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March 2010 FAQs

Questions

What is the cross-reactivity of cephalosporins and carbapenems in a patient with a penicillin allergy?

What are the latest recommendations for the prevention of torsade de pointes in the hospital setting?

What are the REMS requirements for hospitals dispensing ESAs to patients with cancer?

Dihydroergotamine in the treatment of migraines: recommended dosing strategies


Answers

What is the cross-reactivity of cephalosporins and carbapenems in a patient with a penicillin allergy?

Cephalosporins and carbapenems are antimicrobials that have a broad spectrum of activity against gram-positive and gram-negative bacteria.1 Cephalosporins and carbapenems are utilized for the treatment of a variety of common infections. A documented allergy to penicillin automatically flags a patient against the use of a cephalosporin or carbapenem, which can limit therapeutic options for treatment of infection. It is important to appropriately evaluate a patient’s allergy to medication since this can aid in the assessment of whether or not to use a related medication for treatment.2

Many patients will report an allergy to a medication, but in fact the reaction is more likely due to intolerance to the medication, not a true allergy.2 Allergies to penicillin are frequently documented, but the reaction is rarely documented. This is an important piece of information that is useful in determining whether or not a patient is eligible to receive other antimicrobial therapies. Allergic reactions are classified into 4 different types, as listed in Table 1.2-4 Each type of allergic reaction has a different causative antibody, clinical manifestation and onset. The type I allergy, also known as anaphylactic or immediate hypersensitivity, is mediated by IgE antibodies, occurs within 60 minutes of administration, causing symptoms from urticaria to bronchoconstriction to circulatory collapse. This is the most serious type of allergic reaction due to the potential severity of reactions.

Table 1. Gell and Combs Allergy Classification.2-4

Type of Allergic Reaction 2-4

Antibody Class

Onset

Clinical Manifestation

Type I

(anaphylaxis)

IgE

Within 60 min

Bronchoconstriction, hypotension, circulatory collapse, urticaria

Type II

(cytotoxic)

IgG, IgM

5-12 hrs

Thrombocytopenia, hemolytic anemia, granulocytopenia

Type III

(immune complex)

IgG, IgM

3-8 hrs

Glomerulonephritis, serum sickness, drug fever

Type IV

(cell-mediated)

None known

24-48 hrs

Contact dermatitis, graft rejection

Cephalosporins are semi-synthetic beta-lactam antibiotics, with similarities to penicillin in structure and spectrum of activity.3 There are currently 4 generations of cephalosporins which have activity against both gram positive and gram-negative bacteria; more gram-negative coverage with the increase in generation. Cephalosporins are beta-lactam antibiotics and contain a beta-lactam ring. One of the structural differences between penicillins and cephalosporins is the type of ring the beta-lactam ring is fused to. Penicillins have a beta-lactam ring fused to a 5-membered thiazolidine ring, whereas cephalosporins are fused to a 6-membered dihydrothiazine ring. Another structural difference between penicillins and cephalosporins is in the side chains on the base structure. Penicillins have only 1 side chain located on position 6, whereas cephalosporins have 2 side chains located on positions 7 and 3. These side chains determine activity and pharmacokinetic parameters within the drug class.

Carbapenems are beta-lactam antibiotics also structurally similar to penicillins but with a spectrum of activity that is one of the broadest amongst antimicrobial agents.3,4 Carbapenems have a beta-lactam ring fused with a 5-membered ring, similar to penicillin, but the main difference in the 5-membered ring structure is the sulfur atom at position 1 is replaced by a carbon atom in the carbapenem ring.

Literature Review

Literature has reported that penicillin allergy occurs in up to 20% of patients.5,6 Older literature reported that cephalosporins had a cross-reactivity rate of about 7-18%; however this is thought to be falsely elevated due to a non-allergic adverse drug reaction (ADR) being documented as an allergy.3,7,8 The studies were also open-label, not single or double-blinded. Also it is thought that cephalosporins may have been contaminated with penicillin product during manufacturing, which may be cause for elevated allergy rates historically.3,6 Studies that evaluate the cross-reactivity of cephalosporins in subjects with confirmed penicillin allergies via skin testing are considered to be more reliable.5 In more recent studies that enrolled patients who were penicillin-allergic documented by skin testing the rates of cross-reactivity were approximately 2%.

The mechanism behind cross-reactivity of cephalosporins with penicillin is thought to have more to do with the similarity between the side chains rather than the beta-lactam ring structure.9 Studies have shown that drugs with similar side chains will have a higher likelihood of cross-reactivity than those with structurally different side chains.10 First generation cephalosporins have similar side chain structures with penicillin, hence in increase incidence of cross-reactivity.6 Whereas second and third generation cephalosporins have a higher variability within the side chain structures, decreasing the probability of cross-reactivity with penicillins. Figure 1 documents the similar side chains between various penicillins and cephalosporins. This mechanism of side-chain comparison can be used to evaluate antimicrobial management of a truly penicillin allergic patient. For example, if a patient has a documented allergy to amoxicillin, there would be a higher potential for cross-reactivity with cephalexin than with cefepime.

Figure 1. Penicillin-cephalosporin side chain similarities.3

Amoxicillin Ampicillin Cefadroxil Cephalexin Cefotetan Cefoxitin Cefuroxime Cefdinir Cefixime Cefotaxime Ceftazidime Ceftriaxone Cefepime
Amoxicillin X X X
Ampicillin X X X
Cefadroxil X X X
Cephalexin X X X
Cefotetan
Cefoxitin X
Cefuroxime X
Cefdinir X
Cefixime X
Cefotaxime X X
Ceftazidime
Ceftriaxone X X
Cefepime X X

Any “X” in a column represents similarity between side-chains.

Carbapenem cross-reactivity has been documented to have a wide range of incidence from 1-50%.4,6 Like the data with cephalosporins, early studies evaluating carbapenem cross reactivity were poorly designed. More recently, well-designed trials indicate a cross-reactivity of ~1%.4

Table 2. Carbapenem Cross-reactivity Studies.4

Trial

PCN allergic/Total patients (%)

PCN allergy verification

Carbapenem allergy verification

Results of cross-sensitivity (%)

Romano (2006)

112/112 (100)

Skin testing

Skin test, IM challenge

1/112 (0.9%) in skin test- positive patients

Romano (2007)

104/104 (100)

Skin testing

Skin test, IV challenge

1/104 (1%; CI 0.02-5.2%) in skin test-positive patients

Atanaskovic-Markovic (2008)

108/128 (84)

Skin testing

Skin test, IV challenge

1/108 (0.9) in skin test- positive patients

IM=intramuscular; IV=intravenous

Conclusions

Based on the information available in the current literature, the cross-reactivity between penicillin, cephalosporins, and carbapenems tends to be less than older literature suggests. The cross-reactivity between cephalosporins and penicillin appears to be dependent on the side-chains of the antibiotics with a general rule being the higher you go up in generation of cephalosporin, the lower the incidence of cross-reactivity. Overall, the incidence of cross-reactivity with cephalosporins is ~1%, but the incidence may be higher with the first and second-generation cephalosporins. With carbapenems, the latest data suggest the incidence of cross-reactivity with penicillins is about 1% as well.

For patients with a non-type I allergy, the use of cephalosporins or carbapenems has less potential for harm. For patients with true type I allergic reactions to penicillin, cephalosporins with dissimilar side chains, typically in the newer generations, appear to have a low probability of allergic reaction. Carbapenem use in a true type-I allergy is cautioned, but still has a low probability of allergic reaction. With any challenge of a new agent in a patient with a historical allergy, caution and frequent monitoring should be utilized and documented appropriately.

References

  1. Petri WJ. Penicillins, Cephalosporins and Other β-Lactam Antibiotics. In: Brunton LL, Parker KL, eds. Goodman & Gillman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006:728-750.
  2. Golembiewski J. Allergic Reactions to Drugs: Implications for Perioperative Care. J Perianesth Nurs. 2002;17(6):393-398.
  3. DePestel DD, Benninger MS, Danziger L, et al. Cephalosporin use in treatment of patients with penicillin allergies. J Am Pharm Assoc. 2008;48(4):530-540.
  4. Frumin J, Gallagher JC. Allergic Cross-Sensitivity Between Penicillin, Carbapenem, and Monobactam Antibiotics: What Are the Chances? Ann Pharmacother. 2009;43(2):304-315.
  5. Solensky R. Use of cephalosporins, carbapenems, and monobactams in penicillin allergic patients. Up-To-Date. http://www.uptodate.com/online/content/topic.do?topicKey=drugalle/9961&selectedTitle=1~150&source=search_result. October 15, 2009. Accessed February 8, 2009.
  6. Weiss ME, Adkinson NF. Β-lactam allergy. In: Mandell GL, Bennett JE, Dolin R. Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 7th ed. Maryland Heights, MO: Churchill Livingstone; 2009:347-354.
  7. Kelkar PS, Li JT. Cephalosporin allergy. N Eng J Med. 2001;345(11):804-809.
  8. Robinson JL, Hameed T, Carr S. Practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic. Clin Infect Dis. 2002;35(1):26-31.
  9. Pichichero ME. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients. Pediatrics. 2005;115(4):1048-1057.
  10. Mayorga C, Obispo T, Jimena L, et al. Epitope mapping of betalactam antibiotics with the use of monoclonal antibodies. Toxicology. 1995;97(1-3):225–234.

By: Megan Prasse, PharmD

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What are the latest recommendations for the prevention of torsade de pointes in the hospital setting?

Torsade de Pointes (TdP) is a rare ventricular tachycardia that can lead to ventricular fibrillation and sudden cardiac death.1,2 It is primarily characterized by 2 electrocardiographic (ECG) features: twisting of the peaks of QRS complexes and a prolonged QT (or QTc) interval. It was first described as an adverse effect of quinidine administration, and drugs remain a common culprit of the arrhythmia.3 Multiple agents have been removed from the US market due to their propensity to cause TdP.

Hospitalized patients may be more at risk for TdP than outpatients due to their multiple medications and co-morbidities. The American College of Cardiology (ACC), American Heart Association (AHA), American Association of Critical-Care Nurses (AACN), and the International Society for Computerized Electrocardiology (ISCE) have recently released a statement on the prevention of TdP in hospitalized patients.4 This statement focuses on risks and monitoring for TdP.

Risk Factors

Although a prolonged QT interval is necessary for the diagnosis of TdP, patients with prolonged QT intervals often do not develop the arrhythmia.5 Therefore, identification of other risk factors is essential for TdP prevention. Table 1 lists risk factors that are clinically recognizable in hospitalized patients.4 Patients with multiple risk factors are reported to be at the greatest risk. Risk factors that are not clinically recognizable include latent congenital long QT syndrome and genetic polymorphisms that predispose patients to prolonged QT. Congenital long QT syndrome is reported to account for 5% to 20% of drug-induced TdP cases.

Table 1. Risk factors for TdP in hospitalized patients.4

QTc > 500 ms
QT-prolonging drugs
Heart disease (congestive heart failure and myocardial infarction)
Age > 65 years
Female sex
Electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia)
Diuretic treatment
Impaired hepatic metabolism (due to drug interactions or hepatic dysfunction)
Bradycardia

ms=milliseconds

Diuretics are not known to prolong the QT interval but are listed as a risk factor for TdP primarily due to their association with hypomagnesemia and hypokalemia, as well as the fact that they are commonly used in patients with congestive heart failure.4 Hypomagnesemia and hypokalemia are well-known risks and every effort should be made to maintain normal levels in patients who are at risk for TdP.

QT-prolonging Drugs

Concomitant use of more than 1 QT-prolonging drug or rapid intravenous administration of a QT-prolonging drug increases the TdP risk.4 Table 2 lists drugs that carry a risk for causing TdP. The Arizona Center for Education and Research on Therapeutics provides additional information.6 Lists of drugs with “possible risk”, “conditional risk”, and drugs that should be avoided by patients with a congenital long QT syndrome are available on their Web site at www.qtdrugs.org in addition to the drugs with “risk” list. Interestingly, not all QT-prolonging drugs lead to TdP. Amiodarone is an example of a medication that has profound QT prolongation but rarely causes TdP. The reason for this is not yet known but may be due to the fact that amiodarone prolongs repolarization throughout the myocardial wall while other drugs affect only the mid myocardium myocytes. Another theory is that amiodarone also inhibits the late sodium channels that play a role in the arrhythmia.

Table 2. Drugs with risk for TdP*.4,6

Amiodarone**

Dofetilide

Methadone

Arsenic trioxide

Droperidol

Pentamidine

Chloroquine

Erythromycin

Pimozide

Chlorpromazine

Halofantrine

Procainamide

Cisapride

Haloperidol

Quinidine

Clarithromycin

Ibutilide

Sotalol

Disopyramide

Mesoridazine

Thioridazine

*Drugs removed from the US market and those with “possible” or “conditional” risk are not listed.

**Amiodarone was excluded from the list of drugs in the scientific statement by AHA/ACC/AACN/ISCE because they consider it a low risk drug.

The incidence of TdP varies greatly amongst the agents listed in the table and is poorly defined for most drugs.4 In most cases, higher plasma concentrations of the drug increase the TdP risk. Therefore, drugs or disease states that reduce the elimination of the QT-prolonging drug increase the TdP risk. Antiarrhythmics have the highest reported incidence, especially the Class Ia agents that block sodium and potassium channels (quinidine, disopyramide, and procainamide) as well as Class III agents that block potassium channels (sotalol, dofetilide, and ibutilide). These drugs are reported to have a TdP incidence of 1% to 10%. The risk-benefit of using a QT-prolonging agent should be weighed. In some cases the benefit may outweigh the risk and therapy with these agents may be appropriate. Alternative agents with lower TdP risk are preferred when they are available.

Symptoms and Monitoring

Symptoms of TdP are similar to other ventricular arrhythmias and include palpitations, chest pain, dyspnea, and syncope.2 Some patients will be asymptomatic; therefore, appropriate ECG monitoring is necessary. In hospitalized patients who are continuously monitored with ECG, the arrhythmia or signs of impending arrhythmia can be detected and appropriate measures can be employed; however, it is not practical for all patients to have continuous monitoring. Indications for ECG monitoring include the following:4,7

  • Initiation of a QT-prolonging drug
  • Overdose of proarrhythmic agents (or all overdose situations as the agent is frequently unknown)
  • New-onset bradyarrhythmias
  • Severe hypokalemia
  • Severe hypomagnesemia

There is no exact QTc interval that will produce TdP; however, the AHA/ACC/AACN/ISCE statement recommends considering QTc intervals greater than 480 milliseconds (ms) in females or 470 ms in males abnormal.4 Additional ECG features indicating risk for TdP include TU wave distortions, macroscopic T-wave alternans, new ventricular ectopic beats, and episodes of ventricular tachycardia that occur after a pause. In addition to monitoring baseline QTc intervals prior to initiating the QT-prolonging agent, further monitoring should be done every 8 to 12 hours, with a dose increase of the QT-prolonging agent, or after an overdose of a QT-prolonging drug. More frequent monitoring is prudent if an increase in the QTc interval is observed. The necessary length of monitoring depends on the half-life or elimination rate from the body; whether the drug is given once or for chronic administration; how long it takes for QTc to return to baseline; and whether any arrhythmias are present. The AHA/ACC/AACN/ISCE statement also recommends that patients be monitored in a consistent manner (with the same device, ECG lead, measurement tool, and heart rate-correction formula) so that the method of measurement is not a factor in determining QT-interval changes.

Management

In the case of drug-induced QT prolongation, the offending agent should be discontinued when the QTc exceeds 500 ms or there is a 60 ms or greater increase from baseline.2,4 The patient should be assessed for other risk factors for TdP including drug interactions, bradyarrhythmias, and electrolyte disturbances. Alternative therapeutic agents to replace the offending agent should be explored and a defibrillator should be immediately available. Patients who develop ventricular fibrillation should immediately undergo direct-current cardioversion.

Bradycardia, a risk factor for TdP, may need to be treated in patients at risk for TdP.4 Nonpharmacologic therapy with atrial or ventricular pacing to achieve rates greater than 70 beats per minute has been recommended. Isoproterenol may be useful for patients who do not have congenital long QT syndrome but have TdP episodes that are pause dependent (occurring in the beat after a pause).2,4

Patients with TdP episodes may respond to intravenous infusions of magnesium sulfate.2,4 This response is not limited to patients who are hypomagnesemic; patients with normal magnesium levels may also respond. The recommended dose is 2 grams, and additional doses of 2 grams may be given.4 Potassium supplementation to achieve levels of 4.5 to 5 mEq/L has been recommended, but the current statement comments that there is little evidence available for this recommendation.

Summary

The AHA/ACC/AACN/ISCE statement provides an overview for prevention of TdP in hospitalized patients.4 Pharmacists should be aware of the availability of this statement; however, it does not alter current clinical practice. Prevention of TdP by identifying patients at risk, choosing appropriate medications for those at risk, and monitoring these patients with ECG is vital. When ECG signs are indicative of TdP the suspected medications should be discontinued, magnesium should be administered, potassium may be replaced, and pacing can be considered. Patients should be transferred to an area of the hospital with the highest level of ECG monitoring and immediate availability of defibrillation.

References:

  1. Olgin JE, Zipes DP. Specific arrhythmias: diagnosis and treatment. In: Zipes DP, ed. Braunwald’s Heart Disease: a Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005:803-863.
  2. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(10):e385-e484.
  3. Roden DM. Cellular basis of drug-induced torsades de pointes. Br J Pharmacol. 2008;154(7):1502-1507.
  4. Drew BJ, Ackerman MJ, Funk M, et al; on behalf of the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology, the Council on Cardiovascular Nursing, and the American College of Cardiology Foundation. Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2010. doi:10.1016/j.jacc2010.01.001.
  5. Kilborn M. Overview of long QT syndrome and torsades. Arizona CERT. http://www.azcert.org/medical-pros/education/practical-approach.cfm. Published 2005. Accessed February 17, 2010.
  6. Drugs with risk of torsades de pointes. Arizona CERT. http://www.azcert.org/medical-pros/drug-lists/list-01.cfm?sort=Generic_name. Accessed February 18, 2010.
  7. Drew BJ, Califf RM, Funk M, et al. Practice standards for electrocardiographic monitoring in hospital settings: an American Heart Association scientific statement from the Councils on Cardiovascular Nursing, Clinical Cardiology, and Cardiovascular Disease in the Young. Circulation. 2004;110(17):2721-2746.

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What are the REMS requirements for hospitals dispensing ESAs to patients with cancer?

Introduction

The erythropoiesis-stimulating agents (ESAs) include epoetin alfa (Epogen, Procrit) and darbepoetin (Aranesp). The safety of these agents has repeatedly been called into question (see FAQ Current Status of ESAs in chronic kidney disease, February 2010 and FAQ Safety Update: ESAs, August 2007). Boxed warnings regarding the use of the ESAs in patients with cancer state that ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.1-3 On February 16, 2010, the Food and Drug Administration (FDA) released a drug safety communication wherein Centocor Ortho Biotech Products and Amgen are required to implement a Risk Evaluation and Mitigation Strategy (REMS).4 The primary component of the REMS is known as the Assisting Providers and cancer Patients with Risk Information for the Safe use of ESAs (ESA APPRISE) Oncology Program.

Components of the REMS

The REMS comprises the following elements: medication guides, communication plan, elements to assure safe use, implementation system, and timetable for submission of assessments of the REMS.5,6

Printed medication guides explaining the risks and benefits of ESAs must be provided to every patient or patient’s representative each time the ESA is dispensed, whether in the retail/outpatient or office/clinic/inpatient setting.5-9 The medication guides can be obtained from the Amgen and Centocor Ortho Biotech Products websites, medical information departments, or field-based personnel, as well as through the ESA APPRISE Oncology Program.

The communication plan will encompass mailing Dear Healthcare Provider Letters to individuals that may potentially prescribe or purchase ESAs for patients with cancer, including professional societies and pharmacy directors.5,6 The ESA APPRISE Oncology Program website and call center will provide further assistance with training, enrollment, and program materials.

The elements to assure safe use include the provision that all healthcare providers who prescribe or dispense ESAs to patients with cancer be specially certified.5,6 This extends to hospitals that dispense ESAs for such patients. Specifically, hospitals must obtain site level enrollment in the ESA APPRISE Oncology Program via a hospital designee, such as the pharmacy director or head of hematology/oncology. On behalf of the hospital, this individual must complete the training module, inform all ESA prescribers at the institution of the program requirements, and establish measures (i.e., a system, order set, or protocol) to ensure ESAs are only prescribed to cancer patients by healthcare providers enrolled in ESA APPRISE. Dispensing of ESAs may only occur after a certified healthcare professional has discussed the risks and benefits with the patient and both have signed the ESA APPRISE Oncology Program Patient and Healthcare Professional Acknowledgement Form.

The acknowledgement form requires patients to acknowledge that they have read and understand the medication guide and had all questions answered, are aware that the medications may make tumors grow faster or cause serious heart problems such as heart attack, stroke, heart failure, or blood clots, and cause them to die sooner.5,6

The implementation system includes requirements for monitoring compliance with the program, in particular, documentation on acknowledgement forms with random audits conducted by the ESA APPRISE Oncology Program Call Center.5,6 In addition, hospitals must track the number of oncology patients who are prescribed ESAs; this number will be cross-checked with the number of acknowledgement forms retained at the hospital in the event of an audit. Shipment of ESAs will be prohibited to noncompliant hospitals.

The timetable for submission of assessments of the REMS to the FDA by the manufacturer is at 8, 12, and 18 months, and then yearly.5,6 In addition, hospitals must retrain and reenroll in the program every 3 years.

Training module

The training module includes key safety information surrounding the use of ESAs in patients with cancer.5,6 Table 1 summarizes several studies highlighted in the module that demonstrated decreased survival and locoregional control, as well as increased risk of tumor progression or recurrence in patients with cancer. The module also makes note of the fact that a systematic review of 57 studies found that patients treated with ESAs are at increased risk of serious cardiovascular and thromboembolic events (relative risk 1.67, 95% confidence interval 1.35 to 2.06).

Table 1. Safety studies of ESAs in cancer patients.4-6

Patients

Hgb Target

Hgb Achieved

Primary Endpoint

Adverse Outcome for ESA-containing Arm</b>

Chemotherapy  

Metastatic breast cancer (n=939)  

12 to 14 g/dL

12.9 g/dL

12-month overall survival

Decreased 12-month survival

Lymphoid malignancy (n=344) 

13 to 15 g/dL (M)

13 to 14 g/dL (F)

11.0 g/dL

Proportion of patients achieving Hgb response

Decreased overall survival

Early breast cancer

(n=733)  

12.5 to 13 g/dL

13.1 g/dL

Relapse-free and overall survival

Decreased 3-year relapse-free and overall survival

Cervical cancer (n=114) 

12 to 14 g/dL

12.7 g/dL

PF and overall survival, locoregional control

Decreased 3-year PF and overall survival, locoregional control

Radiotherapy alone

Head and neck cancer (n=351) 

>15 g/dL (M)

>14 g/dL (F)

Not available

Locoregional PF survival

Decreased 5-year locoregional PF and overall survival

Hand and neck cancer (n=522)  

14 to 15.5 g/dL

Not available

Locoregional disease control

Decreased locoregional disease control

No chemotherapy or radiotherapy  

Non-small cell lung cancer (n=70)  

12 to 14 g/dL

Not available

Quality of life

Decreased overall survival

Non-myeloid malignancy (n=989) 

12 to 13 g/dL

10.6 g/dL

RBC transfusions

Decreased overall survival

Hgb=hemoglobin, M=males, F=females, PF=progression-free, RBC=red blood cell

The training module also delineates the appropriate use of ESAs in patients with cancer.5,6 The ESAs are indicated for treatment of anemia due to concomitant myelosuppressive chemotherapy, based on studies demonstrating a reduction in red blood cell transfusions, in patients with metastatic non-myeloid malignancies. They are not to be used in patients on myelosuppressive therapy anticipated to be curative, in patients with hemoglobin ≥10 g/dL, in those on hormonal, therapeutic biologic, or radiation therapy without myelosuppressive therapy, or after chemotherapy is complete. These agents have not demonstrated improvement in anemia symptoms, fatigue, quality of life, or well-being.

Hospital registration

The program enrollment form for hospitals requires the hospital designee to attest that he has completed training, assumes authority and responsibility to coordinate and oversee the program requirements and compliance at the institution, and maintains evidence of compliance (i.e., list of healthcare providers able to prescribe the ESAs to cancer patients, documentation of ESA APPRISE Oncology Program enrollment, and acknowledgement forms).5,6

All patients prescribed ESAs, regardless of the indication, are required to receive the medication guide; however, enrollment in the ESA APPRISE Oncology Program is mandatory only for healthcare professionals who use ESAs in patients cancer.4 The ESA APPRISE Oncology Program Call Center may be contacted at (866) 284-8089; the website (http://www.esa-apprise.com) will be available starting March 24, 2010, at which time the program will launch and training and enrollment will commence.4-6,10-12 Potential enrollees are encouraged to visit the ESA APPRISE website beginning March 24 for further details and clarification on enrollment deadlines and requirements.

References

  1. Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc; 2010.
  2. Epogen [package insert]. Thousand Oaks, CA: Amgen Inc; 2010.
  3. Procrit [package insert]. Thousand Oaks, CA: Amgen Inc; 2010.
  4. The U.S. Food and Drug Administration. Drug Safety Communication: Erythropoiesis-Stimulating Agents (ESAs): Procrit, Epogen and Aranesp. http://www.fda.gov/Drugs/DrugSafety/
  5. PostmarketDrugSafetyInformationforPatientsandProviders/ucm200297.htm. Accessed February 23, 2010.
  6. Aranesp Proposed Risk Evaluation and Mitigation Strategy (REMS). http://www.fda.gov/downloads/Drugs/
  7. DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM200104.pdf. Accessed February 23, 2010.
  8. Epogen/Procrit Proposed Risk Evaluation and Mitigation Strategy (REMS). http://www.fda.gov/downloads/Drugs/
  9. DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM200105.pdf. Accessed February 23, 2010.
  10. Aranesp Medication Guide. http://pi.amgen.com/united_states/aranesp/ckd/aranesp_mg_hcp_english.pdf. Accessed February 23, 2010.
  11. Epogen Medication Guide. http://www.epogen.com/pdf/epogen_mg.pdf. Accessed February 23, 2010.
  12. Procrit Medication Guide. http://www.procrit.com/sites/default/files/shared/OBI/PI/MedGuide.pdf. Accessed February 23, 1020.
  13. The ESA APPRISE Oncology Program. http://www.esa-apprise.com. Accessed February 23, 2010.
  14. Centocor Ortho Biotech Products. Centocor Ortho Biotech Products and Amgen finalize ESA risk evaluation and mitigation strategy (REMS) with FDA. http://www.centocororthobiotech.com/cobi/viewDocumentByTitleAlias.html?title=PR_02162010. Accessed February 24, 2010.
  15. Amgen Inc. Amgen and Centocor Ortho Biotech Products finalize ESA risk evaluation and mitigation strategy (REMS) with FDA. http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1391301. Accessed February 24, 2010.

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Dihydroergotamine in the treatment of migraines: recommended dosing strategies

Migraine

Migraine headache is a common neurologic disorder, affecting an estimated 28 million adolescents and adults in the United States.1 In addition to having a physical and emotional impact on patients, migraine headaches can result in significant disability, loss of productivity, and family or social stress. An estimated $13 billion is lost in missed work annually due to migraine headaches. All of these factors make appropriate treatment and prevention of migraine headache critical in improving quality of life for individuals with migraine headaches.

Treatment options

Treatment of migraine can be abortive, to relieve pain and symptoms associated with a migraine episode, or preventative. Preventative therapy is usually recommended for patients who experience frequent migraines (> 4 per month), for patients unresponsive or intolerant to abortive agents, or for patients who have severely disabling migraine symptoms.1 For treatment of an acute attack, the serotonin (5-HT1B/1D) receptor agonists, or triptans, are generally considered first-line for most patients with moderate to severe migraine headaches.2 The triptans are generally effective and are available in non-oral dosage formulations, such as intranasal and subcutaneous, for patients unable to take oral medications due to migraine symptoms. Adjunctive therapies, such as antiemetics for nausea and vomiting, may also be needed. Patients with mild to moderate severity migraines may respond to analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDS).

Ergot alkaloids—dihydroergotamine

Prior to the availability of the triptans, ergot alkaloids were frequently used for treatment of migraine headaches.1,3 Ergotamine tartrate was introduced in the United States in the early 1930s and was successfully used for migraine treatment for many years.4 Dihydroergotamine (DHE) became available for treatment of migraines in 1945.3 Although DHE has comparable efficacy for treatment of migraines, it is a less potent vasoconstrictor than ergotamine, is less emetogenic, and has a lower risk of rebound headaches.

Dihydroergotamine carries a boxed warning regarding the risk of serious and/or life-threatening cerebral or peripheral ischemia when used in combination with cytochrome P450 3A4 inhibitors, such as macrolides and protease inhibitors.5 Dihydroergotamine is also contraindicated for use in patients with ischemic heart disease, coronary artery vasospasms, uncontrolled hypertension, hemiplegic or basilar migraines, peripheral artery disease, with severe hepatic/renal dysfunction, or within 24 hours of other ergot-type medications (including ergotamine) or triptans. Adverse effects associated with DHE include nausea, vomiting, diarrhea, chest pain, tiredness, paresthesias, and coldness.6 Cardiac events (myocardial infarction, arrhythmias) and vasospastic events (peripheral vascular, colonic ischemia) have also been reported.5

Dihydroergotamine is available as an injection as well as a nasal spray.1 The usual dose of the nasal spray is 0.5 mg (one spray) in each nostril, followed by one additional spray in each nostril 15 minutes later, for a total dose of 2 mg. The maximum dose is 3 mg in a 24-hour period or 4 mg within 7 days.7 For the injection, the recommended dose is 1 mg intravenous (IV), subcutaneous (SC), or intramuscular (IM) at 1-hour intervals for a total of 3 mg for IM or SC administration or 2 mg for IV administration. The total dose per week should not exceed 6 mg.

Extended dosing of dihydroergotamine

Although injectable DHE is recommended for a total of 6 mg per week, there are some data to support extended dosing for treatment of severe, intractable migraine headaches. Intravenous DHE may be preferred over triptans for treatment of status migrainous—migraine headaches lasting more than 72 hours—in part because of its longer half-life and lower risk of headache recurrence or rebound compared with the triptans. 1,8

In 1986, Raskin published the results of a study using repetitive dosing of DHE in a group of patients with intractable migraine.9 A total of 55 patients with sustained migraine headaches were given DHE, beginning with a test dose of 0.5 mg IV, along with 10 mg of metoclopramide. Subsequent doses were determined based on patients’ head pain and the side effect of nausea. If no nausea was present and headache pain persisted, a second dose of 0.5 mg was given, followed by 1 mg IV every 8 hours for 2 days. After 2 days of IV treatment, DHE 2 mg rectal suppositories were given every 12 hours. For patients still not responding, DHE was given as 1 mg SC every 12 hours, along with propranolol. If DHE was still needed after 1 month, propranolol was discontinued and ergonovine 1.2 mg was given daily. Dihydroergotamine was stopped if headaches were mild and occurred less than 3 times per week. After a mean follow-up of 16 months, the author reported the average treatment duration for DHE to be 3 weeks (range 1 week to 4 months) after IV treatment. Total or mean doses of DHE were not given.

Silberstein also reported the results of repetitive dosing of DHE in a retrospective review of 300 patients with refractory headache.10 Similar to the Raskin protocol9, patients were given DHE 0.5 mg IV along with metoclopramide.10 Subsequent doses were determined by patients’ pain response and blood pressure. Patients tolerating the first dose, but with persistent pain, were given a second 0.5 mg dose, followed by 1 mg every 8 hours, with metoclopramide as needed. Therapy with DHE was continued until the patient was headache-free, and tapered before discontinuation to every 12 hours for 2 or 3 doses. Dihydroergotamine was generally effective. For 214 patients with chronic daily analgesic rebound headaches (the most common headache type in the study), 141 were headache-free by the third day of treatment. Thirty-seven patients were headache-free by 4 to 6 days of treatment, and 19 at more than 6 days. Similar results were seen for other headache types. However, the author did not provide the total or mean dose of DHE administered. Nausea (32%), tightness and burning (7.7%), leg cramps (7.0%), vomiting (6.0%), and elevated blood pressure (4.7%) were the most commonly reported side effects.

Continuous IV DHE was compared to repetitive IV DHE in a study by Ford.11 Repetitive IV dosing of DHE was similar to the Raskin protocol9, beginning with a 0.5 mg IV test dose, and subsequent doses determined by patient response and tolerability.11 If DHE was tolerated and headache persisted, a dose of 1 mg IV every 8 hours was used. Continuous DHE was given as 3 mg over 24 hours (in 1000 mL of normal saline), with dose adjustments based on patients’ response and tolerability. For both treatment groups, as headache pain resolved, the dose of DHE was reduced during the 24 hours prior to hospital discharge. Efficacy of treatment was determined by the number of days of treatment with IV DHE needed to become headache-free or have minimal headache pain. For continuous IV DHE, 2 patients required 7 days of treatment, 3 required 6 days, and 15 required 4 days of IV DHE. However, most patients responded within 3 days (64.5%). Similar results were found for repetitive IV DHE, with 1 patient needing 7 days of treatment, 7 patients requiring 6 days, 1 patient needing 5 days, and 6 patients needing 4 days. Again, most patients responded within 3 days (66.5%). The author did not report on the mean or total dose of DHE given.

Kabbouche described the use of IV DHE in children and adolescents with intractable migraine.12 After a test dose, DHE was given as 1 mg IV every 8 hours until headache-free (plus 1 additional dose) or a maximum of 20 doses was given. For children less than 25 kg or 9 years old or younger, the dose was reduced to 0.5 mg. Patients were given at least 5 doses before being considered unresponsive. The mean total dose of DHE reported was 7.0  4.6 mg. About 40% of patients reported to be headache-free by the fifth dose of DHE, with 67% by doses 12 to 13. Nearly all patients (91.4%) had nausea and vomiting, with chest tightness in 6%, and hives and elevated blood pressure in 2.8% (DHE was discontinued in these patients).

Summary

Repetitive dosing of IV DHE, in the inpatient setting, has been shown to be effective in relief of pain associated with chronic migraine or other headache types. In a statement from the Working Panel of the Headache and Facial Pain Section of the American Academy of Neurology, Silberstein and Young summarized data from available studies on repetitive DHE dosing.6 Per their review, DHE given for 3 to 7 days (total doses of 10 to 15 mg) was beneficial in relieving pain associated with rebound or cluster headaches and intractable migraines. Doses up to 20 mg have been given over a 1-week period (but only for 1 week). It is important to note that this method of DHE administration was done under medical supervision with patient monitoring for adverse effects and tolerability and dose adjustments as necessary. Patients also received concurrent antiemetics (such as metoclopramide).

References

  1. Diamond S, Wenzel R. Practical approaches to migraine management. CNS Drugs. 2002;16(6):385-403.
  2. Silberstein S. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):754-762.
  3. Silberstein S, McCrory D. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache. 2003;43(2):144-166.
  4. Tfelt-Hansen P, Koehler P. History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward. Cephalagia. 2008(28):877-886.
  5. Dihydroergotamine [package insert]. Bedford, OH: Bedford Laboratories; 2008.
  6. Silberstein S, Young W. Safety and efficacy of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainous. Neurology. 1995;45(3 pt 1):577-584.
  7. Wickersham R, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2009.
  8. Marcus D. Treatment of status migrainous. Exp Opin Pharmacother. 2001;2(4):549-555.
  9. Raskin N. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997.
  10. Silberstein S, Schulman E, Hopkins M. Repetitive intravenous DHE in the treatment of refractory headache. Headache. 1990;30(6):334-339.
  11. Ford R, Ford K. Continuous intravenous dihydroergotamine in the treatment of intractable headache. Headache. 1997;37(3):129-136.
  12. Kabbouche M, Powers S, Segers A, et al. Inpatient treatment of status migraine with dihydroergotamine in children and adolescents. Headache. 2009;49(1):106-109.

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