P&T News: May/June 2002
Sarah J. Johnson, Pharm.D., Clinical Pharmacist, Medication Use
Evaluation Program, Department of Pharmaceutical Care
Internally Peer Reviewed by: Roger Gingrich,
M.D., Professor, Division of Hemetology/Oncology, Department of
Internal Medicine
Cancer-related anemia is often worsened by the cytotoxic effects of chemotherapy. Depending on the severity of the anemia, symptoms such as fatigue, drowsiness, and compromised cardiac and respiratory function can result in a significant decrease in the quality of life for cancer patients. Blood transfusions, the primary treatment option for anemia in this population, have immediate beneficial effects; however, they may be associated with serious adverse events including allergic reactions, infectious complications, iron overload, and sensitization to histocompatibility antigens that may reduce the efficacy of platelet transfusions. Erythropoietin (EPO) is a recombinant form of the glycoprotein normally produced in the kidneys and is used to stimulate red blood cell production. EPO has successfully been used to treat cancer-related anemia and is FDA-approved for the treatment of anemia associated with chemotherapy in non-myeloid malignancies. EPO therapy may reduce the number of transfusions required to maintain an acceptable quality of life. Randomized, placebo-controlled trials have shown EPO response rates of 32% to 82% in non-myeloid malignancies.1 Although not FDA-labeled for anemia in myeloid malignancies, studies have shown EPO response rates of 25% in myelodysplastic syndrome.2 For patients with a history of anemia in previous chemotherapy cycles, some reports in the literature have shown a decreased need for transfusions when EPO is initiated at the start of therapy rather than after the anemia has developed.3 Despite the potential benefits that EPO offers, the primary drawback to this therapy is its expense.
Considerations Prior to Initiation of EPO Therapy
Because not all cancer patients will respond well to EPO therapy,
several factors must be considered prior to initiation of therapy.
Dosing
Currently, there are no consensus guidelines for dosing EPO, but dosing recommendations have been published.1,5 The manufacturer recommends a starting dose of 150 units/kg subcutaneously (SQ) three times a week. The maximum recommended dose is 300 units/kg SQ three times weekly. If a patient has not responded to therapy at this dose, it is unlikely that any benefit will be seen by further increasing the dose.6 See Figure 1, above.
Monitoring
To achieve an optimal response, EPO therapy must be appropriately monitored and doses should be optimized to ensure that a safe and adequate response to therapy has been obtained. No consensus statement exists to help determine what to consider as a "response" to EPO therapy. As defined in the literature, a rise in hemoglobin (Hgb) of at least 2 gm/dl above baseline or a rise in hematocrit (Hct) of at least 6% after 4 weeks, independent of blood transfusions, is considered a response to EPO treatment.1 However, the reticulocyte response may be an early predictor of whether or not a patient will be a responder to EPO; if the pre-treatment low reticulocyte count doesn't increase by >50% after two weeks of therapy, it is unlikely that a rise in hemoglobin will be achieved at 4 weeks.
It is important to monitor Hgb and Hct while the patient is receiving EPO to maximize efficacy. If results are not seen in 4 weeks, it may be necessary to increase the dose to obtain the desired effect. If no effect is seen after "optimized" therapy, or if red cell transfusions are still required, consider discontinuing EPO.
References:
Metoclopramide -Induced Akathisia
Barbara A. Mutnick, MHP
Metoclopramide is typically well tolerated in most patients at usual dosages. However, its use has been associated with extrapyramidal side effects, and in some cases, the cause of these effects has been misinterpreted, leading to treatment for other disorders. Metoclopramide, a substituted benzamide derivative, is a gastrointestinal prokinetic agent that increases gastrointestinal motility. This dopamine antagonist has FDA labeled-indications that include treatment of gastroparesis in diabetic patients, diabetic gastric stasis, gastroesophageal reflux, use in radiographic procedures to increase the rate of gastric emptying, and treatment of postoperative and chemotherapy-induced vomiting1. It also has been used successfully for a number of other indications, including nondiabetic gastroparesis, migraine headache, neurogenic bladder, orthostatic hypotension, and treatment of peptic ulcer disease2.
Akathisia is listed as one of the extrapyramidal side effects (EPS) attributable to the drug. Other EPS seen with the use of metoclopramide are acute dystonic reactions, Parkinsonian-like symptoms, and tardive dyskinesia. (Table 1)1. The manufacturer reports that the range of occurrence of EPS is as low as 0.2% in patients treated with 30 to 40 mg of metoclopramide a day to 25% in children receiving high doses to manage chemotherapy-induced emesis1. A 1982 letter in The Lancet 3 states that 25% of the subjects with no psychiatric history who received a 10 mg intravenous bolus dose of metoclopramide complained of symptoms of akathisia. These types of EPS are most likely mediated by metoclopramide's inhibition of dopamine and acetylcholine in the central nervous system4.
|
Table 1. Extrapyramidal Symptoms Seen with Metoclopramide Use |
|||
| Motor restlessness (akathisia) | Acute dystonic reactions | Parkinsonian-like symptoms | Tardive dyskinesia |
|
Anxiety |
Involuntary movements of limbs |
Bradykinesia |
Involuntary movements of face, tongue, mouth, or jaw |
Akathisia is an extrapyramidal effect of the drug that may be particularly difficult to diagnose. The term "akathisia" was coined in 1904 to describe an inner feeling of restlessness, an inability to sit still, and a compulsion to move about. Symptoms are prominent in the lower extremities and include constant crossing, uncrossing, and swinging of legs when patients are sitting; while standing, patients will pace and walk in place. In advanced forms, patients are unable to concentrate. Loss of weight is present in a number of these cases5.
In addition to these symptoms, patients receiving metoclopramide have experienced behavioral changes2. Some case reports describe patients who are unable to "think properly," feel that they are unable to cope, have feelings of losing control, experience panic attacks, and suffer from suicidal ideations4,5,6,7,8. Patients who have experienced these adverse effects have been misdiagnosed and treated for psychiatric disorders including depression, anxiety disorder, panic disorder, and agitation.
Signs of EPS can occur after the first dose of metoclopramide, but onset has been seen later in long-term therapy. Symptoms can resolve as early as 24 hours after withdrawal of therapy2, but the literature reports a patient who continued to have symptoms for as long as 27 months after withdrawal of the drug6. In the patients in The Lancet study5, symptoms began 10 to15 minutes after a dose and subsided in 3 to 4 hours.
A review of the UIHC Adverse Drug Reaction Reporting Program reveals that in the last 2-1/2 years seven patients were reported to have experienced various extrapyramidal symptoms with metoclopramide therapy. Three patients had reports of dystonic reactions secondary to the drug; two patients experienced reactions described as extrapyramidal symptoms; one patient experienced symptoms of torticollis, agitation, and hallucinations; and one patient experienced akathisia. Three of these patients received the drug orally, three had intravenous administration of metoclopramide, and one patient had both dosage forms administered.
Anticholinergic agents such as benztropine and diphenhydramine have been used to treat symptoms. It has been suggested that the neurologic complications of intravenous metoclopramide can be prevented by a prolonged rate of administration1. Recommendations for intravenous dosing at UIHC are to dilute doses of 10 mg or greater of metoclopramide in 50 ml of diluent and administer over 20 to 30 minutes, or to infuse undiluted doses of less than 10 mg over 1 to 2 minutes.
Metoclopramide should be used cautiously in patients with Parkinson's disease or a history of depression and patients who are taking MAO inhibitors, tricyclic antidepressants, sympathomimetic amine therapy1, or other drugs with dopamine antagonist activity6. Although the true incidence of EPS symptoms secondary to metoclopramide use is still unclear, it should be considered as a potential cause of the symptoms listed above in patients using metoclopramide.
All staff at UIHC are encouraged to report adverse drug reactions (ADRs) encountered in their practices. Pharmacists are able to assist in reporting and documenting ADRs. Also, the staff of the Drug Information Center (6-2600) are available Monday through Friday from 8:00 a.m. to 4:30 p.m. to answer questions regarding ADRs and aid in the documentation of suspected ADRs.
References
DRUGS ADDED TO STOCK
INSULIN ASPART
Injection: 100 units/ml
Insulin aspart (Novolog® - NovoNordisk) is a rapid-acting human
insulin analogue that has a more rapid onset and shorter duration of
action than regular insulin.
PANTOPRAZOLE
Injection: 40 mg
Pantoprazole injection (Protonix IV® - Wyeth) is only FDA-labeled
for the short-term treatment of GERD. There are no published studies
for the use of pantoprazole injection for the treatment of an acute
gastrointestinal bleed or for stress ulcer prophylaxis; therefore,
the appropriate dose for these uses has not been determined.
Note: Pantoprazole injection is a protocol drug with its use restricted to the following indications: 1) Treatment of documented erosive esophagitis and medication cannot be administered nasogastrically or enterally; 2) Gastrointetinal bleed with thrombocytopenia (platelet count less than 50 k/mm3) related to IV H2RA therapy and medication cannot be administered nasogastrically or enterally; or 3) Treatment of documented Zollinger-Ellison Syndrome and medication cannot be administered nasogastrically or enterally.
PORACTANT ALFA
Intratracheal Suspension: 120 mg/1.5 ml
Poractant alfa (Curosurf®) is indicated for the treatment of
respiratory distress syndrome in premature infants.
ADDITIONAL ACTIONS
AMPHETAMINE AND DEXTROAMPHETAMINE SALTS MIXTURE
5 mg, 10 mg, and 20 mg regular-release tablets (Adderal®) have been added to stock.
10 mg, 20 mg, and 30 mg sustained-release capsules (Adderal XL®) have been added to stock.
DIHYDROTACHYSTEROL
A 0.4 mg tablet has been added to stock.
HEPATITIS A 720 E.L.U. PLUS HEPATITIS B 20 mcg VACCINE
This combination vaccine (Twinrix® - GlaxoSmithKline) has been
added to stock. It is indicated for active immunization of adult
patients.
HUMULIN® AND NOVOLIN® brands of human insulin have been deemed to be therapeutically equivalent and may be used interchangeably. Therefore, the least expensive product line will be stocked.
METHYLPHENIDATE
A 27 mg sustained-release tablet (Concerta®) has been added to
stock.
A 20 mg sustained-release capsule (Metadate CD®) has been added
to stock.
A 10 mg sustained-release tablet (Metadate ER®) has been added to
stock.
HEPATITIS A 720 E.L.U. PLUS HEPATITIS B 20 mcg VACCINE
This combination vaccine (Twinrix® - GlaxoSmithKline) has been
added to stock. It is indicated for active immunization of adult
patients.
HUMULIN® AND NOVOLIN® brands of human insulin have been deemed to be therapeutically equivalent and may be used interchangeably. Therefore, the least expensive product line will be stocked.
METHYLPHENIDATE
A 27 mg sustained-release tablet (Concerta®) has been added to
stock.
A 20 mg sustained-release capsule (Metadate CD®) has been added
to stock.
A 10 mg sustained-release tablet (Metadate ER®) has been added to
stock.