HEALTHLINE
February 2006
NEW DRUGS AND INDICATIONS
Angeliq® (drospirenone and estradiol) Tablets: Angeliq has been approved by the FDA to
treat the hot flashes, night sweats, and vaginal dryness that can accompany menopause. Angeliq
is a hormone replacement therapy containing estradiol and the progestin drospirenone, a
hormone that counters the excess water and sodium buildup that is a side effect of estradiol.
Arranon® (nelarabine) Injection: Arranon is a newly approved chemotherapy agent indicated
for the treatment of adults and children with T-cell acute lymphoblastic leukemia (T-ALL) and Tcell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed
following treatment with at least two chemotherapy regimens.
Citalopram hydrobromide (HBr): Biovail has received FDA approval to market an orally disintegrating
tablet (ODT) formulation of citalopram hydrobromide, the active ingredient in Celexa. Biovail’s ODT
product will be available in 10-, 20- and 40-mg tablets.
Clobex® (clobetasol propionate) Spray 0.05%: Clobex spray is a non-aerosol spray
formulation of the corticosteroid clobetasol, approved for the treatment of moderate-to-severe
plaque psoriasis.
Effexor XR® (venlafaxine) Extended-Release Capsules: has been approved for the treatment
of adults with panic disorder, a condition characterized by recurrent, unexpected panic attacks.
Effexor XR was first approved for the treatment of depression, generalized anxiety disorder and
social anxiety disorder.
Humira® (adalimumab) Injection: Humira is now indicated for reducing the signs and symptoms
of active arthritis in patients with psoriatic arthritis. Humira can be used alone or with
methotrexate or other DMARDs (disease modifying anti-rheumatic drugs). Humira, a
recombinant human IgG monoclonal antibody specific for human tumor necrosis factor (TNF),
was first approved for reducing the signs and symptoms, inducing major clinical response,
slowing the progression of joint damage, and improving physical function in adult patients with
moderate to severe rheumatoid arthritis.
Nexavar® (sorafenib tosylate) Tablets: The FDA has approved Nexavar, an anticipated kidney
cancer drug. Nexavar has been called “a major advance in the treatment of advanced renal cell
carcinoma”. Study results show Nexavar doubles progression-free survival rates in patients with
advanced renal cell carcinoma.
Rozerem® (Ramelteon) Tablets: A newly approved hypnotic (melatonin agonist) indicated for insomnia
with difficulty in sleep onset. Melatonin is an endogenous hormone that is involved in the maintenance of
circadian rhythm. Ramelteon is a melatonin receptor agonist with high affinity for melatonin receptors 1
and 2 (MT1 and MT2), which have been identified as playing a selective role in sleep patterns. It is
theorized that the activity of ramelteon at the MT1 and MT2 receptors contributes to its sleep-promoting
properties.
Soltamox® (tamoxifen) Oral Solution: Soltamox is an oral liquid formulation of tamoxifen,
indicated for the treatment of breast cancer in adjuvant and metastatic settings and to reduce
risks of breast cancer in women with ductal carcinoma in situ (DCIS) and reduction of breast
cancer incidence in women with high risk of breast cancer.
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Tarceva® (erlotinib) Tablets: is now approved for the treatment of pancreatic cancer. Tarceva
is approved in combination with gemcitabine chemotherapy for the treatment of advanced
pancreatic cancer in patients who have not received previous chemotherapy. Tarceva is a
Human Epidermal Growth Factor Receptor Type 1/Epidermal Growth Factor Receptor
(HER1/EGFR) tyrosine kinase inhibitor originally indicated for the treatment of patients with
locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one
prior chemotherapy regimen.
WARNINGS AND ADVERSE EFFECTS
Pure Red Cell Aplasia and Anemia Associated with Aranesp, Procrit and Epogen
Pure red blood cell aplasia, has been associated with darbepoetin alfa (Aranesp®), and
erythropoietin alfa (Epogen® and Procrit®). Pure red blood cell aplasia is an anti-erythropoietinantibody-mediated severe anemia and red blood cell aplasia. The prevalence of antierythropoietin-antibodies has been reported at 3% in cancer patients and 4% in patients with
chronic kidney disease, but due to the immunogenicity of erythropoietic products, antierythropoietin antibodies can develop during therapy. The antibodies neutralize the hematopoietic
factor rendering it ineffective and producing a severe anemia. As a result of this information,
clinicians and facilities should employ the following steps in following the guidance put forth by
manufacturers for patients receiving erythropoietic factors:
• Monitor hemoglobin weekly upon initiation of therapy with an erythropoietic factor and then monthly
once stabilized at the desirable hemoglobin concentration;
• Monitor for a sudden loss of response (i.e. hemoglobin declines and can no longer be maintained at the
target concentration);
•If a sudden loss of response occurs, an anemia assessment including a reticulocyte count should be
performed with a comprehensive assessment of causative factors.
ANEMIA ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD)
Introduction
Anemia can be defined as a reduction in the number of red blood cells or the quantity of hemoglobin (Hb)
in blood. Anemia can be measured by the red blood cell (RBC) count or hemoglobin concentration. Loss
of blood (bleeding), increased destruction (inflammation), or decreased production (chronic kidney
disease/decreased erythropoietin) are all possible causes of anemia.
In an individual with normal kidney function, the occurrence of hypoxia triggers the kidneys to produce
erythropoietin (EPO). In patients with CKD, the diseased kidneys are typically unable to produce enough
EPO resultings in a normochromic, normocytic anemia. Other factors that may contribute to anemia in
these patients include a shortened life span of RBCs, low iron stores, loss of blood during the hemodialysis
process, or other nutritional deficiencies, and conditions such as infection and inflammation that can inhibit
normal RBC development. There is a high prevalence of gastrointestinal bleeding in patients with CKD,
which could also lead to blood loss anemia.
A high percentage of patients with CKD have anemia. A recent study found that after controlling for other
patient characteristics associated with increased prevalence of anemia, the prevalence of anemia increased
as kidney function decreased, and anemia was present in 47.7% of 5,222 pre-dialysis patients with CKD.
Additional predictors of anemia include diabetes, female sex, and race/ethnicity.
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Many clinical signs and symptoms occur throughout the body when the oxygen-carrying capacity of the
blood is unable to meet the oxygen requirements of the tissues. Anemia, or inadequate delivery of oxygen
to the tissues, results in potentially serious problems throughout the body, in every major system. While
fatigue is the primary symptom of anemia, it can also cause a range of other symptoms, including
palpitations, impaired cognitive function, nausea, reduced skin temperature, impaired immune function,
dizziness, headache, chest pain, shortness of breath, and depression. However, although anemia is common
in patients with CKD, patients may be asymptomatic. This normochromic, normocytic anemia typically
develops early in the course of CKD and worsens as the kidney disease progresses.
Figure 1. Signs and Symptoms of Anemia
Cardio Respiratory System
Exertional dyspnea, tachycardia,
palpitations, cardiac enlargement,
hypertrophy, increased pulse pressure,
systolic ejection murmur, risk of cardiac
failure
Central Nervous System
Fatigue
Depression
Impaired cognitive function
Immune System
Impaired T cell and
macrophage function
Gastrointestinal System
Anorexia
Nausea
Genital Tract
Menstrual problems
Loss of libido
Vascular System
Low skin temperature
Pallor of skin, mucous
membranes, conjunctivae
Ludwig H, et al. Semin Oncol 1998;25(supp 7):2-6
Consequences of Anemia in CKD
Anemia of CKD is associated with several implications and problems. A number of these problems affect
the cardiovascular system, in an attempt to compensate for the inadequate delivery of oxygen to the
peripheral tissues. These include an increase in cardiac output, a decrease in peripheral vascular resistance,
and lower blood viscosity. Reduced oxygen delivery to the myocardium, and exacerbation of myocardial
ischemia which in turn leads to left ventricular hypertrophy, are other cardiovascular complications of
anemia.
The effects of anemia on the cardiovascular system and on skeletal muscle function lead to changes in
exercise physiology. The capacity for physical work is reduced in patients with CKD due to a decrease in
pulmonary diffusion, a decrease in oxygen utilization in the peripheral tissues, and reduced aerobic exercise
capacity, causing an alteration in the anabolic threshold resulting in breathlessness, tiredness, and muscle
fatigue. The ability of elderly patients to perform activities of daily living (ADLs) independently as anemia
progresses impacts negatively on quality of life. CKD patients with anemia exhibit diminished energy
levels, lethargy, sexual dysfunction and impaired concentration, memory, and intellectual ability.
Studies have shown a correlation between anemia and falls in the elderly. In one study, the authors
concluded after adjustment for other risk factors that community residents >65 years old with anemia have
a 50% greater risk of experiencing a fall-related injury than those without anemia (N = 1,158). In a
retrospective cohort study it was revealed that eight chronic diseases are predictive of 1-year mortality.
These eight chronic diseases are dementia, cancer, heart failure, renal failure, emphysema/ chronic
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HEALTHLINE
February 2006
obstructive pulmonary disease, diabetes mellitus, and anemia. Of these chronic diseases, anemia is the most
readily treatable, yet often under recognized.
Anemia Assessment:
All patients with glomerular filtration rates of less than 60 ml/min/m2 (CKD stages 3-5) should be evaluated
for the presence of anemia. Measures used to assess anemia and its causes include hemoglobin, hematocrit,
and iron stores (Table 1). Measurement of hemoglobin, rather than hematocrit, is the preferred method for
assessing anemia. Hemoglobin concentrations are directly affected by lack of erythropoietin production
from the kidney and thus serve as a more precise measurement of erythropoiesis. Hemoglobin
concentration (Hgb) measures the concentration of the major oxygen-carrying pigment in whole blood.
Table 1: Evaluation of Anemia
 Hemoglobin and/or Hematocrit
 Red-blood-cell indices
 Reticulocyte count and reticulocyte hemoglobin content (CHr)
 Iron parameters
- Serum iron
- Total iron-binding capacity (TIBC)
- Percent transferrin saturation (TSAT)
- Serum ferritin
 Test for occult blood in stool
Anemia can be graded based on hemoglobin concentration. Two commonly used scales are those of the
National Cancer Institute (NCI) and the World Health Organization (Table 2). Treatment decisions are
made based on the grade or severity of anemia.
Table 2: Classification of Anemia
Grade (severity)
NCI Scale
WHO Scale
Hgb (g/dL)
Hgb (g/dL)
0 (none)
Men: 14-18
>11
Women: 12-16
1 (mild)
10 to gender-specific lower limit
9.5-10
of normal
2 (moderate)
8-9.9
8-9.4
3(serious/severe)
6.5-7.9
6.5-7.9
4 (life-threatening)
<6.5
<6.5
where: Hgb=hemoglobin, NCI=National Cancer Institute, and WHO=World Health Organization
It is important to understand the different types of anemia and treat accordingly. Iron deficiency anemia
commonly coexists with anemia of chronic disease and until proven otherwise should be assumed to be a
sign of chronic gastrointestinal blood loss. The gold standard therapy for this type of anemia is oral iron
supplementation with a usual recommended dose of 50 to 100 mg of elemental iron three times a day.
Megaloblastic anemia is most commonly associated with inadequate dietary intake and can be corrected
with nutrient supplementation (vitamin B12 or folic acid). Anemia of chronic disease is marked by elevated
inflammatory cytokines causing reduced intestinal iron absorption and storage. This type of anemia may
require EPO therapy. Anemia caused by chronic kidney disease requires EPO and iron therapy (some may
need IV iron). It is important to note that one or more types of anemia may coexist, especially in the
elderly.
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Treatment of Anemia:
Oral iron therapy is often effective for the treatment of iron deficiency anemia in patients not receiving
dialysis and has been considered the treatment of choice. However, parenteral iron therapy is usually
superior to oral therapy for the maintenance of iron stores in chronic iron deficiency anemia in dialysis
patients. Intravenous injection is the preferred method of parenteral administration because the
intramuscular route can require multiple injections to complete a single course of therapy and carries a
greater risk of local adverse reactions. Older patients have diminished muscle mass, making intramuscular
administration less desirable. Parenteral iron is indicated in pre-dialytic patients whose iron stores cannot
be repleted with oral iron (e.g., gastrointestinal disease such as sprue, celiac disease, regional enteritis, or
status post surgery). In addition, intravenous iron is indicated for those that do not respond to oral iron –
i.e. increasing anemia despite full replacement doses of oral iron (i.e. 300 mg/day of elemental iron).
One of the most important factors making intravenous iron therapy safer than in the past is the availability
of iron glucose (Venofer). Experience with iron sucrose has shown that doses up to 200 mg can be given as
a slow IV push over five minutes or up to 300 mg diluted in saline and infused over 1-2 hours.
Epoetin alfa therapy is preferred for the treatment of anemia of chronic kidney disease because it
significantly reduces or eliminates the need for red blood cell transfusion, improves quality of life, and
results in significant improvements in other physiologic functions, including exercise capacity and
cognition. Darbepoetin alfa is safe and effective for management of anemia associated with CKD and has
an adverse effect profile comparable to epoetin alfa.
Conclusion:
Anemia of chronic kidney disease is common in the nursing home population and is treatable.
Clinicians caring for elders in this population should assess residents for anemia, especially if the
patient’s GFR is < 60 ml/min/1.73m2. Treatment of anemia associated with CKD typically involves
the use of epoetin alfa therapy and the use of iron therapy, whether oral or parenteral, to provide the
proper iron stores in the body. If Epoetin alfa therapy is utilized monitoring for pure red blood cell
aplasia is necessary. As Omnicare launches it Chronic Kidney Disease Health Management Program
in 2006, look for additional information including education, and assessment tools from your
Omnicare Consultant Pharmacist.
Kelly A. Hollenack, PharmD, CGP, FASCP; National Director, Health Management, Omnicare, Inc.
References
o NKF-K/DOQI Guidelines. Am J Kidney Dis 2002;39:Supplement 1.
o McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemia in patients with chronic kidney
disease. Curr Med Res Opin 2004;20:1501-10.
o Kausz AT, et al. Dis Manage Health Outcomes 2002;10:505-513.
Editorial Board
Karen Burton, R. Ph., GCP, FASCP
Mark Coggins, Pharm. D., GCP, FASCP
Kelly Hollenack, Pharm. D. CGP
Philip King, Pharm. D., GCP, FASCP
Susan Kleim, B.S., Pharm., GCP, FASCP
Terry O’Shea, Pharm. D., GCP, FASCP
Elmer Schmidt, Pharm. D., GCP, FASCP
Barbara J. Zarowitz, Pharm. D., GCP, FASCP
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