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HEALTHLINE
March 2006
FOCUS ON BONE DISEASE OF CHRONIC KIDNEY DISEASE
NEW DRUGS AND INDICATIONS
NEW DRUGS/INDICATIONS
Aspirin Prevents Cardiovascular Disease in Healthy Adults
A meta-analysis was conducted of prospective, randomized controlled trials of aspirin therapy in
patients without cardiovascular disease published between 1966 and 2005. Among women,
aspirin prophylaxis reduced the odds of a cardiovascular event by 12%. It did not significantly
alter the risk of MI or hemorrhagic stroke, but it did reduce the risk of ischemic stroke by 24%.
Among men, aspirin reduced the risk of major cardiovascular events by 14%, and of MI by 32%.
While it had no effect on the risk of ischemic stroke among men, it did increase their risk of
hemorrhagic stroke by 69%. Both genders taking aspirin had a 70% increased risk of major
bleeding. The drug appeared to have no effect on cardiovascular or all-cause mortality among
men or women. This is more evidence in favor of low dose aspirin (81 mg/day) for the prevention
of cardiovascular disease. JAMA 2006;295:306-313.
Ibandronate Sodium (Boniva) Injection for Osteoporosis
The FDA has approved the first intravenous (IV) bisphosphonate for the treatment of
postmenopausal osteoporosis. Boniva injection is administered as a 15-to-30 second injection
once every three months for the treatment of postmenopausal osteoporosis. Boniva provides an
alternative for patients who have difficulty with oral bisphosphonate dosing requirements,
including an inability to sit upright for 30 to 60 minutes and/or swallow a pill.
Letrozole (Femara) Tablets for Hormone-Sensitive Breast Cancer
Femara is now approved as treatment for use after surgery in postmenopausal women with
hormone-sensitive early breast cancer (adjuvant setting). Femara is a once-a-day oral aromatase
inhibitor indicated for first-line treatment of postmenopausal women with hormone receptor
positive or hormone receptor unknown locally advanced or metastatic breast cancer. Femara is
also indicated for the treatment of advanced breast cancer in postmenopausal women with
disease progression following antiestrogen therapy.
WARNINGS AND ADVERSE EFFECTS
CDC Recommends against the Use of Amantadine and Rimantatine for the Treatment or
Prophylaxis of Influenza during the 2005–2006 Season
For the 2005–2006 season, 120 influenza A viruses isolated from patients in 23 states have been
tested at Centers for Disease Control and Prevention through January 12, 2006; 109 of the
isolates (91%) are resistant to amantadine and rimantadine. All influenza viruses from the United
States that have been screened for antiviral resistance at CDC have demonstrated susceptibility
to Tamiflu. On the basis of available antiviral testing results, CDC is providing an interim
recommendation that neither amantadine nor rimantadine be used for the treatment or
prophylaxis of influenza A in the United States for the remainder of the 2005–2006 influenza
season. During this period, Tamiflu should be selected if an antiviral medication is used for the
treatment and prophylaxis of influenza. Testing of influenza isolates for resistance to antivirals will
continue throughout the 2005–2006 influenza season, and recommendations will be updated as
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HEALTHLINE
March 2006
needed. Annual influenza vaccination remains the primary means of preventing morbidity and
mortality associated with influenza. Specific information regarding the use of Tamiflu is available
at http://www.cdc.gov/flu/protect/antiviral/index.htm
NEW DRUG WARNING AND REVISION OF MONITORING FOR
CLOZAPINE
Clozapine is used in treatment of refractory schizophrenia when other antipsychotic agents have
failed. Clozapine is available in tablet formulation and in a new oral disintegrating tablet
FazaClo®. The Food and Drug Administration (FDA) has advised a new monitoring schedule for
clozapine. The major changes include:
o
o
o
o
Requirement that the absolute neutrophil count (ANC) be determined and reported along with
each WBC count. The ANC is calculated by obtaining the percentage neutrophils (usually 50
to 60%) into an actual number of cells. Therefore, a complete blood cell (CBC) with
differential will have to be obtained on patients in the future.
New parameters for initiation of clozapine treatment: WBC ≥ 3500/mm3 and ANC ≥
2000/mm3.
Initiation of monthly monitoring schedule after one year (six months weekly, six months every
two weeks) of WBC counts and ANCs in the normal range (WBC ≥ 3500/mm 3 and ANC ≥
2000/mm3).
Increased risk of agranulocytosis (no WBCs) in patients who are re-challenged with clozapine
following recovery from an initial episode of moderate leucopenia (3000/mm 3 > WBC ≥
2000/mm3 and/or 1500/mm3 > ANC ≥ 1000/mm3). After recovering from such an episode,
these patients are now required to undergo weekly monitoring for 12 months if they are rechallenged.
Table 1: Frequency of Monitoring based on Stage of Therapy or Results from WBC Count
and ANC Monitoring Tests
Situation
Hematological Values for Monitoring
Initiation of therapy
WBC ≥ 3500/mm3
ANC ≥ 2000/mm3
Note: Do not initiate in patients with 1)
history of myeloperoliferative disorder or
2) clozapine induced agranulocytosis or
granulocytopenia
All results for
WBC ≥ 3500/mm3
ANC ≥ 2000/mm3
All results for
WBC ≥ 3500/mm3
ANC ≥ 2000/mm3
N/A
N/A
6 months – 12 months of
therapy
≥ 12 months of therapy
Immature forms present
Discontinuation of Therapy
Substantial drop in WBC or
ANC
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Single Drop or cumulative drop within 3
weeks of
WBC ≥ 3000/mm3 or
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Frequency of WBC and ANC
Monitoring
Weekly for 6 months
Every 2 weeks for 6 months
Every 4 weeks
Repeat WBC and ANC
Weekly for at least 4 weeks from day of
discontinuation or until WBC ≥
3500/mm3 and ANC ≥ 2000/mm3
1. Repeat WBC and ANC
2. If repeat values are 3000/mm 3 ≤
WBC ≤ 3500/mm 3 and ANC,
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HEALTHLINE
March 2006
ANC ≥ 1500/mm3
Mild Leukopenia
-----------------------------------------Mild Granulocytopenia
3500/mm3 > WBC ≥ 3000/mm3
and/or
2000/mm3 > ANC ≥ 1500mm3
Moderate Leukopenia
-----------------------------------------Moderate Granulocytopenia
3000/mm3 > WBC ≥ 2000/mm3
and/or
1500/mm3 > ANC ≥ 1000mm3
Severe Leukopenia
-----------------------------------------Severe Granulocytopenia
WBC < 2000/mm3
and/or
ANC < 1000mm3
Agranulocytosis
ANC ≤ 500/mm3
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2000/mm3, then monitor twice
weekly
Twice-weekly until WBC >3500/mm 3
and ANC > 2000/mm 3 then return to
previous monitoring frequency.
1. Interrupt therapy
2. Monitor daily until WBC >
3000/mm3 and ANC >
1500/mm3
3. Then, monitor twice-weekly
until WBC> 3500/mm3 and ANC
> 2000/mm3
4. May rechallenge when WBC >
3500/mm3 and ANC >
2000/mm3
5. If rechallenged, monitor weekly
for 1 year before returning to
the usual monitoring schedule
of every 2 weeks for 6 months
and then every 4 weeks
infinitum.
1. Discontinue treatment and do
not rechallenge patient
2. Monitor until normal and for at
least four weeks from day of
discontinuation as follows:
o Monitor daily until WBC >
3000mm3 and ANC >
1500/mm3
o Then, monitor twice weekly until
WBC > 3500/mm3 and ANC >
2000/mm3
o Then, monitor weekly After
WBC > 3500/mm3
1. Discontinue treatment and do
not rechallenge patient
2. Monitor until normal and for at
least four weeks from day of
discontinuation as follows:
o Monitor daily until WBC >
3000/mm3 and ANC >
1500/mm3
o Then, monitor twice weekly until
WBC > 3500/mm3 and ANC >
2000/mm3
o Then, monitor weekly after
WBC >3500/mm3
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HEALTHLINE
March 2006
Modifications to the frequency of monitoring following interruptions in therapy were also
revised.
o
o
o
Patients receiving clozapine who are being monitored on the previous schedule of weekly
for the first 6 months are to continue this monitoring schedule and report ANCs from this
point forward. If WBC ≥ 3500/mm 3 and ANC ≥ 2000/mm3, patients may transition to
every 2 weeks monitoring for the next 6 months.
Patients who are currently being monitored on the previous schedule of every other
week, are to continue this monitoring schedule for a total of six months and should report
ANCs from this point forward. If WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3, patients may
transition to every monthly monitoring.
WBC and ANC values following the discontinuation of clozapine therapy should be
submitted to the Clozapine National Registry (CNR) for all non-rechallengeable patients
(WBC <2000/mm3 and/or <1000/mm3), until WBC ≥ 3500/mm 3 and ANC ≥ 2000/mm 3.
The National Registries by IVAX, Alamo and Novartis Pharmaceuticals have updated or will be
updating their registry information to require insertion of the ANC value in the next several weeks.
All pharmacies will be required to obtain a copy of the CBC with differential to calculate the ANC
and record the WBC value on all Clozapine prescriptions.
As a reminder,
o
o
o
Clozapine is contraindicated in patients with paralytic ileus as this is an adverse effect of
clozapine.
Clozapine has been associated with hypercholesterolemia and/or hypertriglyceridemia.
Concomitant use of clozapine and citalopram results in clinically significant elevations of
clozapine blood concentrations.
Remember, clozapine is considered “Unacceptable” in older persons when safer, equally
effective alternatives, such as atypical antipsychotics exist.
References
Novartis Pharmaceuticals Corporation (resource on the World Wide Web). URL:
http://www.fda.gov/medwatch/safety/2006/Clozaril_chart_letter_final12-2005.pdf.com. Available from internet. Accessed
2006 January 25.]
Alamo Pharmaceuticals Corporation (resource on the World Wide Web). URL:
http://www.fazaclo.com/PDF_Files/FAZACLO_PI.pdf. Available from internet. Accessed 2006 January 25.]
New Warning About Rosiglitazone (Avandia)
GlaxoSmithKline and the Food and Drug Administration recently notified health care
professionals about post-marketing reports of new onset and worsening diabetic macular edema
for patients receiving rosiglitazone. In the majority of these cases, the patients also reported
concurrent peripheral edema. In some cases, the macular edema resolved or improved following
discontinuation of therapy and in one case, macular edema resolved after dose reduction. To
read the complete MedWatch 2006 Safety summary, including a link to the GSK Dear Healthcare
Professional letter, visit: http://www.fda.gov/medwatch/safety/2006/safety06.htm#Avandia
FDA APPROVES BLACK BOX WARNING FOR ECZEMA CREAMS
The Food and Drug Administration approved a black box warning that will be added to
pimecrolimus (Elidel) and tacrolimus (Protopic) used to treat atopic dermatitis.
The drugs' labels will now include the warning of a possible cancer risk associated with the drugs
and clarify that the drugs should be used as second-line treatments. A Medication Guide will also
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be distributed to inform patients of the potential risk. The FDA noted that these drugs are not
recommended for use in patients 2 years of age or less. Medication Guides will be available
shortly on the FDA web site and should be provided to patients who self-medicate. For more
information visit: http://www.fda.gov/cder/drug/infopage/elidel/default.htm
PATIENT CARE
Bone Disease Associated With Chronic Kidney Disease
Elevated concentrations of serum intact parathyroid hormone (iPTH) leads to a condition called
secondary hyperparathyroidism (HPT) which is a common complication of chronic kidney disease
(CKD). It is characterized by abnormalities in bone and mineral metabolism. The term renal
osteodystrophy is used to collectively describe all of the skeletal changes of chronic renal
disease.
This serious disorder arises from disturbances in the regulation of the intracellular and
extracellular concentrations of PTH, calcium, phosphorus, and vitamin D3 (calcitriol), which
become more severe as kidney function declines. Abnormalities associated with secondary HPT
begin in the early stages of CKD. Although most patients with renal osteodystrophy are
asymptomatic, there are many pathologic features associated with this disease including bone
and joint pain, fractures and deformities, extraskeletal calcification, osteoporosis, and osteopenia,
skin ulceration, soft tissue necrosis, tendon rupture, periarthritis, and an increased risk of
mortality.
Lab Monitoring and Treatment Goals
Serum concentrations of calcium, phosphorus, and intact plasma parathyroid hormone (iPTH)
should be measured in all patients with CKD and glomerular filtration rate (GFR) < 60
mL/min/1.73 m2.
Table 1: Patient Treatment Goals
Concentration
Corrected
Calcium
Phosphorus
Ca x PO4
iPTH
Stage 3
Stage of Kidney Disease
Stage 4
Stage 5
GFR 30-59 mL/min/m2
GFR 15 – 29 mL/min/m2
GFR < 15 mL/min/m2
8.4-10.2
mg/dL
2.7-4.6
mg/dL
8.4-10.2
mg/dL
2.7-4.6
mg/dL
8.4-9.5
mg/dL
3.5-5.0
mg/dL
< 55
< 55
< 55
35-70
mg/dL
70-110
mg/dL
150-300
mg/dL
Phosphate Binders:
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If phosphorus or iPTH concentrations cannot be controlled within the target range despite dietary
phosphorus restriction, phosphate binders should be prescribed. There are two categories of
phosphate binders, the calcium-based phosphate binders which include calcium carbonate
(Tums, Oscal) and calcium acetate (Phos-Lo), and non calcium-based phosphate binders which
include sevelamer (Renagel) and lanthanum (Fosrenol).
All phosphate binders are similarly effective. Calcium-based products are often used as first line
due to their ease of administration, and limited risk of toxicity. However, non-calcium based
products are a safer alternative in patients who experience hypercalcemic symptoms or have an
elevated calcium-phosphate product (>55 mg2/dL2). The total dose of elemental calcium provided
by the calcium-based phosphate binders should not exceed 1,500 mg/day, and the total intake of
elemental calcium (including dietary calcium) should not exceed 2,000 mg/day.
Patients should take their phosphate binder with meals and snacks for maximal effectiveness.
Calcium acetate and sevelamer should be taken with meals, whereas calcium carbonate can be
taken directly before meals. Clinicians should keep in mind that some multivitamins and laxatives
may contain phosphorus and should be avoided. Gastrointestinal symptoms are common with all
phosphate binders; however, patients may tolerate on product better than others.
Table 2: Phosphate Binders
Compound
Estimate of
(Brand name)
% Calcium absorbed
Calcium carbonate
(Tums, Oscal, etc)
Calcium Acetate
(Phos-Lo)
Approximately 20-30%
is absorbed
With meals: ~21%
Between meals: ~40%
Potential
side effects
Hypercalcemia, extraskeletal
calcification, GI side effects,
constipation
Hypercalcemia, extraskeletal
calcification, GI side effects
Sevelamer
(Renagel)
None
(non-calcium)
GI side effects
Lanthanum (Fosrenol)
None
(non-calcium)
GI side effects
Vitamin D Analogs
Vitamin D analogs approved for treating secondary hyperparathyroidism include paricalcitol
(Zemplar), doxercalciferol (Hectoral), and calcitriol. All three agents are effective in directly
suppressing PTH synthesis and reducing PTH concentrations. Dosing must be individualized
and based on iPTH concentrations (Table 1).
When Vitamin D analogs are used to suppress PTH concentrations, they may increase intestinal
absorption of calcium and phosphorus because vitamin D receptors also are present in the
gastrointestinal tract. Hypercalcemia, hyperphosphatemia, and an elevated calcium-phosphorus
product are limitations of vitamin D treatment, particularly when administered with calciumcontaining phosphate binders.
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Calcium and phosphorus concentrations should be obtained weekly, and PTH concentrations
should be obtained at least every 4 weeks when initiating or titrating vitamin D doses. Once
patients are stabilized on a maintenance dose, monitoring frequency can decrease to monthly for
calcium and phosphorus and quarterly for PTH concentrations.
Bone disease is a complex disorder related to CKD, and there is a growing body of literature
demonstrating its significant morbidity and mortality. Awareness of this disorder in long-term care
facilities can help to prevent and treat this disease. Measurement of calcium, phosphorus and
PTH serum concentrations should occur when the GFR is < 60ml/ min/1.73 m2, with appropriate
treatment and follow up for abnormal results.
Please contact your Consultant Pharmacist if you have questions or would like additional
information.
K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. 2004.
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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