P&T News: December 2004

Adverse Drug Reaction (ADR) Reporting Program:
Update and Recent Drug Safety Warnings

Kevin Bebout, R.Ph.
Peer Review Status: Internally Peer Reviewed

During fiscal year 2003-2004, the Pharmacy and Therapeutics (P&T) Subcommittee reviewed 360  adverse drug reaction (ADR) reports submitted directly through the Adverse Drug Reaction Reporting Program; beginning in March 2004, an additional 223 ADR notifications were automatically submitted electronically to the UIHC ADR Reporting Program via INFORMM Patient Record (IPR).  From all of these reports, 25 were subsequently submitted to the Food and Drug Administration (FDA) via the MedWatch Program because they were identified as severe, unusual, or occurring with a newly marketed drug.

During the year, the ten most frequently reported causative agents were: phenytoin, carboplatin, warfarin, vancomycin, heparin, eptifibatide, levofloxacin, enoxaparin, morphine, and piperacillin/tazobactam. (See Figure 1 for a summary of the agents and drug classes associated with ADRs.)  As in years past, anti-infective agents and drugs that affect the central nervous system were associated with over one half of all ADR reports submitted directly to the UIHC ADR Reporting Program.  Within these two therapeutic drug classes, penicillins were identified 22 times, cephalosporins 21 times, and opioids 20 times.  It should also be noted that anticoagulants and blood formation modifying drugs were likewise associated with a substantial number of adverse reactions (47 reports total).

Figure 1


The Important Role of Health Care Professionals
All health care professionals must perform vigilant post-marketing surveillance in order to continue the necessary monitoring after new agents reach the market.  New data are used to update the prescribing information of recently approved agents and, in some cases, drug entities that have been marketed for years.

Whenever you become aware of an adverse drug reaction (whether in the inpatient or ambulatory care environments), please complete and submit an adverse drug reaction incident report using IPR.  Look for “Adverse Drug Reaction (NOT Med Error)” under IPR’s Incident Reporting tab. All ADR reports submitted via IPR are automatically forwarded to the UIHC ADR Reporting Program for review and summary report generation for the Pharmacy and Therapeutics Subcommittee; no additional notifications are required. Alternatively, staff who wish to report an adverse drug reaction may telephone the Drug Information Center at 6-2600. 

Recent Drug Safety Warnings
In recent months, the FDA and/or drug manufacturers have distributed new nationwide safety warnings and instituted labeling changes on various prescription drug products prompted by submission of adverse drug event reports to the MedWatch Program and because of findings in post-marketing safety studies.  New warnings and revised product labeling, which are summarized below, have been issued for bevacizumab, risperidone, venlafaxine, bupropion, paroxetine, and trazodone.

Bevacizumab
FDA and the manufacturer of bevacizumab (Avastin®- Genentech), an antineoplastic agent, issued an important drug warning to healthcare providers that there is evidence of an increased risk of serious arterial thromboembolic events, including cerebrovascular accident, myocardial infarctions, transient ischemic attacks, and angina related to bevacizumab use. The risk of fatal arterial thrombotic events is also increased. In randomized, active-controlled studies conducted in patients with metastatic colorectal cancer, the risks of a serious arterial thrombotic event was approximately two-fold higher in patients receiving infusional 5-FU based chemotherapy plus Avastin®, with an estimated overall rate of up to 5%. A revised Avastin® package insert containing more detailed information on arterial thromboembolic events is in development.

Risperidone
FDA and Janssen, the maker of the atypical antipsychotic drug risperidone (Risperdal®), revised the WARNINGS section of this product’s labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Risperdal.  FDA asked all manufacturers of atypical antipsychotic medications, including Janssen, to add this Warning statement to labeling:

WARNING

Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including Risperdal®. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

“Dear Healthcare Provider” Letter, July 2004
Janssen Pharmaceutica, Inc.

 

Venlafaxine 
FDA and the maker of venlafaxine HCl (Effexor® and Effexor XR® - Wyeth Pharmaceuticals) notified healthcare professionals of revisions to the WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of labeling to alert healthcare providers of potential harm to neonates when this antidepressant drug is used during the third trimester of pregnancy:

PRECAUTIONS,  PregnancyNon-teratogenic Effects

Neonates exposed to Effexor®, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. When treating a pregnant woman with Effexor® during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

“Dear Healthcare Professional” Letter, June 2004
Wyeth Pharmaceuticals

 

 

Bupropion,  Paroxetine, and  Venlafaxine
FDA and the manufacturers of several antidepressant drug products (including bupropion [Wellbutrin®, Wellbutrin SR® and Wellbutrin XL®- GlaxoSmithKline]; paroxetine  [Paxil®â and Paxil CR®- GlaxoSmithKline]; and venlafaxine [Effexor® and Effexor XR®- Wyeth Pharmaceuticals]) notified healthcare professionals of revisions to the WARNINGS and PRECAUTIONS sections of product labeling to alert healthcare professionals that patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications.

WARNINGS

Clinical Worsening and Suicide Risk

Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.

“Dear Healthcare Professional” Letters, May/June 2004
GlaxoSmithKline
Wyeth Pharmaceuticals

 

Trazodone

FDA and Bristol-Myers Squibb (maker of trazodone, Desyrel®) notified healthcare professionals of revisions to the CLINICAL PHARMACOLOGY and PRECAUTIONS sections of the Desyrel® labeling. Desyrel® is indicated for the treatment of depression. In vitro drug metabolism studies suggest that there is a potential for drug interactionswhen trazodone is given with the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir. It is likely that CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. Conversely, carbamazepine reduced plasma concentrations of trazodone when coadministered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taken with carbamazepine.

The following label changes include modifications to the Clinical Pharmacology section:

Drug-Drug Interactions
In vitro drug metabolism studies reveal that trazodone is a substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and trazodone metabolism can be inhibited by the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cmax of trazodone increased by 34%, the AUC increased 2.4-fold, the half-life increased by 2.2-fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were coadministered.  Carbamazepine induces CYP3A4. Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone (as well as mCPP) by 76 and 60%, respectively, compared to pre-carbamazepine values.

“Dear Healthcare Professional” Letter, May 2004
Bristol-Myers Squibb

Summary

Additional information about recent safety alerts for drugs, biologics, medical devices, and dietary supplements available in the United States may be viewed on the FDA’s web site at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm.

 


CLARIFICATION OF FEDERAL REGULATIONS PERTAINING TO THE PRESCRIBING OF C-II DRUGS VIA AMBULATORY CARE PRESCRIPTION

The U.S. Drug Enforcement Administration (DEA) has recently changed its interpretation of the U.S. Controlled Substances Act (CSA) pertaining to ambulatory prescriptions for Schedule II (C-II) drugs.  Specifically, the DEA now stipulates that prescribers can no longer prepare multiple prescriptions for the same Schedule II drug on the same day with instructions to the patient and pharmacist to fill the prescriptions on different dates in the future (the prescriber writing, for example, “Do not fill until February 1, 2005”).  For a prescriber to prepare multiple prescriptions on the same day with instructions to fill on different dates is now judged by the DEA to be tantamount to writing a prescription authorizing refills of a Schedule II controlled substance, thus conflicting with one of the fundamental tenets of the CSA.  The primary purpose for this limitationin the law is to prevent the prescribing of controlled substances for unlawful (nonmedical) purposes. 

While the prescribing of pain medications was initially the focus of this clarification statement, the DEA has confirmed that the law pertains to prescriptions for all C-II drugs (including stimulants such as methylphenidate).

This information is being provided to clarify earlier information from the DEA that informed DEA registrants that multiple prescriptions could be written at the same time with instructions for future fills. Complete information from the DEA may be viewed at: http://a257.g.akamaitech.net/7/257/2422/06jun20041800/edocket.access.gpo.gov/2004/04-25469.htm

Please note that the DEA has also stated that C-II prescriptions with future fill dates currently on file at a pharmacy may be honored and filled by that pharmacy.  However, pharmacies may not now fill any new C-II prescriptions with future fill dates brought to the pharmacy by a patient or prescriber; such prescriptions must be written at the time of patient need.

Questions may be addressed to Kevin Bebout, Administrative Pharmacy Practice Specialist in the Department of Pharmaceutical Care, at 6-2577 or kevin-bebout@uiowa.edu.

PHARMACY  AND  THERAPEUTICS  SUBCOMMITTEE  ACTIONS

DRUGS ADDED TO STOCK

APOMORPHINE

CANTHARIDIN 0.7% IN FLEXIBLE COLLODION AND CANTHARIDIN 1%, PODOPHYLLUM 5%, AND SALICYCLIC ACID 30% IN FLEXIBLE COLLODION

DIPHENYLCYCLOPROPENONE IN ACETONE

EMTRICITABINE WITH TENOFOVIR

TRICHLOROACETIC ACID

TRICHOPHYTON

DELETED FROM STOCK

BLADDER MIXTURE WITHOUT PHENABARBITAL ORAL SOLUTION
Deleted due to low use.  Oxybutynin and tolterodine are available.

DIFLUNISAL TABLETS
Deleted due to low use.  Ibuprofen, naproxen, and salsalate are available.

HYDROCORTISONE HEMISUCCINATE RECTAL SOLUTION
Deleted due to low use.  Hydrocortisone retention enemas are available.

LUNELLE® INJECTION
Discontinued by the manufacturer.  Oral contraceptives and medroxyprogesterone injection are available.

PANTOPRAZOLE INJECTION
Replaced with lansoprazole injection.

PROPANTHELINE TABLETS
Deleted due to low use.  Oxybutynin and tolterodine are available.

ADDITIONAL ACTIONS

BORIC ACID POWDER
This compounded powder for ear insufflation was added to stock.

HEPARIN FLUSH SOLUTION
10 units/ml and 100 units/ml solutions for catheter flush were added to stock.

IDOCHLORHYDROXYQUINE 5% IN BORIC ACID POWDER
This compounded powder for ear insufflation was added to stock.

LIDOCAINE 4% WITH PHENYLEPHRINE 1% NASAL SOLUTION
This compounded product has been added to stock.

OLANZAPINE INJECTION
This product (Zyprexa®) is indicated for the treatment of agitation associated with schizophrenia and bipolar mania.

Cost:  $17.27 per 10 mg vial.

OXYBUTYNIN EXTENDED-RELEASE TABLETS
This product (Ditropan® XL) is indicated for the treatment of overactive bladder.

OXYBUTYNIN TRANSDERMAL PATCH
This product (Oxytrol®) is indicated for the treatment of overactive bladder.

REMINDER:  Use Metric Weight - Not Volume - To Express Liquid Medication Doses

PROBLEM: When doses of single ingredient liquid medications (oral or parenteral) are expressed by volume alone, the risk of serious medication errors increases.  For example, an order for a liquid medication with the dose expressed in milliliters (mL) rather then milligrams (mg), micrograms (mcg), units or grams can easily lead to transcription and dispensing errors that may culminate in a drug overdose.  This can be especially problematic if the medication is available in multiple concentrations; inadvertant use of the wrong product to fulfill an order prescribed by volume alone can also lead to significant drug overdoses (or under dosages).

SAFE PRACTICE RECOMMENDATION:  To reduce the possibility of medication errors, it’s critical for prescribers to use metric weight, not just the volume, for liquid medication doses.  If orders are received without the dose expressed in metric weight, pharmacists and nurses should always clarify the intended concentration with the prescriber.  Similarly, doses transcribed to medication administration records or other medication profiles should always be written using metric weight.  [Note: orders written for multiple-ingredient liquid medications may be written using volume when it is clearly understood which drug product is being prescribed.]

Additional information about safely prescribing medications at the UIHC can be found in the following hospital policies located on the UIHC Policies and Procedures Web Site:

I.23 Prescribing Medications for Hospitalized Patients (Inpatients) and Clinic Patients

I.17 Prescribing “Take Home” Medications for Clinic Patients or for Inpatients at the Time of Discharge (Ambulatory Care Patients)          

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