TABLE OF CONTENTS. Drug Shortages

TABLE OF CONTENTS Drug Shortages 1 Medication Safety: New Gemini Neonatal and Pediatric Standard Drips Methotrexate Warning in Gemini HIV/AIDS Therapeutic Guidelines 2 HIV/AIDS Drugs on the Horizon 4 P& T Committee Formulary Action 6 Drug Shortages While the incidence of drug product shortages has been gradually increasing since the early 1990 s, health care professionals nationwide began reporting an escalation of the problem in 1999. In response, the American Society for Health-System Pharmacists (ASHP) launched a Drug Product Shortages Management Resource Center on its Web site (www.ashp.org/shortage). Since its launch in 2001, there has been an increase in the number of drug shortage bulletins and updates issued on the site, which is maintained by the University of Utah s Drug Information Service. Purportedly, the Web site resource center receives approximately 60 reports of shortages each month. Currently, more than 50 products are represented in bulletins on the site, and information about availability is provided for another 20 products. Furthermore, three months into 2002, the Food and Drug Administration (FDA) identified eight medically necessary drug products as being in short supply and 11 other products as having limited distribution. Drug product shortages stem from several factors including a shortage of raw materials, manufacturing problems, voluntary recalls, and the FDA halting a manufacturer s processing plant. Additional shortages have occurred as pharmaceutical manufacturers discontinue drug product lines. Drug shortages have the potential to negatively impact patient care through several mechanisms including: Disruption of medical procedures Less than optimal therapeutic alternatives Prolonging patients hospital stays Increasing medication errors and adverse drug events Furthermore, health care providers face the ongoing challenge to provide equivalent medications to patients and to conserve and ration inventories. Recently, the American Medical Association (AMA) and ASHP collaborated in bringing together a group of medical experts to explore solutions to the ongoing drug shortages problem. Various stakeholders representing the FDA, trade associations for research-based and generic pharmaceuticals manufacturers and distributors, purchasing group organizations, drug wholesalers, American Society of Anesthesiologists, the American Hospital Association, the Institute of Medicine and the Department of Veterans Affairs, assembled to identify and categorize potential causes and solutions to the problem of drug shortages. In short, participants at the meeting cited the need for improvement in the areas of: Communications Manufacturing Distribution and inventory management Regulation and enforcement Economic incentives Research and study Better communication, including notifications about imminent shortages and future drug availability, topped the list of possible solutions for prevention or effective resolution of drug shortages. One strategy involved requiring manufacturers to notify the FDA of potential product shortages. Overall, the group acknowledged the importance of a centralized resource to provide physicians, pharmacists, and other health care providers with ready access to up-to-date, reliable information about alternative therapies. Readers who require additional information are referred to the published summary of the session available at www.ashp.org/public/pubs/ajhpopen/11b-sf-witmer.pdf. Drug Shortages at University of Illinois Hospital It is recognized that ongoing drug shortages can present a serious threat to patient care and safety. Therefore, the Department of Hospital Pharmacy Services promotes preparedness for such occurrences by employing several procedures as described below: Information regarding current and impending drug shortage information is sought through literature search and web site (ie. ASHP, FDA, etc.) on a regular basis. This includes direct communication with the manufacturer for information including reason for the shortage, a product release date, direction for ordering drugs on allocation or for emergency supplies. 1 2

All attempts are made to obtain needed supplies. This includes obtaining supply from alternative suppliers/wholesalers or ordering allocated or emergency supplies from the manufacturer. Manufacturers sometimes require physicians to initiate the request based on individual patient s need. Literature search and drug use evaluation (if necessary) is performed for the purpose of identifying clinically appropriate uses of a drug, the lowest optimal dose, strategies to decrease drug waste, alternative products and priority uses for extreme shortages. Based on the extent of the shortage, the availability of alternatives, and results of a drug use evaluation (if performed), a plan is developed to restrict use, reduce waste or select an alternative product. A plan to restrict use of drug is developed by consulting literature, web sites, physician experts who use the product and other local hospitals. Strategies are also planned to avoid inappropriate use or dosing confusion of alternative drugs. Drug supply may be removed from nursing unit floor stock or other non-pharmacy storage areas when necessary. Drug is dispensed from the pharmacy in accordance with the developed restricted use plans. All medical center personnel are alerted to the shortage, possible substitutes and potential adverse events. UIC Drug Shortages Update Critical Shortage: Glucococorticoids for injection betamethasone, hydrocortisone, methylpredisolone ü Use oral agents whenever possible. ü Consider dexamethasone inj. only for patients unable to take oral medications. ü Reserve methylprednisolone inj. for critical indications such as spinal cord injuries or exacerbations of multiple sclerosis. ü Reserve betamethasone inj. for use in obstetric patients. Other Drug Shortages: Limited supply on backorder Isoniazid inj. Diazepam inj. Benztropine inj. Out of stock Clonidine inj. Diazoxide inj. HibTiter Meruvax II Methohexital inj. Neomycin oint. Piperacillin injection Prevnar Prochlorperazine inj. Streptokinase inj. Zinc oxide paste Medication Safety New Gemini Neonatal and Pediatric Standard Drips New Neonatal and Pediatric common IV orders are available under the IV Solutions clinical category in PowerChart. Click the Common Drips - Adult and Neonate/Peds folder to order. There are standard orders for neonatal electrolyte bags based on infusion rate and line access and other medications that include normal starting doses with appropriate infusion rates based on weight. New pediatric IVs include standard ArtLine and CVP IV orders. These new IV orders should facilitate proper ordering of IVs for neonatal and pediatric patients. Methotrexate warning in Gemini In response to an alert from the Institute of Safe Medication Practices, clinicians ordering oral methotrexate on the Gemini patient care system will receive the following alert: DEATHS HAVE BEEN REPORTED WITH DAILY ADMINISTRATION OF ORAL METHOTREXATE WHERE WEEKLY DOSING WAS INTENDED. Please choose an appropriate dosing frequency for the indication This alert will fire to the ordering clinician to prompt a double-check that the right frequency is chosen for the patient s indication. An additional alert fires to the pharmacist on the PharmNet system to make them aware to check the medication frequency for appropriateness as well. HIV/AIDS Therapeutic Guidelines The guidelines for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) change frequently. This is due to new and changing information about the disease, which calls for revising and updating the treatment guidelines, to ensure optimal therapeutic outcomes in patients. There are biological markers that detect the activity of HIV in the body. One such marker is the CD4 cell count, and the other marker is the HIV viral load. CD4 cells (called helper-t cells) are important to the immune system. When a large number of these cells are destroyed, AIDS develops. These markers help to assess the risk of disease progression to AIDS, and to monitor response to therapy. The restoration of the number and function of both CD4 and CD8 cells during HIV-1 replication has resulted in dramatic reductions in morbidity and mortality. The goal of therapy in HIV patients is to prolong life while suppressing viral replication. The optimal time to initiate therapy remains in question. However, as suggested by the results of a recently completed cohort study, the major determinant of initiating therapy appears to be the CD4 count. Results from this study suggest an increase in mortality when antiretroviral therapy is initiated in patients with CD4 counts below 200/µL compared with initiation at higher levels. Therefore, the International AIDS Society- USA Panel has recently updated their recommendations on when antiretroviral therapy should be initiated, and what guidelines should be utilized. The Panel now recommends 2

that therapy with highly active antiretroviral therapy (HAART) be initiated at CD4 counts higher than 200 cells/µl. There is however, still some debate as to what level above 200 cells/µl therapy should be initiated. In primary HIV infection, physicians must thoroughly consider the risk and benefits of starting antiretroviral therapy for CD4 counts above the 200/µL range, and make individualized informed decisions based on the patient s immunologic status, as well as the patient s willingness to initiate an often complex drug-regimen. For patients with established infection but who are asymptomatic, the recommendation for treatment is based on both the CD4 count and the viral load. Due to the high risk of opportunistic infections, therapy should be initiated in patients who have late disease and/or symptomatic HIV infection with a persistent CD4 count of <200 cells/µl, or who have been diagnosed with AIDS or severe recurrent HIV related illnesses or tumor. There are three classes of antiretroviral agents currently available: Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) which are zidovudine (AZT, ZDV), didanosine (ddi), zalcitabine (ddc), stavudine (d4t), lamivudine (3TC), abacavir (ABC) and the nucleotide reverse transcriptase inhibitor (NtRTI), tenofovir; Non-nucleoside reverse transcriptase inhibitors (NNRTI) which are efavirenz (EVF), nevirapine (NVP), and delavirdine (DLV); Protease inhibitors (PI) which are indinavir, ritonavir, nelfinavir, saquinavir, amprenavir, and lopinavir+ritonavir (Kaletra). Although no single agent or regimen has been identified as curative against HIV, combinations of these agents have been shown to be potent inhibitors of viral replication, reducing the virus to below detectable levels. In general, there are 3 different combination regimens for the initial treatment of an established HIV infection: PI (with or without low-dose ritonavir) + NRTIs NNRTI + 2 NRTIs 3 NRTIs (patients with low viral loads and adherence concerns). There is no optimal drug regimen, and therapy must be individualized based on specific patient criteria. Factors to consider when selecting agents for use include, efficacy and durability of antiretroviral activity, tolerability and adverse effects, drug regimen convenience, requirements, and potential drug interactions (see table 1). Monitoring parameters include CD4cell and viral load counts, complete drug adherence, drug resistance testing, and drug concentration monitoring. Clinical efficacy is associated with a decrease in viral load and an increase in CD4 cell count. Treatment naïve patients typically experience at least one treatment failure within the first year of therapy. Individuals fail therapy for different reasons including; adherence and tolerability of the regimen(s), and baseline virologic or immunologic status. Therapy should be changed based on the initial antiretroviral regimen (see table 2). Table 1. Recommended antiretroviral agents for initial treatment of HIV infection. (Antiretroviral drug regimens inlude one choice each from columns A and B of this table. Drug are listed in alphabetical order.) Recommendation Column A Column B Strongly recommended Alternative recommendations No Recommendation; insufficient data Not Recommended- Should not be offered Efavirenz Indinavir Nelfinavir Ritonavir + indinavir Ritonavir/lopinavir (Kaletra ) Ritonavir + saquinavir (softgel or hardgel capsules) Abacavir Amprenavir Delavirdine Nelfinavir+saquinavir softgel capsules Nevirapine Ritonavir Saquinavir softgel capsules Didanosine + lamivudine Stavudine + didanosine Stavudine + lamivudine Zidovudine + didanosine Zidovudine + lamivudine Zidovudine+zalcitabine Hydroxyurea in combination with antiretroviral drugs Ritonavir + amprenavir Ritonavir + nelfinavir Tenofovir Monotherapy with any agent (except in pregnancy) Saquinavir hard gelatin capsule Stavudine + zidovudine (Invirase)-except in combination Zalcitabine + didanosine with ritonavir Zalcitabine + lamivudine Zalcitabine + stavudine From: CDC Guidelines for using antiretroviral agents, MMWR 2002;51(no. RR-7)1-69. 3 3

Table 2. Antiretroviral Regimens And Management Strategies For Suspected Treatment Failure Initial Regimen Failure 2 NRTIs plus an NNRTI Change Both NRTIs and add a ritonavir boost PI component if not part of original regimen or Change to 2 PIs 2 NRTIs plus a PI Change the 2 NRTI components and add an NNRTI or 2 NRTIs plus 2 PIs or 2 NRTIs plus an NNRTI plus 1 or 2 PIs 3 NRTI 2 NRTIs plus an NNRTI or 2 NRTIs plus 1 or 2 PIs or 2 NRTIs plus an NNRTI plus 1 or 2 PIs or Consider adding a nucleotide reverse transcriptase inhibitor (NtRTI) Fixed-Combination Products Kaletra (Lopinavir + ritonavir) is a fixed combination of two protease inhibitors: ritonavir, decreases metabolism and increases the plasma concentrations of lopinavir. The antiretroviral activity of the combination is due to lopinavir since ritonavir is not present in a therapeutic dosage. In general, Kaletra is administered orally twice daily with. Trizivir contains the fixed combination of 3 nucleoside analogs (abacavir sulfate, lamivudine, zidovudine). The agent abacavir sulfate (Ziagen) has been associated with fatal hypersensitivity reactions in approximately 3% to 5% of patients, and should be discontinued as soon as a hypersensitivity reaction is suspected. Symptoms associated with abacavir hypersensitivity include fever, rash, fatigue, abdominal pain/gastrointestinal symptoms, cough, dyspnea, and pharyngitis.trizivir should not be reintroduced following an initial hypersensitivity reaction, as severe or fatal hypersensitivity reactions can occur within hours after restarting therapy with abacavir. In general, the recommended oral dose of Trizivir for adults and adolescents is 1 tablet twice daily. Nucleotide Reverse Transcriptase Inhibitor Viread (tenofovir disoproxil fumarate, [tenofovir DF] Gilead Sciences) is a nucleotide analog recently approved for use in combination with other antiretroviral agents for the treatment of HIV infection. Tenofovir DF should be reserved for use in patients currently receiving antiretroviral treatment and experiencing resistance, treatment failure or in salvage therapy. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir, and subsequent phosphorylation to form tenofovir diphosphate and in this form it has a prolonged half-life, which allows for its once daily dosing. It inhibits the activity of HIV reverse transcriptase by competing with the natural substrate deoxyadenosine 5 -triphosphate and, after incorporation into the DNA, by DNA chain termination. The risk-benefit ratio has not been established in antiretroviral naïve patients; studies are ongoing in this population. The recommended dose of tenofovir DF is 300mg orally taken once daily, preferably with a full meal that contains some fat. Drug interactions include increase in concentrations of didanosine when given concurrently with tenofovir DF. Other interactions include cidofovir, ganciclovir, acyclovir, valacyclovir, and valganciclovir. These drugs can increase the concentrations of tenofovir DF by competing for tubular secretion or by their reduction in renal function. The most common adverse events are diarrhea, nausea, vomiting, and flatulence. Renal impairment has been reported with the use of tenofovir DF, especially in patients with underlying systemic or renal disease, or in those taking nephrotoxic agents. Some adverse events that were reported voluntary with post-approval use of Viread include asthenia, pancreatitis, dizziness, dyspnea, hypophosphatemia lactic acidosis, rash, elevated creatinine, renal insufficiency, and kidney failure. The reports were from an unknown population size so frequencies could not be determined. Reports of lactic acidosis and severe hepatomegaly with steatosis have been documented, with the most data reported in females. Risk factors for this seem to be obesity, prolonged exposure to nucleosides, and known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors for liver disease. Treatment with Viread should be withheld in patients with clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity. Its role in therapy is for use in combination with other antiretrovirals in patients who have clinically progressed disease. Drugs on the Horizon There are currently a total of 16 FDA-approved antiretroviral agents; however, several antiretroviral drugs are currently under investigation. The following lists comprise investigational antiretroviral agents in the currently available drug classes: Nucleoside reverse transcriptase inhibitors (NRTIs) Emtricitabine (aka FTC; brand: Coviracil) Lodenosine (aka F-ddA) DOTC (aka BCH 10652) Amdoxovir (aka DAPD) D-D4FC DPC 817. Non-nucleoside reverse transcriptase inhibitors (NNRTs) Emivirine (aka MKC 442; brand: Coactinon) DPC 083, Capravirine (aka AG1549 or S-1153) Calanolide A TMC 125 (aka R165335). Protease inhibitors (PIs) Tipranavir (aka PNU 140690) Atazanavir (aka BMS 232632) GW-433908 (aka VX-175) Mozenavir (aka DMP 450) TMC 126 or TMC 114 DPC 681 & 684. Cross- resistance, intolerance, and serious long-term side effects are associated with the available classes of antiretroviral drugs. Efforts to develop drugs that target HIV molecular entities other than NRTIs, NNRTIs, or PIs are in progress. Integrase inhibitors and fusion inhibitors are potential new classes of antiretroviral drugs that may become available in the near future. 4

Integrase inhibitors: (DCQA/DCTA, Zintevir [aka AR 177]) Mechanism of action: HIV-1 integrase, the enzyme that inserts the double-stranded viral DNA copy of the RNA genome into the chromosomes of a human infected cell, is inhibited and viral replication is shut down. Like reverse transcriptase and protease, integrase is absolutely essential for viral replication. HIV mutants with inactive integrase enzymes can infect cells and even produce (via reverse transcriptase) viral DNA, but because this new DNA cannot then be integrated into cellular DNA, no new viruses are produced. Fusion inhibitors: (Pentafuside [aka T-20], T-1249, PRO 542) Mechanism of action: bind to HIV envelop protein, gp 120, Generic name Brand Food effect/alcohol effect Major/severe adverse drug reactions & special instructions Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Abacavir (ABC) Ziagen Take without regard to Fatal hypersensitivity -DO NOT RECHALLENGE Didanosine (ddi) Videx EC -Alcohol increases ABC level by 41% Taken on an empty stomach -buffered formulation -pancreatitis, peripheral neuropathy Lamivudine (3TC) Epivir Avoid alcohol Take without regard to Generally well tolerated Stavudine (d4t) Zerit Take without regard to Dose-dependent peripheral neuropathy, pancreatitis Zalcitabine (ddc) Hivid Take without regard to Severe peripheral neuropathy, oral ulcers Zidovudine (AZT, ZDV) Retrovir Take without regard to Bone marrow suppression, anemia, myopathy Zidovudine + lamivudine Combivir Take without regard to Bone marrow suppression, anemia, myopathy Abacavir + zidovudine + lamivudine Trizivir Take without regard to Bone marrow suppression, anemia, myopathy, fatal hypersensitivity DO NOT RECHALLENGE Tenofovir disoproxil fumarate Viread Take with a meal -nucleotide reverse transcriptase inhibitor Fatal ADR: lactic acidosis and severe hepatomegaly with steatosis have been reported. Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Delavirdine Rescriptor Take without regard to Efavirenz Sustiva Avoid taking after high fat meals Nevirapine Protease inhibitors (PIs) Amprenavir Indinavir Viramune Agenerase Crixivan Take without regard to Take with or without meals, but avoid high fat meals Take on empty stomach or light snack. Nelfinavir Viracept Take with Diarrhea Ritonavir Norvir Take with Saquinavir hard gel cap Saquinavir soft gel cap Invirase Fortovase Take without regard to Take with Rash, Stevens-Johnson syndrome (SJS), increased transaminases, headache Rash, central nervous symptoms (dizziness, insomnia, abnormal dreams), increased transaminases, contraindicated in pregnancy Rash, SJS, increased transaminases, hepatitis Stepped dose (200mg qd x14 days then 200mg bid thereafter) Oral solution contains propylene glycol; contraindicated in pregnant women and children < 4 years old, patients with hepatic or renal failure, & patients treated with disulfiram or metronidazole. Gastrointestinal, rash Patients must be well hydrated, and should be instructed to drink 1.5 liters of fluid/day Gastrointestinal, nephrolithiasis, hyperbilirubinemia Refrigerate capsules; refrigeration of oral solution is not necessary Taste perversion, paresthesias, increased triglycerides, elevated CPK and uric acid Refrigerate soft gel capsule (SGC) Elevated transaminase enzymes, acute hyperglycemia Refrigerate capsules until they are dispensed. Capsules stored at room temperature should be used within 2 Lopinavir + ritonavir Kaletra Take with months. Oral solution contains 42% alcohol. Pancreatitis, hepatic toxicity, hyperlipidemias, and hyperglycemia Empty = take on an empty stomach, two hours before or after 5 Light meal = not high in calories, fat or protein, e.g. toast +jelly, crackers, corn flakes + skim milk

to prevent HIV virus from binding to CD4+ cell surface. The HIV virus can enter into CD4+ cells by different ways: -With viral envelope protein, gp 120, HIV virus is able to attach to the cell surface of the CD4+ molecule. -HIV may change the structure of its gp120 in order to bind the chemokine co-receptors (CCR5 or CXCR4) on the surface of CD4+ molecule for cell signaling. -By changing the structure of gp41, another viral envelope protein, HIV virus is able to fuse with CD4+ cell surface. Chemokine Receptor Antagonists: (T-22, AOP-Rantes, TAK-779, NSC651016) Mechanism of action: chemokine receptor antagonists include CCR5 and CXCR4 inhibitors. They prevent the second step in viral entry by blocking gp120 from binding to chemokine co-receptors, either CCR5 or CXCR4. Cardiac abnormalities such as QT prolongation and abnormal conduction have been observed during clinical development. Other new classes: Hydroxyurea-like compounds: BCX-34 (purine nucleoside phosphorylase inhibitor), Didox (ribonucleotide reductase inhibitor), VX497 (inosine monophosphate dehydrogenase inhibitor). Immune modulators: HE2000 Interleukin 2 alpha interferon Another limitation of currently available antiretroviral therapy involves the complexity of the regimens due to the high pill burden and dosing frequency. There is a new trend to develop once-daily dosing regimens to facilitate compliance. Efavirenz 600 mg, amprenavir 1200 mg plus ritonavir 200 mg, and lamivudine 300 mg are currently FDA-approved for once-daily dosing, and several other agents including stavudine, abacavir, lopinavir/ritonavir, and saquinavir plus ritonavir are under investigation for this purpose. Deletions (cont.) Pindolol 20mg tablet Piroxicam Plicamycin Deletions cont. Prazosin 2mg, 5mg capsule Rose bengal Secretin 75 unit/ml injection Tranexamic acid Trioxsalen CONTRIBUTORS: Ijeoma Nwazue, PharmD candidate Hoang Nguyen, BS Pharm, PharmD Candidate Connie Larson, PharmD Jamie Paek, PharmD Mariela Diaz-Linares, PharmD Editors: Linda Kay, PharmD, MS Candidate Amy Lodolce, PharmD, BCPS P&T COMMITTEE FORMULARY ACTIONS Additions Voriconazole (200mg tab, inj) Restricted, ID Consult Required Piperacillin/Tazobactam (3.375gm, 4.5gm inj) Restricted, Adult/Peds Oncology or ID, ICU Line Extensions Secretin 16mcg injection Changes in Restrictions Nifedipine IR capsules Restricted, Pediatrics, OB/Gyne, Cath Lab Deletions Due to low use or manufacturer discontinuation Methazolamide Metyrapone Mexiletine Nafarelin Naphazoline Naphazoline/antazoline Orphenadrine Phenazopyridine 200mg tablet