS : Ramelteon is contraindicated in patients with a hypersensitivity to
ramelteon or any components of the formulation.
WARNINGS AND PRECAUTIONS : Sleep disturbances may be the presenting manifestation of
a physical and/or psychiatric disorder. Failure of insomnia to recover after a reasonable time may
indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.
Worsening of insomnia, or the emergence of new cognitive or behavioral abnormalities, may be
the result of an unrecognized underlying psychiatric or physical disorder and requires further
evaluation of the patient. Exacerbation of insomnia and the emergence of cognitive and
behavioral abnormalities were seen with ramelteon during the clinical development program.
In primarily depressed patients, worsening of depression, including suicidal ideation, has been
reported in association with the use of hypotics.
Ramelteon should not be used in patients with severe hepatic impairment, and should be used
with caution in patients with moderate hepatic impairment.
After administration of ramelteon, patients should confine their activities to those necessary to
prepare for bed. Avoid engaging in hazardous activities that require concentration (such as
operating a motor vehicle or heavy machinery).
Ramelteon is not recommended to use in patients with severe sleep apnea or severe COPD.
Avoid alcohol consumption in combination with ramelteon.
Ramelteon is Pregnancy Category C and not recommended for use in nursing mothers.
May cause disturbances of reproductive hormonal regulation in women. Studies were performed
to evaluate effects on endocrine function. One study reported an increase in serum prolactin
levels in 32% of ramelteon-treated (16 mg) patients as compared to 19% of placebo-treated
patients, respectively. In another study, two patients were noted to have abnormal morning
cortisol levels and ACTH stimulation tests. There was one report of prolactinoma. Decreased
testosterone levels have also been documented.
It is not recommended to give fluvoxamine in combination with ramelteon. Use caution when
administering ramelteon with CYP1A2 inhibiting drugs.
Ramelteon is not recommended for pediatric or adolescent use.
ADVERSE REACTIONS : The most common adverse events that caused discontinuation of
ramelteon in trials were somnolence, dizziness, nausea, fatigue, headache, and insomnia. 2.4%
of patients discontinued treatment due to an adverse event compared with 1.9% of placebo
patients. In a one year follow up study, 12% of patients discontinued treatment due to an adverse
Incidence (% of subjects) of Treatment-Emergent Adverse Events in Phase 1-3 Studies
DRUG INTERACTIONS : Substrate of CYP1A2 (major), CYP3A4 (minor), and CYP2C (minor)
• CNS depressants: additive sedative and/or respiratory effects • CYP1A2 inhibitors, strong CYP3A4 inhibitors (such as ketoconazole), strong CYP2C9 inhibitors (such as fluconazole): may increase levels of ramelteon. Monitor for toxicity/increased sedation. • Fluvoxamine (strong CYP1A2 inhibitor): concurrent use is not recommended due to • Strong CYP enzyme inducers (such as rifampin): may decrease efficacy of ramelteon. DOSING AND ADMINISTRATION : The recommended dose is 8 mg taken within 30 minutes of
bedtime. It is recommended that ramelteon not be taken with or immediately after a high fat meal
due to higher AUC, lower Cmax, and delayed Tmax. No dosage adjustment is necessary for
patients with renal impairment, patients that require hemodialysis, or patients with mild to
moderate hepatic impairment.

: Therapeutic response, adverse effects.
PRODUCT AVAILABILITY AND STORAGE : Available in 8 mg tablets. Store at 25◦C.
CONCLUSION: Ramelteon appears to be moderately effective for treatment of insomnia
characterized by difficulty with sleep onset when compared to placebo. Comparative studies
evaluating efficacy with other sedative-hypnotics are lacking. Ramelteon exhibits a novel
mechanism of action for the treatment of insomnia. It may interact less with other drugs as
compared to the other non-benzodiazepine agents. Ramelteon appears efficacious in improving
sleep onset, while other hypnotics appear to improve both sleep onset and sleep maintenance.
Subjective measures of sleep efficiency and effects on duration of sleep were less pronounced
and inconsistent among studies. The safety profile appears favorable when compared to other
sleeping agents. It is also well tolerated with little residual sedation. Ramelteon may offer an
alternative to patients that have developed tolerance to other hypnotics. Ramelteon has no reported abuse or dependence potential, thus being the only hypnotic agent classified as a noncontrolled substance. LVHHN’s formulary drug options for sleep hypnotics include zolpidem and temazepam. An additional option is not necessary at this time, especially since studies have not shown that ramelteon is any better than the existing formulary options. In conclusion, the Therapeutics Committee has recommended that ramelteon remain NON-FORMULARY, but will permit use to Psychiatrists for patients that have failed other hypnotic formulary options, or for patients that have a history of substance abuse. REFERENCES: 1. Takeda Pharmaceuticals America, Inc. Rozerem (ramelteon tablets) product information. 2. Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep 2005;28:303-7. 3. Zammit G, Schwartz H, Roth T, et al. The effects of ramelteon in a first-night model of transient insomnia. Sleep Med 2008;1-5. August 6. 4. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose response study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006;7:17-24. 5. Zammit G, Roth T, Erman M, et al. Double-blind, placebo-controlled polysomnography and outpatient trial to evaluate the efficacy and safety of ramelteon in adult patients with chronic insomnia [abstr]. Sleep 2005;28(Suppl.):A228-9. 6. Roth T, Seiden D, Zee P, et al. Phase III outpatient trial of ramelteon for the treatment of chronic insomnia in elderly patients [abstr]. J Am Geriatr Soc 2005;53(suppl 4):S25. 7. Roth T, Seiden D, Weigand S, et al. Phase III study to determine the efficacy of ramelteon in elderly patients with chronic insomnia [abstr]. Presented at the 45th annual meeting of the new clinical drug evaluation (NCDEU), Boca Raton, FL, June 6-9, 2005. 8. Roth T, Seiden D. Sainati S. et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic isomnia. Sleep Med 2006;7:312-8. 9. Mini L, Wang-Weigand S, Zhang J. Ramelteon 8 mg/d versus placebo in patients with chronic insomnia: post hoc analysis of a 5-week trial using 50% or greater reduction in latency to persistent sleep as a measure of treatment effect. Clinical Therapeutics 2008;30(7):1316-23. 10. Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med 2007;3:495-504. 11. Erman M, Seiden D, Zammit G. Phase II study of the selective ML-1 receptor agonist TAK-375 in subjects with primary chronic insomnia [abstr]. Sleep 2003;26(Suppl.):A298. 12. Roth T, Seiden D, Wang-Weigand s, et al. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007;23:1005-14. 13. DeMicco M, Wang-Weigand s, Zhand J. Long-term therapeutic effects of ramleteon treatment in adults with chronic insomnia: a one year study [abstr]. Sleep 2006;29:A234. 14. Wang-Weigand S, Mayer G, Roth-Schechter B. Long-term efficacy and safety of ramelteon 8 mg treatment in adults with chronic insomnia: results of a six-month, double-blind, placebo-controlled, polysomnography trial [abstr]. Presented at: World Federation of Sleep Research and Sleep Medicine Societies 2007, Queensland, Australia, September 2-6, 2007. 15. Mini LJ, Wang-Weigand S, Zhang J. Self-reported efficacy and tolerability of ramleteon 8 mg in older adults experiencing severe sleep-onset difficulty. Am J Geriatr Pharmacother 2007;5:177-84. 16. Seiden D, Wang-Weigand S, Zhang J, et al. Sleep promoting effects of ramelteon, a selective MT/MT2 receptor agonist, in older adults with chronic insomnia. Sleep 2006, 29 [abstr]:A238. 17. Mini L, Wang-Weigand S., Zhang J. Effects of ramelteon 8 mg on latency to persistent sleep in adults with severe sleep-initiation difficulty; post-hoc analysis of a 5-week trial. Sleep 2007;30 [abstr]:A243. 18. Mini L, Maloney P, Wang-Weigand S, et al. Efficacy and next-day residual effects of ramelteon 8 mg in adults with chronic insomnia: a combined analysis of 2 double-blind, placebo-controlled, crossover trials. Sleep 2007;30 [abstr]:A229-30. 19. Seiden D, Zee P, Weigand S, et al. Double-blind, placebo-controlled outpatient clinical trial of ramelteon for the treatment of chronic insomnia in an elderly population. Sleep 2005;28 [abstr]:A228. 20. Mini LJ, Wang-Weigand S, Zhang J, et al. Self-reported efficacy of 8 mg ramelteon in elderly chronic insomnia patients with severe sleep-initiation difficulty. Sleep 2006;29[abstr]:A237. 21. Griffiths R, Suess P, Johnson M. Ramelteon and triazolam in humans: behavioral effects and abuse potential [abstr]. Sleep 2005;28(Suppl.):A44.
Antiviral Medications: Herpes Viruses
Famciclovir and valacyclovir are antiviral medications used in the treatment and prophylaxis of
diseases caused by herpes viruses. Currently, valacyclovir is the formulary medication in this
class however famciclovir is also available for physician ordering through Lastword. Valacyclovir
is used much more frequently than famciclovir at Lehigh Valley Health Network.
While these medications are both commonly used for a number of herpes virus infections,
valacyclovir is FDA-approved for a greater number of indications including pediatric use and is
used more frequently than famciclovir at Lehigh Valley Health Network.
Safety and efficacy are comparable between these medications with the exception of thrombotic
microangiopathy, which has been reported rarely in immunocompromised patients receiving high
doses of valacyclovir. (One study reported an incidence of 1.46%.) This condition has not been
reported in patients receiving famciclovir.
Costs per regimen are comparable for both medications. For intermittent treatment of genital
herpes, treatment with valacyclovir costs $34.20 or $50.85 depending on the course prescribed,
while treatment with famciclovir costs $37.60. Regimens for herpes zoster cost $213.57 for
valacyclovir or $197.40 for famciclovir. Other treatment regimens were also comparable with
regard to cost.
The P&T committee approved the removal of famciclovir from the physician’s ordering screen and
will be moved to the pharmacist only side of the VT as a non-formulary item.
Alteplase for STEMI
To streamline the Formulary, the Therapeutics committee has removed reteplase. Alteplase –
tPa, which has recognized clinical indications for the management of acute ischemic stroke,
pulmonary embolism, peripheral vascular occlusions, and catheter clearance data can also be
utilized in the treatment of STEMI. As Lehigh Valley Hospital has focused its efforts on a PCI
treatment pathway for STEMI, the need for thrombolytic therapy in this patient population has
essentially disappeared. Hence, reteplase, which only has an FDA approval for STEMI treatment
has languished unused on the ‘shelf’.
Alteplase (STEMI patients) will be only used in ‘default’ situations where PCI is not readily
available. The transition date for implementation is February 2, 2009.
The dosing for alteplase in STEMI is listed below and will be included into a CAPOE order set.
For patient > 67 kg;

15mg bolus over 2 minutes
50mg infusion over 30 minutes
then follow with 35 mg infusion over 60 minutes
Total dose= 100mg; total time 90 minutes
For patient < or = 67 kg
15mg bolus
0.75mg/kg infusion over 30 minutes--maximum 50mg
then follow with 0.5mg/kg infusion over 60 minutes--maximum 35mg
Total time 90 minutes
New Addition to Therapeutics at a Glance: The Retail View
With this Issue articles will be included from Health Spectrum Pharmacy Services, retail
pharmacists. The information will be of use to any caregiver & their staff who have dealings with
retail pharmacies. We hope you will find the articles useful.
All CFC-Propelled inhalers will be discontinued.
As a reminder, no CFC-propelled Inhalers including Albuterol (Proventil, Ventolin) may be
produced, marketed or sold in the US after Dec 31, 2008. HFA based alternative products are
available to take the place of the CFC-propelled Inhalers.
HFA inhalers are just as safe and effective as CFC inhalers when used appropriately.
The shape and size of the inhalers is almost identical.
HFA inhalers are better for the environment.
HFA inhalers might taste, feel, and smell different than CFC inhalers. People usually say the puffs
feel warmer and are less forceful than their old inhalers.
HFA inhalers should be cleaned at least once a week to prevent clogging. To clean the device
you should remove the metal canister, rinse the plastic portion with warm water for about 30
seconds and let it air dry thoroughly before reassembling it.
HFA inhalers generally need to be primed less frequently. Before you use your albuterol inhaler
for the first time, or if you haven't used it for two weeks or more, prime it by firing three (ProAir
) to four puffs (Proventil HFA, Ventolin HFA) into the air.
What this means to you- Some patients will complain that the new inhaler does not work as well. In fact they
are getting the exact same amount of medication - but due to the propellant change - the puff is not as
forceful. So they think it isn’t as good.
Unavailable Products
Due to changes in the FDA rulings:
All Prescription products containing Guaifenesin are no longer available. Some examples are
Entex LA, Entex PSE, Duratuss, Humibid and the generics. Mucinex (Guaifenesin 600mg) is
available OTC, either by itself, with DM (Dextromethorpan) or with D (Pseudoephedrine).
All products that contain Flouride are being reviewed by the FDA and will only be available in very
limited and sporatic quantities until a ruling of their efficacy is established. Some examples are
Luride, Poly-Vi-Flor and Tri-Vi-Flor and the generics.
Zostavax, MSD’s Zoster Vaccine may not be available until mid January 2009 due to
manufacturing difficulties. Some Retail Pharmacies are taking names of patients who have
Prescriptions and will notify them when it is available. Urge patients to call first to make sure
which pharmacies in the area are carrying it and to put their name on the list. Medicare Part D
reimbursement for injections allows specially trained and Licensed Pharmacists to administer
them. Patients should also ask their Pharmacies if such a Pharmacist is on staff.

Caution needed with IVR use
Most Retail Pharmacies now have IVR, Interactive Voice Response system. This is the
answering machine you or your staff uses to leave recorded Prescription orders for the
Pharmacy. Please make sure that the caller leaves all the needed information in a slow & clear
fashion. The caller has all the information in front of them but the Pharmacy is hearing it for the
first time, without a point of reference. So if the caller speaks too quickly or is not complete, the
Pharmacy must listen to the call over and over to decipher the message, wasting time, prompting
a call back or worse filling the order incorrectly. IVR is a valuable tool to increase everyone’s
efficiency and decrease hold time on the phone, please be complete and speak slowly so that
information heard is the correct information.

Pt/12 08 newsletter


Microsoft word - 2009-07-21-efd-statute_en.doc


Highlights of prescribing information

HIGHLIGHTS OF PRESCRIBING INFORMATION (NSAID) or colchicine upon initiation of treatment) may be beneficial These HIGHLIGHTS do not include all the information needed to use ULORIC safely and effectively. See full prescribing • Cardiovascular Events: A higher rate of cardiovascular information for ULORIC. thromboembolic events was observed in patients treated with ULORIC tha

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