Volume 23, Number 6 June 2009 Drugs & Therapy B N U N L N L N E N T N I N N MEDICATION SAFETY FORMULARY UPDATE The Pharmacy and Therapeutics Prochlorperazine — Committee met May 19, 2009. No drugs were added in the Formulary while 1 was deleted. 9 drugs or dos- the forgotten antiemetic age forms were designated nonfor- mulary and not available. Criteria ata from 2006 attributed 3.7% of and to reduce narcotic requirement in were changed for 6 drugs, including D Emergency Department (ED) visits some surgical situations. 2 exceptions to “contraindications.” to nausea and vomiting, which was the Although phenothiazines like pro- 4th most common reason for an ED visit. chlorperazine and promethazine are Nausea and/or vomiting are the result in the same general pharmacologic ◆ ADDED of peripheral or central stimulation of class, they do not have identical pri- None the chemoreceptor trigger zone (CTZ). mary mechanism of actions or adverse Precipitating factors include ingestion events. Prochlorperazine blocks post- of medications or toxins, infection, gas- synaptic mesolimbic dopaminergic D1- ◆ DELETED - trointestinal obstruction, gastroparesis, and D2 receptors, which includes the Lomustine (CeeNu® Dosepack)* pregnancy, migraines, and surgical CTZ, explaining its antiemetic effect. *Nonformulary and must be ordered procedures. Treatment options are usu- Prochlorperazine also has moderate on Chemotherapy Order Form ally described as 2 broad categories: anticholinergic and alpha-adrenergic antiemetics and prokinetics. Antiemet- receptor-blocking activity. Prometha- ics include phenothiazines, antihis- zine is primarily a competitive hista- ◆ NONFORMULARY AND tamines, anticholinergics, dopamine mine1-receptor blocker with muscarinic NOT AVAILABLE antagonists, and 5-HT3 antagonists. M1-receptor-blocking activity resulting Darifenacin Prokinetic agents used for dysmotility in antihistaminic, sedative, anti-mo- (Enablex® by Novartis)† syndromes include metoclopramide tion-sickness, antiemetic, and anticho- Fesoterodine (Toviaz® by Pfizer)† and erythromycin. linergic properties. Phenothiazines, specifically prochlor- Despite proven efficacy, these medi- Flavoxate (Generic)† perazine and promethazine, are often cations are not without risks. As recent Oxybutynin ER overlooked with the presence of newer, as March 2009, promethazine was the (Ditropan® XL by Ortho)† more heavily promoted antiemetic center of a US Supreme Court decision agents like 5-HT3 antagonists (eg, about product liability. In 2000, a musi- Oxybutynin Transdermal ondansetron). However, these agents cian went to the emergency room for ® (Oxytrol by WatsonPharma)‡ should not be disregarded. The 5-HT3 a migraine with nausea. She received ‡Prescriber must change to tolterodine antagonists are used mainly for preven- meperidine and promethazine intra- ER or oxybutynin IR tion of nausea. Clinical experience sug- venously (IV). At the site of infusion, gests that 5-HT antagonists are not as she developed gangrene that required Solifenacin 3 effective once a patient is vomiting. amputation of the forearm.1 Intrave- (Vesicare® by GlaxoSmithKline)† Promethazine was developed in the nous preparations of pro methazine Tolterodine IR (Detrol® by Pfizer)† 1930s, followed by prochlorperazine have a pH between 4 and 5.5. At this in the 1950s. Initially developed for pH, the surrounding tissue can become Trospium IR/ER anesthesia and antipsychotic use, severely damaged if extravasation from (Sanctura®/XR by Allergan)† these agents were later found to have the IV site occurs. We have previously †Interchanged to tolterodine ER antiemetic effects. Over time, anti- cautioned about this potential problem emetic use became their principal place in the Bulletin. Also, cautionary alerts ◆ INTERCHANGES in therapy. Not only are phenothiazines warning nurses to dilute the vial into effective, there are multiple dosage (continued on page 6) Tolterodine ER (Detrol® LA) for forms available, from oral formulations Darifenacin (Enablex®) to suppositories and parenteral routes. Tolterodine ER (Detrol® LA) for Prochlorperazine has labeled indica- ◆ Fesoterodine (Toviaz®) tions for the control of severe nausea INSIDE THIS ISSUE and vomiting as well as treatment of Tolterodine ER (Detrol® LA) for schizophrenia. Promethazine is labeled ◆ Flavoxate (Generic) Use Cockcroft-Gault for renal dosing for the treatment of active motion sick- ness, prevention of postoperative nau- ◆ Ceftriaxone + calcium (continued on next page) sea and vomiting, allergic reactions, ◆ CRITERIA-FOR-USE CHANGES (cont.) Formulary update, from page 1 THERAPEUTIC INTERCHANGE OF OAB AGENTS Interchanged to Tolterodine ER 2 mg daily ◆ INTERCHANGES (cont.) Tolterodine IR 1 mg twice a day Oxybutynin ER 5 mg daily Darifenacin 7.5 mg daily Solifenacin 5 mg daily Tolterodine ER (Detrol® LA) for Trospium IR 20 mg daily Flavoxate 100 mg 3-4 times/day Oxybutynin ER (Ditropan® XL) Tolterodine ER (Detrol® LA) for Interchanged to Tolterodine ER 4 mg daily Solifenacin (Vesicare®) Tolterodine IR 2 mg twice a day Oxybutynin ER 10-30 mg daily Darifenacin 15 mg daily Solifenacin 10 mg daily Tolterodine ER (Detrol® LA) for Trospium IR 20 mg twice a day Trospium ER 60 mg daily Tolterodine IR (Detrol®) Flavoxate 200 mg 3-4 times/day Fesoterodine 4-8 mg daily Tolterodine ER (Detrol® LA) for ® OAB may affect quality of life for some the stimulation of clotting factors (ie, fac- Trospium ER (Sanctura XR) patients and is characterized by symp- tor VIII and von Willebrand factor [vWF]). Tolterodine ER (Detrol® LA) for toms of frequency and urgency, with or DDAVP has labeled indications for Trospium IR (Sanctura®) without urge incontinence. Antimusca- diabetes insipidus, enuresis, and rinic agents are first-line pharmacological bleeding in patients with hemophilia ◆ CRITERIA-FOR-USE CHANGES options for OAB. There are 6 marketed or von Willebrand’s disease. It is used antimuscarinic drugs with labeled indi- off-label for various uses including ure- Desmopressin Injection (DDAVP cations for the treatment of OAB. Flavox- mic bleeding. Patients with advanced [Generic])§ ate is used off-label for OAB. kidney disease are predisposed to §Use for uremic bleeding permitted There is no consensus on the preferred bleeding because of platelet dysfunc- agent for the treatment of OAB. Oxybu- tion. DDAVP improves platelet func- ® Dofetilide (Tikosyn by Pfizer)¶ tynin IR tablets and syrup and tolterodine tion, presumably because it stimulates ¶Dofetilide Order Form required ER capsules have been listed in the For- vWF. Everolimus mulary. Over the past year, there has been According to the official labeling, (Afinitor® by Novartis)** little use of the other agents in this class. DDAVP use is contraindicated in The comparative efficacy and safety of patients with a creatinine clearance **Chemotherapy Order Form required the various antimuscarinic agents used less than 50 mL/min. The clearance of Heparin, Unfractionated for OAB have been evaluated in system- DDAVP is reduced, which may cause (Generic)†† atic reviews and meta-analyses. The an unexpected degree of water ac- most recent and comprehensive of these cumulation leading to hyponatremia. ††Saline used to flush central catheters reviews show no significant difference However, there are instances in which in efficacy among the antimuscarinic it may be appropriate to use DDAVP in Linezolid (Zyvox® by Pfizer)‡‡ agents for OAB. ER products may be pre- patients with kidney disease. ‡‡Use with sympathomimetics per- ferred over IR products in patients who Uremic bleeding typically presents mitted in monitored units; Progress experience adverse reactions (ADRs). In with ecchymoses, purpura, epistaxis, Note required for use with antide- clinical trials, patients treated with tolt- and bleeding from venipuncture pressants erodine ER rarely discontinued therapy sites. These patients can also present Oseltamivir because of ADRs. with gastrointestinal or intracranial (Tamiflu® by Roche)§§ Detrol® LA is the most commonly bleeding. Because DDAVP normalizes prescribed drug used to treat OAB. It bleeding time in 75% of patients with §§Restricted to ID physician approval is the 66th most common prescription chronic renal failure, it is the most in community pharmacies (ie, 5.6 mil- common agent used in active uremic Lomustine is an oral alkylating lion prescriptions). Tolterodine ER was bleeding. DDAVP doses for uremic agent marketed since 1976 that is selected to represent OAB drugs so that bleeding are approximately 10-fold used to treat Hodgkin’s disease and the fewest number of interchanges will higher than doses used for diabetes brain tumors. The CeeNU® Dose-Pack, be necessary. insipidus (0.3 mcg/kg to 0.4 mcg/kg which contained 10-, 40-, and 100-mg Oxybutynin IR tablet and syrup remain IV or SQ as a single injection). An capsules, is no longer available. Only in the Formulary for patients taking it as important advantage of DDAVP is its the individual capsule strengths are a home medication and for patients un- rapid onset of action for acute bleeding available. able to take oral solid dosage forms. caused by uremic platelet dysfunction. Lomustine has not been used at Desmopressin is a synthetic analog Studies have shown that DDAVP Shands at UF for several years. There- of the endogenous hormone arginine decreases bleeding time within an fore, it was deleted from the Formu- vasopressin, which is often referred to hour after injection. Alternative op- lary. If ordered nonformulary, it still as DDAVP. DDAVP® is a brand name, but tions