Volume 15, Number 6 SHANDS June 2001 at the University of Florida Drugs & Therapy B ◆ U ◆ L ◆ L ◆ E ◆ T ◆ I ◆ N

SHORTAGES FORMULARY UPDATE ® The Pharmacy and Therapeutics Shortage of Benadryl Committee met May 15, 2001. 3 drugs or dosage forms were added Injection ≠ IV hydroxyzine in the Formulary and 3 drugs were deleted. 3 drugs were designated rug shortages have become a way Why intramuscular hydroxyzine? nonformulary and not available. D of life. Prescribers are trying to Why can’t hydroxyzine be given IV? figure out what to do when something When given intramuscularly, the onset is not available or when it has limited of action is approximately the same as ◆ ADDED availability. It is hard to believe, but the oral. Therefore, the only reason to Estradiol tablets injectable diphenhydramine (ie, use this route would be when nothing, (generic of Estrace®) Benadryl® injection) has been difficult including oral hydroxyzine liquid, can Estradiol transdermal be given orally. ◆ Injectable hydroxyzine is not recom- (Climara® by Berlex) mended for intravenous administra- Pantoprazole injection During the shortage tion. The most recent labeling (ie, (Protonix® Injection by of injectable revised 1993) for Vistaril® Injection Wyeth-Ayerst) diphenhydramine, states in the Contraindications section, “Hydroxyzine hydrochloride ◆ DELETED prescribers have to intramuscular solution is intended only Anthralin cream determine the best for intramuscular administration and (Drithrocreme® by Dermik) alternative to an should not, under any circumstances, Guanethidine be injected subcutaneously, intra- (Ismelin® by Novartis) injectable antihistamine. arterially, or intravenously.” Because this is in the Contraindications section Rapacuronium of the labeling, it would be risky to use (Raplon® by Organon) to get. Hopefully, by the time this intravenous hydroxyzine under any article is published, this shortage will circumstances. Further, the Precau- ◆ NONFORMULARY AND be resolved. During the shortage of tions section of the labeling it states, NOT AVAILABLE injectable diphenhydramine, prescrib- “As with all intramuscular prepara- Conjugated estrogens + ers have to determine the best alter- tions, Vistaril® Intramuscular Solution medroxyprogesterone native to an injectable antihistamine. should be injected well within the body ® (PremPro by Wyeth-Ayerst) Alternatives to injectable diphenhy- of a relatively large muscle. Inadvert- Esterified estrogens dramine include oral diphenhydra- ent subcutaneous injection may result (Estratab® by Solvay or mine or hydroxyzine, intramuscular in significant tissue damage.” Menest® by SmithKline Beecham) hydroxyzine, intravenous promethaz- The reasons for these warnings ine, and injectable corticosteroids. are not well-known. Before 1970, the Estropipate Although not listed in the Formulary, labeling for parenteral hydroxyzine (Ogen® by Upjohn) injectable dimenhydrinate would be included the intravenous route of ad- another alternative, if the diphenhy- ministration. In 1970, the intravenous It is impractical to list every dramine shortage persists. route of administration was removed estrogen product and/or estrogen The onset of action is slower for after several reports of thrombosis and combination product in the Formu- oral diphenhydramine or hydroxyzine; gangrene were associated with the IV lary in order to continue therapy however, the oral route is usually the route of administration. These unfor- that patients are taking as outpa- best option. Oral hydroxyzine is more (continued on page 4) tients. However, the P&T Commit- potent and is preferred to diphenhy- tee made changes that extend the dramine. In patients who cannot take ◆ oral medications, intramuscular hy- listing of the estrogen products in INSIDE THIS ISSUE the Formulary, while designating a droxyzine or an alternative injectable H1-blocker may be used. Intravenous few products nonformulary and not ◆ No controls with PPD testing available. corticosteroids or epinephrine are (continued on next page) needed for patients experiencing ◆ Td and tetanus toxoid shortage anaphylaxis or urticaria. Formulary update, from page 1 high levels to the liver and stimulate is a fixed combination product that Only conjugated estrogen (Premarin®) increased synthesis of triglycerides, was designated nonformulary and tablets, injection, and cream have transcortin, sex hormone-binding not available. Orders written for been listed in the Formulary. Several globulin and angiotensinogen. Trans- PremPro® will be automatically sub- other forms of estrogens are com- dermal estrogens may be preferred in stituted with the individual ingredi- monly used as hormone replacement women with hypertension, hypertri- ents that are listed in the Formulary. therapy in postmenopausal women. glyceridemia, or a history of increased PremPro® orders will be changed to Some women refuse to take conju- risk of cholelithiasis. orders for Premarin® 0.625 mg and gated estrogens because they have The major disadvantage of trans- medroxyprogestrone 2.5 mg with ethical issues with the method of dermal estrogen is the risk of skin the designation: P&T-Authorized collecting the urine from pregnant irritation (rash). This can be alleviated Change. horses. The urine of pregnant mares by rotating applications sites (ie, never If there are other fixed combina- is the raw material used to produce use the same site twice in a row) and tions of nonformulary estrogens, the equine conjugated estrogens. applying the patch on the buttocks. prescriber will be contacted to pre- Estrogens are commonly used as Moisture under the patch is also a scribe the individual constituents. hormone replacement therapy in problem and may contribute to the When the ingredients of combination postmenopausal women. The incidence of rash. products are not listed in the Formu- benefits in postmenopausal women lary, the prescriber may substitute ◆ include relief of moderate-to-severe the closest formulary alternatives or vasomotor symptoms, decreased risk The major disadvantage the product can be requested by the of osteoporosis, decreased vulvo- nonformulary process. vaginal signs and symptoms, and of transdermal estrogen Esterified estrogens contain 75% possibly decreased cardiovascular is the risk of skin irritation to 85% sodium estrone sulfate and disease. Hormone replacement 6% to 15% sodium equilin sulfate. It therapy may also be used in female (rash). Moisture under the was designated nonformulary and hypogonadism, castration, or primary patch is also a problem not available. Patients can be ovarian failure. and may contribute to switched to either estradiol tablets Estradiol tablets and transdermal (1 mg estradiol = 0.625 mg esterified patches were added in the Formu- the incidence of rash. estrogens) or conjugated estrogens lary. Estradiol tablets and patches are (0.625 mg = 0.625 mg). frequently requested nonformulary Estropipate is crystalline estrone products. These requests are usually Federal Law requires that patients solubilized as the sulfate and to continue therapy that has been receiving estrogen products be in- stabilized with piperazine. It was started on outpatients. formed of possible risks associated also designated nonformulary and Estradiol tablets were added as a with their use via written patient not available. Patients can be synthetic alternative to conjugated package inserts, which meet federal switched to either estradiol tablets (1 estrogens. Estradiol is the major requirements, before the administra- mg estradiol = 0.625 mg estropipate) hormone produced by a female’s tion of the first dose and every 30 days or conjugated estrogens (0.625 mg = ovaries. Although 6 different natural thereafter as long as therapy contin- 0.625 mg). estrogens have been isolated from ues. This statute neither applies to Pantoprazole injection is the only the human female, only 3 are present estrogen products used for contracep- injectable proton-pump inhibitor in significant quantities (ie, 17-beta- tion, nor does it apply if the agent in (PPI) currently on the US market. We estradiol, estrone, and estriol). question is being used to treat cancer. liberally use an extemporaneously Estradiol is rapidly and reversibly Whenever possible, transdermal compounded omeprazole liquid in oxidized to estrone. Both of these estrogens should be placed prior to a patients who cannot take oral can be converted to the much patient’s admission when the admis- capsules or tablets. Also, an inject- weaker estriol. sion is elective. This may avoid the able PPI could displace the use of Due to almost complete first-pass legal requirement to provide the injectable H2-blockers, which cost metabolism, estradiol must be given patient with the estrogen patient anywhere from 5% to 25% of the cost in a micronized oral dosage form to package insert while they are in the of pantoprazole injection. If inject- ensure therapeutic effect. Estradiol hospital. For more information, refer able pantoprazole is not used is extensively metabolized in the to hospital policy PM 02-04. responsibly, it could have a dramatic gastrointestinal mucosa during The approved patient information impact on pharmaceutical expendi- absorption. The liver also extensively leaflets describe when and how to use tures. Therefore, the use of panto- metabolizes it. Micronization of oral estrogens and the risks of estrogen prazole will be tracked for the 1st 6 estradiol tablets slows oral absorp- treatment. The information is designed months that it is available. tion and decreases 1st-pass metabo- for patients and contains a discussion Injectable pantoprazole was lism by the liver. Absolute bioavail- on the risk of cancer (ie, breast and approved as a 2nd-line agent for ability of micronized estradiol is uterus), gallbladder disease, pancreati- gastroesophageal reflux in patients roughly 5 to 10% of an administered tis, abnormal clotting, and endometro- unable to take oral medications. dose. sis. It explicitly warns against using Injectable pantoprazole should be Some clinicians prefer transdermal estrogens in pregnancy and in the discontinued as soon as the patient estradiol. The advantages of trans- post-partum period…not only because is able to resume treatment with oral dermal estrogen (compared with oral) of the possible effects on women (ie, therapy, which is emphasized in the include less interpatient variability in abnormal clotting), but because of labeling. Therefore, pantoprazole blood levels achieved (ie, oral estro- the possible effects on the fetus (ie, was added to the IV-to-PO policy. gens undergo extensive first-past possible birth defects and cancer later Taking other oral medications or oral metabolism and enterohepatic recircu- in life). solid feedings is the primary criteria lation) and less liver exposure to Conjugated estrogens plus for automatic switching. estrogens. Oral estrogens present medroxyprogesterone (ie, PremPro®) (continued on next page) 2 Formulary update, from page 2 SHORTAGES The following criteria for use are considered appropriate for inject- Controls not recommended able pantoprazole: ■ ICU patients with clinically- with PPD testing active GI bleeding. ■ Patients s/p gastric surgery. andida, mumps, and tetanus dation is based on the lack of stan- ■ Patients with post-op ileus C toxoid are in the Formulary at dardization of the products and the meeting the criteria for an oral Shands at UF. These skin tests are lack of validation of this practice proton-pump inhibitor. frequently ordered with PPD testing The Anti-Infective Subcommittee ■ Combination therapy with an IV with the clinician’s intent of using of the P&T Committee discussed H2-blocker should only be for these as controls with the PPD test for whether or not these skin tests should patients with refractory ulcer tuberculosis. be removed from the Formulary. Al- healing with nocturnal break- In the early 1990s, the Centers for though skin tests are not recommended through bleeding (PPI in AM, H2- Disease Control (CDC) recommended to be used as controls for PPD skin blocker in PM). the use of controls when testing for testing, some physicians use these ■ Maximum duration 14 days. tuberculosis in HIV infected patients agents in testing for anergy. Shands at ■ IV to PO when patient is eating and persons who have an increased UF currently spends $15,000 per year solid food. risk for tuberculosis infection (ie, on the candida, mumps, and tetanus Intravenous pantoprazole must intravenous drug users and those skin tests. be used with an in-line filter. The persons from countries endemic for The Anti-infective Subcommittee filter is supplied with each dose of tuberculosis). However, while the PPD recommends that these agents not injectable pantoprazole. skin test has been extensively studied be used as controls for PPD testing. Anthralin cream is a topical and validated, anergy tests have not In addition, due to the shortage of antipsoriatic agent. This product been standardized and the utility of tetanus toxoid and tetanus diphtheria has not been used in the last year anergy skin testing in helping to toxoid (see below), tetanus toxoid will at Shands at UF. The manufacturer interpret results of a negative PPD has no longer be dispensed at Shands at has discontinued it; therefore, it not been validated. UF when “controls” are ordered. was deleted from the Formulary. The most recent CDC recommenda- By Joanne J. Orrick, PharmD Guanethidine is a postganglionic tions for screening for tuberculosis REFERENCE adrenergic blocking agent that was infection do not recommend that 1. Anon. Screening for Tuberculosis and Tuberculosis used for the treatment of hyperten- anergy testing be routinely performed Infection in High-Risk Populations Recommendations of the Advisory Council for the Elimination of Tuberculosis. sion. It was approved by the FDA in high risk patients. This recommen- MMWR September 8, 1995, 44(RR-11);18-34. in 1960 and is rarely used today. It causes depletion of norepinephrine SHORTAGES in the synapse, causing reductions in total peripheral resistance and Tetanus-diphtheria toxoids producing reductions in blood pressure. Guanethidine has a sig- nificant side effect profile, specifi- and tetanus toxoid shortage cally pronounced postural hypoten- hands at UF is being impacted by In a recent Notice to Readers, the sion. It has not been used in the a severe shortage of tetanus and CDC reinforced the need to reserve last year at Shands at UF. The S diphtheria toxoids (Td) and tetanus the use of Td and TT for the priority manufacturers of guanethidine no toxoid (TT). We were first alerted indications listed above. Effective longer make this product. There- about this shortage in November 2000 immediately, clinicians should fore, it was deleted from the and, until recently, had been able to discontinue the use of Td and TT Formlary. keep enough product in stock to meet for routine booster vaccinations. To Rapacuronium is a nondepolariz- the needs of Shands at UF and the assure vaccine availability for priority ing neuromuscular blocking agent facilities that the Shands at UF indications, all routine Td boosters in that was used as an adjunct to Pharmacy serves. This shortage is adolescents and adults should be general anesthesia, for endotra- expected to last another 12 months. delayed until 2002. cheal intubation, and for neuro- Per CDC recommendations, the During this shortage, each clinic muscular blockade during short following are the criteria with the that the Shands at UF Pharmacy surgical procedures. The onset of highest priority for use during this serves will be restricted to ordering 1 action of rapacuronium is similar to shortage: multi-dose vial of TT or Td at a time. succinylcholine and it has a short 1. Persons traveling to a country where This vial should only be used for the duration of effect. the risk of diphtheria is high (Td); above priority indications. On March 29, 2001 the FDA 2. Persons requiring tetanus vaccina- By Joanne J. Orrick, PharmD announced that Organon is volun- tion for prophylaxis in wound tarily withdrawing rapacuronium REFERENCE management (Td or TT); 1. Anon. Deferral of Routine Booster Doses of Tetanus from the market. This action was 3. Persons who have received fewer and Diphtheria Toxoids for Adolescents and Adults. MMWR based on reports associating rapa- Weekly May 25, 2001/50(20); 418, 427. than 3 doses of any vaccine contain- curonium with bronchospasm. 5 ing Td; and deaths have been associated with 4. Pregnant women who have not been its use. vaccinated with Td during the Succinylcholine is an alternative, preceding 10 years. but it is in short supply. There is a nationwide back-order on succinyl- choline because the manufacturer has had difficulty acquiring the raw material to make it. 3 Drugs & Therapy SHANDS NON-PROFIT ORG. U.S. POSTAGE B ◆ U ◆ L ◆ L ◆ E ◆ T ◆ I ◆ N Shands at the University of Florida DRUG INFORMATION SERVICE PAID GAINESVILLE, FL Volume 15, No. 6 June 2001 PO Box 100316 PERMIT NO. 286 Gainesville, FL 32610-0316 This publication is produced by the Drug Information and Pharmacy Resource Center under the direction of the Department of Pharmacy Services and the Pharmacy and Therapeutics Committee. EDITOR, DRUGS & THERAPY BULLETIN Randy C. Hatton, PharmD DIRECTOR, PHARMACY SERVICES Alan Knudsen, MS, RPh CHAIRMAN, PHARMACY & THERAPEUTICS COMMITTEE Ricardo Gonzalez-Rothi, MD EDITING, DESIGN, & PRODUCTION Shands HealthCare’s Publication Svcs.  Copyright 2001. All rights reserved. No portion of the Drugs & Therapy Bulletin may be reproduced without the written consent of its editor.

Shortages, from page 1 Phenergan® Injections states, “The 25 mg per minute; it is preferable to tunate adverse events were actually preferred parenteral route of adminis- inject through the tubing of an intra- associated with inadvertent intra- tration for Phenergan® Injection is by venous infusion set that is known to arterial administration. deep intramuscular injection. The be functioning satisfactorily.” When an injectable H1-blocker is proper intravenous administration of It is expected that the shortage of needed, intravenous hydroxyzine is this product is well tolerated, but use injectable diphenhydramine will be NOT an option. The shortage of di- of this route is not without some resolved soon; however, there are some phenhydramine could lead to unfortu- hazard. It is not for subcutaneous lessons we can learn from this short- nate adverse drug events, if these administration. INADVERTENT age. Oral hydroxyzine is an excellent precautions are not known. INTRA-ARTERIAL INJECTION CAN alternative. Injectable promethazine There are limited alternatives to RESULT IN GANGRENE OF THE may be a reasonable alternative in injectable diphenhydramine. Injectable AFFECTED EXTREMITY. SUBCUTA- patients who require an injectable promethazine (eg, Phenergan®) does NEOUS INJECTION IS CONTRAINDI- antihistamine. have antihistaminic activity, but it has CATED, AS IT MAY RESULT IN Histamine binds more avidly to rarely been used for this pharmaco- TISSUE NECROSIS. Injection into or receptors than antihistamines. There- logic property. It also can be irritating near a nerve may result in permanent fore, pre-treatment with an oral anti- when injected IV, so it should only be tissue damage. When used intrave- histamine is always preferred to an used with caution. Although the nously, Phenergan® Injection should injectable antihistamine given after intravenous route of administration is be given in a concentration no greater a reaction has already begun. not contraindicated, the labeling for than 25 mg/mL at a rate not to exceed

4