AUGUST 2001
FORMULARY
ADDITIONS
Ramipril (AltaceÒ) 1.25 mg, 2.5 mg, 5 mg, 10 mg Capsules Ramipril, an angiotensin converting enzyme inhibitor
(ACEI), is indicated for the treatment of hypertension, heart failure, and
recently for reduction in risk of myocardial infarction, stroke, and death
from cardiovascular causes.
Angiotensin converting enzyme (ACE) catalyzes the conversion of
angiotensin I to angiotensin II.
Angiotensin II causes vasoconstriction and sodium and water retention,
which induces left ventricular remodeling.
Ramipril, a prodrug, has an active metabolite with a half-life of
13-17 hours in patients with normal renal function and an approximate
duration of action of 24 hours. The
usual dose is 2.5-20 mg daily, given once or twice daily (max 20 mg
daily). The half-life is prolonged in
patients with impaired renal dysfunction and dosage reduction may be
necessary to avoid accumulation. Adverse
effects associated with ramipril include cough, headache, dizziness, hypotension,
syncope, elevated serum creatinine and potassium, and less commonly,
hypersensitivity reactions and acute renal failure. All ACEIs are pregnancy
category C during the first trimester and category D during the second and
third trimester; ramipril should be avoided during lactation. All ACEIs interact with
diuretics/sympathomimetics, resulting in additive hypotension; with potassium
sparing diuretics, resulting in hyperkalemia; and lithium, resulting in
lithium toxicity. The drugs in this
class also interact with NSAIDs, with loss of hypotensive action and
deterioration of renal function as potential effects. Recently, results of the
HOPE trial and MICRO-HOPE trial were published indicating that ramipril may
have beneficial effects in reducing mortality rates associated with
myocardial infarction, and stroke.
The HOPE trial was a placebo-controlled, double- blinded, multicenter
clinical trial in which 9297 high risk patients (evidence of vascular disease
or diabetes with one other cardiovascular risk factor but no known evidence
of low ejection fraction or CHF) received vitamin E (400 IU daily) with
ramipril (2.5 to 10 mg daily) or placebo.
Specific inclusion criteria included adults aged 55 years, history of
coronary artery disease, stroke, peripheral vascular disease, or diabetes,
and at least one other cardiovascular risk factor. Primary endpoints were MI,
stroke, or death from cardiovascular causes. Secondary endpoints included
death from any cause, revascularization, and hospitalization for unstable
angina, or heart failure, and complications related to diabetes. Ramipril significantly reduced the rates
of death, myocardial infarction, and stroke in a broad range of high-risk
patients who were not known to have a low ejection fraction or heart failure. MICRO-HOPE, a substudy, used the same
endpoints and focused on the effects of ramipril on cardiovascular and
microvascular outcomes in diabetic patients.
Ramipril was beneficial for cardiovascular events and overt
nephropathy in people with diabetes.
This treatment represents a vasculoprotective and renoprotective
effect for people with diabetes.
Without direct comparisons within these studies, the likelihood that this
benefit represents a class effect cannot be excluded.
Ziprasidone (GeodonÒ) 20 mg, 40 mg, 60 mg, and 80 mg
capsules Ziprasidone, an atypical
antipsychotic agent structurally resembling risperidone, is indicated for the treatment of schizophrenia. Ziprasidone is a combined serotonin and
dopamine receptor antagonist. It is a potent 5-HT2A antagonist, with greater
affinity than other atypicals.
Efficacy has been found to be comparable to haloperidol. Ziprasidone therapy should be
initiated at a dose of 20 mg twice daily with food. The dose may be increased, based on response, up to 80 mg twice
daily. Dosage adjustments should
occur at intervals of not less than 2 days.
Patients should be observed for improvement for several weeks before
upward dosage adjustment to ensure the use of the lowest effective dose. Ziprasidone is extensively
hepatically metabolized, mainly by CYP3A4. Agents which inhibit CYP3A4 would
be expected to increase the AUC of ziprasidone. Carbamazepine, a CYP3A4
inducer, has been shown to decrease the AUC, while ketoconazole, a CYP3A4
inhibitor, has been shown to increase the AUC. Cimetidine, a CYP3A4 inhibitor, at 800 mg QD, has shown no
effect on ziprasidone pharmacokinetics. Caution should be used when combining
ziprasidone with agents which inhibit CYP3A4. In patients with mild
to moderate hepatic impairment, the AUC of ziprasidone is increased. Renal
impairment and hemodialysis do not alter the pharmacokinetics of ziprasidone. When deciding which antipsychotic
to use, ziprasidone’s greater capacity to prolong the QT/QTc interval should
be considered. Prolongation of the
QTc interval has been associated with torsades de pointes-type arrhythmia and
sudden death. Ziprasidone is contraindicated
and should not be used with any other medications that prolong the QTc
interval . This includes (not a complete list) quinidine, dofetilide,
pimozode, sotalol, thioridazine, moxifloxacin, and sparfloxacin. For a complete list of drugs that prolong
the QT interval or induce torsades de pointes, visit www.Torsades.org. Ziprasidone is also contraindicated in
patients with a known history of QT prolongation (including long QT
syndrome), history of cardiac arrhythmias, recent acute myocardial
infarction, or uncompensated heart failure. Ziprasidone should be discontinued in
patients who are found to have persistent QTc measurements >500 msec. Side effects of ziprasidone
include dyspepsia, constipation, nausea, abdominal pain, dry mouth, sedation,
headache, postural hypotension, dizziness, insomnia, akathisia, rash,
hypokalemia, and hypomagnesemia.
Hypokalemia may increase the risk of QT prolongation and arrhythmia.
Extrapyramidal effects occurred in 5% of patients in trials. Transient
prolactin elevation has been observed, which returned to baseline levels
within the dosing interval. Weight gain has not been observed
in most trials with ziprasidone.
Weight loss was observed in patients switched from olanzapine or
risperidone to ziprasidone. Reductions in total cholesterol, LDL cholesterol,
and triglycerides were also observed in ziprasidone-treated patients,
independent of weight changes. Patients on ziprasidone should be
monitored for electrolyte disturbances and for any symptoms suggestive of the
occurrence of torsades, such as dizziness, palpitations, or syncope. Any
deficiency of potassium or magnesium should be corrected before proceeding
with treatment. Patients at risk for
hypokalemia or hypomagnesemia (namely those on diuretic therapy) must be
monitored periodically for any deficiencies.
Dofetilide (TikosynÔ) 125 mcg, 250 mcg, 500 mcg capsules Restricted to Cardiology Dofetilide is a selective
class III antiarrhythmic agent approved for both acute cardioversion of
atrial fibrillation/atrial flutter and maintenance of normal sinus rhythm. Dofetilide is a derivative of the
non-beta-blocking moiety of sotalol.
It blocks potassium channels which results in lengthening of the
effective refractory period by prolongation of the action potential, without
blocking the sodium channels or fast inward sodium current. Dofetilide is active against atrial and
ventricular reentrant tachyarrhythmias and fibrillation. This agent lengthens the effective
refractory period and functional refractory period in the atrium and
ventricle, the effective refractory period of the accessory pathways, and the
duration of the atrial and ventricular monophasic action potential, without
effects on intracardiac conduction, sinus cycle length or sinus node
recovery. Dofetilide has no effects on blood pressure and exerts a slight
negative chronotropic effect, but does not exert a negative inotropic effect.
Dofetilide produces a
dose-dependent and plasma concentration-dependent prolongation of the QT
interval. This type of prolongation
has been associated with the development of torsade de pointes. The extent of
QT prolongation is influenced by heart rate, with partial reverse rate
dependence. Dofetilide is well absorbed after
oral administration. The half-life of
dofetilide is 7 to 13 hours. The
majority of the dose (1/2-1/3) is excreted unchanged in the urine and the
remainder is metabolized to essentially inactive metabolites by CYP3A4. The metabolites of dofetilide have some class
I and some class III antiarrhythmic activity, but only at very high
concentrations. Prolongation of the QT
interval during dofetilide therapy has been associated with torsade de
pointes and increasing premature ventricular contractions in up to 3%. This
has been the primary concern for the use of this drug. Medications which inhibit CYP3A4
(eg, erythromycin, ketoconazole) may inhibit dofetilide metabolism resulting
in increased dofetilide levels. These
increased serum levels will increase the risk of adverse reactions and
drug-induced arrhythmias. Dofetilide does not appear to inhibit CYP isozymes,
nor does dofetilide appear to interact with the pharmacokinetics or
pharmacodynamics of digoxin, propranolol or warfarin. It is recommended that this agent
is initiated in the hospital with at least 72 hours of cardiac monitoring.
Dosage must be individualized according to calculated creatinine clearance
and QTc interval. Typical initial dose is 500 mcg BID. Dosage should be
reduced in patients with impaired renal function and those who develop
excessive QT prolongation (> 500 msec or 550 msec in patients with
ventricular conduction abnormalities). Because of concerns about
torsades de pointes, the manufacturer has limited availability of the product
to hospitals and prescribers who have completed an education program.
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