Professional Documents
Culture Documents
Adverse Effects
In common with other thrombolytics streptokinase may cause haemorrhage, particularly from
puncture sites; severe internal bleeding has occurred and may be difficult to control.
Streptokinase is antigenic, and allergic reactions ranging from rashes to rarer anaphylactoid
and serum-sickness-like symptoms have occurred. Fever, sometimes high, and associated
symptoms such as chills and back or abdominal pain are quite frequent. Nausea and vomiting
may occur. There have been a few reports of Guillain-Barr syndrome. Streptokinase infusion
may be associated with hypotension, both direct or as a result of reperfusion; bradycardia and
arrhythmias may also occur due to reperfusion. The break-up of existing clots may
occasionally produce emboli elsewhere; pulmonary embolism and acute renal failure due to
cholesterol embolisation have been reported.
Back pain. Streptokinase infusion has been associated with the development of very severe
low back pain, which resolves within a few minutes of stopping the infusion, and may be
severe enough to warrant opioid analgesia.1-4 The back pain may represent a hypersensitivity
reaction. Providing that the pain is controlled
and that dissecting aortic aneurysm is not suspected, it may still be possible to complete the
streptokinase infusion.4,5 Alternatively, immediate substitution with a different thrombolytic
has been suggested.6
Effects on the blood. Although falls in the haemoglobin value of patients receiving
thrombolytics are most likely to be due to blood loss from haemorrhage, there has been a
report of a patient who had signs of haemolytic anaemia after intravenous infusion of
streptokinase.1 In a subsequent test in vitro the patients serum caused strong agglutination of
streptokinase-treated red blood cells, supporting the view that streptokinase was responsible
for the haemolysis.
Effects on the eyes. Acute uveitis1,2 and iritis,3,4 associated with transient renal impairment
in one patient,3 have followed treatment of myocardial infarction with intravenous
streptokinase. In one case uveitis was associated with serum sickness2 and in all of them
hypersensitivity to streptokinase was suspected.
Effects on the kidneys. Transient proteinuria has been reported after use of streptokinase. In
some patients proteinuria and renal impairment have developed about 7 days after
thrombolytic therapy and have been associated with a syndrome resembling serum
sickness,1,2 suggesting a delayed hypersensitivity reaction;
a similar case in a patient receiving anistreplase was associated with Henoch-Schnlein-like
vasculitis.3 These delayed reactions should be distinguished from the transient and apparently
self-limiting proteinuria that has been reported in some patients in the first 24 to 72 hours
after beginning streptokinase.4,5 Proteinuria within the first 24 hours has been attributed to
deposition of an immune complex in the glomeruli,6 although haemodynamic and
neurohormonal changes associated with acute myocardial infarction may be responsible since
proteinuria has occurred in patients not receiving thrombolytic therapy.7,8 Streptokinase
infusion has also been associated with acute oliguric renal failure due to acute tubular
necrosis, apparently as a result of hypotension during the infusion, in a patient with existing
renovascular narrowing.9 Interestingly, it has been pointed out that a variant streptokinase
may be the pathogenic agent in glomerulonephritis occurring after Streptococcus pyogenes
alteplase is generally preferred. Streptokinase may be used to clear cannulas and shunts and is
used topically with streptodornase to clear clots and purulent matter.
In acute myocardial infarction streptokinase is usually given intravenously as a single dose
of 1.5 million units infused over 1 hour as soon as possible after the onset of symptoms.
Streptokinase has also been given in a suitable dose by intracoronary infusion but coronary
catheterisation with the aid of angiography is required, thus restricting use to suitably
equipped centres.
In the treatment of pulmonary embolism and otherarteriovenous occlusions an initial
loading dose of streptokinase, normally 250 000 units infused intravenously over 30 minutes,
is given to overcome any resistance due to circulating antibodies. This is followed by
infusion of a maintenance dose of 100 000 units/hour for 24 to 72 hours, depending on the
condition to be
treated; for central retinal thrombosis, 12 hours may be adequate. Treatment should be
controlled by monitoring the thrombin clotting time, which should be maintained at 2 to 4
times normal values. Since thrombolytic activity rapidly fades when the infusion stops,
streptokinase treatment is generally followed after 3 to 4 hours by intravenous heparin
infusion, and then oral
anticoagulation, to prevent re-occlusion. Streptokinase, as a solution containing 250 000 units
in 2 mL is used to clear occluded cannulas; 1000 units/mL has been used to clear shunts of
occluding thrombi.
Intracardiac thrombosis. Thrombosis of prosthetic heart valves (see p.1187) is usually
treated surgically, but thrombolytics have also been used. In a study1 of patients with leftsided prosthetic valve thrombosis, thrombolytic therapy was found to be more successful than
surgery, especially in those who were critically ill; most patients were given streptokinase.
Another retrospective study2 in which patients were given streptokinase, urokinase, or
alteplase, concluded that thrombolytics were effective but embolic and haemorrhagic
complications might limit
their use.
Ischaemic heart disease. Thrombolytics such as alteplase, streptokinase, and urokinase have
an established role in the early management of acute myocardial infarction (p.1175).
Myocardial infarction is caused by coronary artery occlusion, usually due to thrombosis, and
thrombolytics are given intravenously to break up the thrombus or clot and restore the
patency of the coronary artery, thereby limiting infarct size and irreversible damage to the
myocardium. Reduction of ECG abnormalities and modification of ventricular remodelling
may also contribute to their effect. Other antithrombotics, in particular aspirin and heparin,
are given as adjunctive therapy. Several large studies have established that thrombolytics can
preserve left ventricular function and improve short-term and 1-year mortality figures;1,2
benefit has been maintained in 5-year3 and 10-year4,5 follow-up studies. Benefit is greatest
with early treatment. Trials such as the GISSI-1 study6 and the ISIS-2 study7 helped to
establish that mortality is reduced if thrombolytics are given within 6 hours of the onset of
symptoms8 and further studies provided evidence9,10 that patients presenting within 12
hours should receive a thrombolytic. Use after 12 hours has been associated with an increase
in adverse effects,8 and is usually reserved for patients with evidence of ongoing ischaemia.
Prehospital thrombolysis is feasible and reduces the time to thrombolysis and short-term
mortality.11 Five-year follow-up of one study12 has suggested that there is also a beneficial
effect on long-term mortality.
stockings.396, 437
In high-risk patients undergoing intracranial neurosurgery
, consider in combination
who have additional risk factors.437 Use in combination with graduated compression stockings
and/or IPC in patients with multiple risk factors.437
Use not recommended for prophylaxis in patients with acute spinal cord injury
.396, 437
Instead, ACCP recommends anticoagulation with a low molecular weight heparin once
primary hemostasis is evident.396, 437 Alternatively, use combination of IPC and unfractionated
heparin or a low molecular weight heparin in patients with acute spinal cord injury.437
Orthopedic Surgery Thromboprophylaxis
to be delayed, may initiate prophylaxis with either low-dose unfractionated heparin or a low
molecular weight heparin.437
Use not recommended by ACCP for prophylaxis of postoperative venous thromboembolism
in patients undergoing hip- or knee-replacement surgery.437
Thromboprophylaxis in Selected Medical Conditions
Prophylaxis of venous thromboembolism in medical patients who have severely restricted
mobility during acute illness (e.g., bedrest, heart failure, severe lung disease) and have one or
more additional risk factors (e.g., previous venous thromboembolism, sepsis, acute
neurologic disease, inflammatory bowel disease).367, 368, 373, 396, 399, 437, 441, 453, 454, 468, 469, 470
Prophylaxis with low-dose unfractionated heparin or a low molecular weight heparin
recommended in critically ill patients who are at moderate risk for thromboembolism (e.g.,
active medical or general surgical condition).437
Prophylaxis with a low molecular weight heparin recommended in critically ill patients who
are at higher risk for thromboembolism, such as those with major trauma or who are
undergoing orthopedic surgery.437
Thromboembolism During Pregnancy
Primary prevention of thromboembolism in pregnant women with inherited causes of
thrombophilia (e.g., deficiencies of antithrombin III, heterozygous genetic deficiency of both
prothrombin G20210A and factor V Leiden, or homozygous genetic deficiency for factor V
Leiden or prothrombin G20210A).387, 436
Secondary prophylaxis of venous thromboembolism (e.g., women with inherited
thrombophilias, 1 episodes of idiopathic venous thromboembolism) during pregnancy.291, 356,
362, 387, 436
.400, 401, 402, 403, 438 ACC, AHA, and European Society of Cardiology (ESC) recommend heparin
or a low molecular weight heparin in all patients with atrial fibrillation, except those with
lone atrial fibrillation or unless contraindicated.400, 439
Base choice of antithrombotic agent on absolute risks of stroke and bleeding and relative risk
and benefits in individual patients.400
In pregnant women with atrial fibrillation and risk factors for thromboembolism
ACC/AHA/ESC suggest use during the first trimester and last month of pregnancy.400
May be substituted for oral anticoagulant (e.g., warfarin) therapy in patients with atrial
fibrillation who require a series of diagnostic or surgical procedures that necessitate
interruption of oral anticoagulation
for >1 week or in selected high-risk patients who
In pregnant women with prosthetic mechanical heart valves, ACCP states that aggressive,
adjusted-dose therapy with low molecular weight heparin or high-dose unfractionated heparin
therapy appears reasonable despite lack of definitive data on optimal therapy because of risks
of withholding anticoagulation.387, 436
Arterial Thromboembolism
Prophylaxis and treatment of peripheral arterial embolism.373, 404, 452, 453, 454, 466, 467, 468, 469 Use
immediately in patients with evidence of arterial emboli or thrombosis to prevent thrombotic
propagation.450
No evidence of efficacy in the treatment of chronic peripheral arterial disease.450
Prophylaxis during cardiac catheterization via an artery in neonates and children.449 Use
following cardiac catheterization if femoral artery thrombosis occurs.449
Treatment of aortic thrombosis in neonates with umbilical artery catheters.449 In neonates
experiencing spontaneous aortic thrombosis with evidence of renal ischemia, ACCP suggests
urgent, aggressive use of thrombolytic or surgical therapy supported by anticoagulation with
unfractionated heparin or a low molecular weight heparin.449
Thromboembolism Associated with Cardiac and Arterial Vascular Surgery
Prevention of activation of the coagulation mechanism as blood passes through an
extracorporeal circuit in dialysis procedures and during arterial and cardiac surgery.373, 380, 381,
384, 452, 453, 454, 466, 467, 468, 469
181, 182, 183, 184, 185, 186, 283, 322, 345, 382, 439, 445
ACC and AHA recommend unfractionated heparin or a low molecular weight heparin for
prevention of systemic embolism following AMI in patients at high risk for such events (e.g.,
large or anterior MI, atrial fibrillation, previous embolus, left ventricular thrombus,
cardiogenic shock).439
Used IV in conjunction with fibrin-selective thrombolytic therapy (e.g., alteplase, reteplase,
tenecteplase) and low-dose aspirin therapy in patients with ST-segment AMI.332, 382, 383, 439, 445
Also recommended in conjunction with non-fibrin-selective thrombolytic therapy in patients
at high risk for systemic embolism.439, 445
Use suggested in patients not receiving thrombolytic therapy who do not have a
contraindication for anticoagulation.439
Acute Ischemic Complications of Percutaneous Coronary Interventions
Reduction in the risk of complications in patients undergoing percutaneous coronary
intervention (PCI) or surgical coronary revascularization.380, 381, 384, 447 Used in conjunction
with aspirin, a GP IIb/IIIa-receptor inhibitor, and/or clopidogrel in such patients.380, 384, 385, 418,
419, 447, 455
419, 444
Patients at intermediate risk for death or nonfatal MI include hospitalized patients with
prolonged rest angina relieved with rest or sublingual nitroglycerin, nocturnal angina,
dynamic T-wave changes, resting ST-segment depression of <1 mm in multiple leads, or
those >65 years of age.349 High-risk patients include those who have unstable angina with
prolonged ischemic pain at rest, elevated troponin I or T concentrations, or rest angina with
dynamic ST changes >1 mm.349
ACCP recommends a low molecular weight heparin over unfractionated heparin for the
short-term treatment in such patients.345, 348, 351, 352, 356, 358, 418, 419, 444
Used concurrently with aspirin and/or other standard therapy (e.g., nitrates, -adrenergic
blockers, clopidogrel, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors).322, 348, 361, 418, 419,
444
Cerebral Thromboembolism
Prophylaxis of venous thromboembolism in patients with ischemic stroke
and
.449
of hemorrhagic venous infarcts.399, 441 Some experts do not recommend heparin for patients
with large hemorrhagic venous infarcts with associated hematomas.441 Treatment of cerebral
venous sinus thrombosis without large ischemic infarctions or intracranial hemorrhage in
neonates.449
Anticoagulant in Blood Transfusions and Blood Samples
In vitro anticoagulant in blood transfusions and in blood samples drawn for laboratory
purposes.373, 453, 454
With intermittent IV injection, perform coagulation tests prior to initiation of therapy, prior to
each injection during the early stages of therapy, and daily thereafter.373, 453, 454, e, 466 467, 468
With deep sub-Q injection, perform coagulation tests prior to initiation of therapy, 4-6 hours
following injection during the early stages of therapy, and daily thereafter.373, 453, 454, e
Perform periodic platelet counts, hematocrit, and tests for occult blood in stool during the
entire course of therapy.373, 452, 453, 454, 373, 466, 467, 468, 469
Conversion to Oral Anticoagulation
Warfarin is generally administered for follow-up treatment after full-dose heparin.360, 362
Usually overlap therapy for 4-5 days or until an adequate response to warfarin is obtained
(e.g., as indicated by INR >2 on two consecutive days).360, 362, 435, 451
Some manufacturers recommend abrupt discontinuance of heparin therapy after confirmation
of adequate response to warfarin.107, 373, 452, 453, 454 466, 467, 468, 469 However, some clinicians
recommend gradual discontinuance of heparin infusions (e.g., reducing the rate by 50% over
6 hours and then discontinuing over the next 12 hours) because of concern about possible
rebound thrombosis.e
Administration
Administer by IV infusion, intermittent IV injection, or deep sub-Q (intrafat) injection.373, 452,
453, 454, 466, 467, 468, 469
Do not administer IM because of frequency of hematoma at injection
site.373, 452, 453, 454, 458, 460, 461, 462, 463, 464, 466, 467, 468
Heparin lock flush solution: Administer by intracatheter instillation into an indwelling IV
injection device.374 Not intended for systemic anticoagulation or injection by any parenteral
route of administration.374, 376, 458, 460, 461, 462, 463, 464
IV Administration
For solution and drug compatibility information, see Compatibility Under Stability.
such reduced potency; may be clinically important in some situations (e.g., treatment or
prevention of a life-threatening thromboembolic event) while less important in others (e.g.,
sub-Q heparin).489 Higher dosages of heparin sodium preparations manufactured and tested
under new USP standard may be required to produce same level of anticoagulation as
previous formulations; more frequent and intensive monitoring of ACT or aPTT also may be
necessary.489, 490 Continue to individualize heparin dosages based on clinical judgment.489
Pediatric Patients
Treatment of Venous Thrombosis and Pulmonary Embolism
>IV
Neonates: Weight-based dosage sufficient to prolong the aPTT to a range that corresponds to
an anti-factor Xa concentration of 0.35-0.7 units/mL.416, 449 Initial treatment with
unfractionated heparin sodium or low molecular weight heparin may be continued for 5-10
days;416 ACCP states that data are insufficient to make strong recommendations and that
treatment should be individualized considering risks versus benefits.449 Follow-up with low
molecular weight heparin for 10 days to 3 months.449 Convert to oral anticoagulation or
initiate or resume therapy with a low molecular weight heparin if thrombus extends following
discontinuance of IV heparin sodium.416 449 (See Conversion to Oral Anticoagulation under
Dosage and Administration.)
Neonates with unilateral renal vein thrombosis that extends into the inferior vena cava:
Adjust dosage adjusted to prolong the aPTT to a range corresponding to an anti-factor Xa
concentration of 0.35-0.7 unit/mL for 6 weeks to 3 months.449
Children >2 months of age with a first thromboembolic event: Adjust maintenance dosage to
prolong the aPTT to a range corresponding to an anti-factor Xa concentration of 0.35-0.7
units/mL for 5-10 days.416, 449 Massive or extensive venous thromboembolism may require a
longer initial treatment period.449 Convert to warfarin therapy for follow-up oral
anticoagulation.416, 449 (See Conversion to Oral Anticoagulation under Dosage and
Administration.)
For full-dose IV heparin sodium therapy in children, some manufacturers recommend an
initial loading dose of 50 units/kg followed by 100 units/kg every 4 hours by intermittent
infusion or 20,000 units/m2 per 24 hours by continuous IV infusion.373, 452, 453, 454, 466, 467, 468, 469
For full-dose IV heparin sodium therapy in children, ACCP recommends a loading dose of
75-100 units/kg given over 10 minutes.416, 449
Infants <1 year of age: An initial maintenance dosage of 28 units/kg per hour recommended
by ACCP, with dosage adjusted to maintain an aPTT of 60-85 seconds (assuming this
corresponds to an anti-factor Xa concentration of 0.35-0.7 units/mL).416, 449
Children >1 year of age: An initial maintenance dosage of 20 units/kg per hour recommended
by ACCP, with dosage adjusted to maintain an aPTT of 60-85 seconds (assuming this
corresponds to an anti-factor Xa concentration of 0.35-0.7 units/mL).416, 449
Weight-adjusted dosage required for older children is similar to that for adults (18 units/kg
per hour).416, 449
Arterial Thromboembolism
>IV
For neonates and children requiring cardiac catheterization via an artery: 100-150 units/kg by
direct injection suggested; multiple doses may be required in prolonged procedures (>60
minutes).449
Neonates or children with femoral artery thrombosis associated with cardiac catheterization:
75-100 units/kg by direct injection, then 20-28 units/kg per hour depending on age for 5-7
days suggested; optimal duration unknown.449
Neonates with aortic thrombosis associated with umbilical artery catheters: 75-100 units/kg
by direct injection, then 28 units/kg per hour for 5-7 days suggested; optimal duration
unknown.449
Disseminated Intravascular Coagulation
>IV
25-50 units/kg given by IV infusion or IV injection every 4 hours.e Discontinue after 4-8
hours if there is no improvement.e
Adults
Treatment of Venous Thrombosis and Pulmonary Embolism
>IV, then Sub-Q
Full-dose intermittent therapy (68-kg adult): 5000 units IV then 10,000-20,000 units sub-Q
initially, followed by 8000-10,000 units sub-Q every 8 hours or 15,000-20,000 units sub-Q
every 12 hours.373, 453, 471
Adjusted-dose therapy: 5000 units IV initially as a loading dose followed by 17,500 units
sub-Q twice daily, with dosage adjusted to prolong the aPTT to 1.5-2.5 times the control
value at the mid-dose interval recommended by some clinicians.435
>IV
Full-dose continuous therapy (68-kg adult): 5000 units initial loading dose, then 20,00040,000 units in 1 L of 0.9% sodium chloride injection or other compatible IV solution infused
over 24 hours recommended by some manufacturers.373, 453 ACCP recommends an initial
loading dose of 5000 units, then 30,000 units infused over the first 24 hours.435
Full-dose intermittent therapy (68-kg adult): 10,000 units initial loading dose, then 500010,000 units every 4-6 hours recommended by some manufacturers.373, 453, e ACCP states that
intermittent IV regimens are associated with a higher risk of bleeding than continuous IV
infusion and are not recommended.435
Adjusted-dose continuous therapy: ACCP recommends 80 units/kg loading dose, then 18
units/kg per hour for 24 hours.435
After 24 hours, adjust dosage to prolong the aPTT to a level corresponding with a plasma
heparin concentration of 0.3-0.7 units/mL (amidolytic anti-factor Xa assay) for 5 days.435
Pregnant women: 5000 units by direct injection followed by a continuous infusion to
maintain aPTT in the therapeutic range) for 5 days.387, 436 (See ThromboembolismDuring
Pregnancy under Dosage and Administration for information on secondary prophylaxis).
General Surgery Thromboprophylaxis
>Sub-Q
Moderate-risk general surgery patients: 5000 units 1-2 hours prior to surgery, then every 12
hours after surgery until patient is ambulatory or discharged from the hospital.437 (See General
Surgery Prophylaxis under Uses for explanation of risk factors.)
High-risk general surgery patients: 5000 units administered 1-2 hours prior to surgery, then
every 8 hours; for patients with multiple risk factors, combine pharmacologic therapy with
intermittent pneumatic compression (IPC) or graduated-compression stockings.437
Gynecologic laparoscopic surgery patients with additional risk factors: 5000 units 2-3 times
daily recommended by ACCP.437
Major gynecologic surgery for benign disease: 5000 units twice daily until hospital
discharge.437
Major gynecologic surgery with additional risk factors: 5000 units 3 times daily until hospital
discharge.437
Major gynecologic surgery for cancer: 5000 units 3 times daily until hospital discharge.437
Major gynecologic surgery at particularly high-risk patients (e.g., >60 years of age, cancer
surgery, history of venous thromboembolism): Continue prophylaxis for 2-4 weeks after
hospital discharge.437
Major open urologic surgery: 5000 units 2-3 times daily.437
Urologic surgical patients with multiple risk factors: 5000 units 2-3 times daily in
combination with IPC or graduated-compression stockings.396, 437
Neurosurgery Thromboprophylaxis
>Sub-Q
Intracranial neurosurgery
: 5000 units administered 1-2 hours preoperatively, then
every 8-12 hours is recommended.396, 437
Elective spinal surgery with additional risk factors: 5000 units 2-3 times daily initiated
postoperatively alone or in combination with IPC or graded compression stockings.396, 437
Hip-fracture surgery: 5000 units administered 1-2 hours preoperatively, then every 8-12
hours.367, 396, 437
Thromboprophylaxis in Selected Medical Conditions
>Sub-Q
Hospitalized patients with CHF, severe respiratory disease, or impaired mobility and
additional risk factors: 5000 units twice daily.437
Critically ill patients at moderate risk: 5000 units twice daily.437 (See Medical Conditions
Associated with Thromboembolism under Uses.)
Thromboembolism During Pregnancy
>Sub-Q
Primary prevention in women with antithrombin deficiency, heterozygous genetic mutation
for factor V Leiden and prothrombin G20210A or homozygous gene mutation for factor V
Leiden or prothrombin G20210A : 5000 units every 12 hours with dosage adjusted to
maintain an anti-factor Xa concentration of 0.1-0.3 units/mL, followed by postpartum oral
anticoagulation (e.g., with warfarin).436
Primary prevention in women with confirmed thrombophilia: 5000 units every 12 hours
suggested.436
Secondary prevention after a single episode of idiopathic venous thromboembolism with or
without thrombophilia with no long-term anticoagulation: 5000 units every 12 hours with or
without adjustment of dosage to maintain an anti-factor Xa concentration of 0.1-0.3 units/mL,
followed by postpartum oral anticoagulation.436
Secondary prevention after a single episode of venous thromboembolism and confirmed
thrombophilia or family history of thrombosis not receiving long-term anticoagulation: 5000
units every 12 hours with or without adjustment of dosage to maintain an anti-factor Xa
concentration of 0.1-0.3 units/mL, followed by postpartum oral anticoagulation.436
Secondary prevention after 2 episodes of venous thromboembolism and/or who are
receiving long-term anticoagulation: Administer every 12 hours with dosage adjusted to
maintain the mid-interval aPTT in the therapeutic range, followed by resumption of
postpartum long-term oral anticoagulation.436
Primary or secondary prevention in women with antiphospholipid syndrome and a history of
multiple pregnancy losses, preeclampsia, intrauterine growth retardation, or abruption: 5000
units twice daily or moderate twice-daily dosage adjusted to maintain an anti-factor Xa
concentration of 0.1-0.3 units/mL and low-dose aspirin.290, 291, 295, 299, 300, 315, 436
Atrial fibrillation with risk factors: 10,000-20,000 units every 12 hours with dosage adjusted
to maintain the mid-interval aPTT (6 hours after dose) at 1.5 times the control value during
the first trimester and last month of pregnancy.400
>IV
Atrial fibrillation with risk factors: Adjusted dose continuous therapy suggested to maintain
the aPTT 1.5-2 times control value during first trimester and last month of pregnancy.400
Embolism Associated with Atrial Fibrillation/Flutter
>IV
Atrial fibrillation with AMI: 60 units/kg loading dose followed by 12 units/kg per hour to
maintain an aPTT of approximately 1.5-2 times the control value.400, 439
Thromboembolism Associated with Prosthetic Heart Valves
>Sub-Q
Pregnant women: Initially, 17,500-20,000 units every 12 hours and adjusted to maintain the
mid-interval aPTT at least twice the control value or anti-factor Xa concentration of 0.35-0.7
units/mL throughout pregnancy suggested.360, 436
Alternatively, 17,500-20,000 units every 12 hours adjusted to maintain the mid-interval aPTT
twice the control value or an anti-factor Xa concentration of 0.35-0.7 units/mL until week 13
of pregnancy, then transfer to warfarin until the middle of the third trimester, followed by
adjusted-dose heparin until close to term.360, 436
Disseminated Intravascular Coagulation
>IV
50-100 units/kg by IV infusion or IV injection every 4 hours.e Discontinue after 4-8 hours if
there is no improvement.e
Thrombosis Associated with Indwelling Venipuncture Devices
>Intracatheter Instillation
Inject a quantity of heparin lock flush solution (e.g., containing 10 or 100 units/mL) sufficient
to fill the device after each use.234, 458, 460 461 462, 463, 464, 465 (See Intracatheter Instillation under
Dosage and Administration: Administration.)
Acute Ischemic Complications of ST-Segment Elevation AMI
>IV
Conjunctive therapy with fibrin-selective thrombolytic agents: Initially, 60 units/kg
(maximum 4000 units) loading dose.382, 383, 439, 445, 455
Maintenance dosage: 12 units/kg per hour (maximum 1000 units/hour in patients weighing
>70 kg), adjusted to maintain a therapeutic aPTT for 48 hours.382, 383, 439, 445, 455 Follow-up
therapy with oral anticoagulation (e.g., warfarin).382, 383, 439, 445, 455
Conjunctive therapy with non-fibrin-selective thrombolytic agents in patients who are at high
risk for thromboembolism: 5000 units by direct injection followed by 800 units/hr for
patients weighing 80 kg or 1000 units/hr for patients weighing >80 kg for 48 hours.439, 445
After 48 hours, change to sub-Q heparin.322, 345, 369, 382, 439
Discontinue after 48 hours in patients at low risk for thromboembolism, convert to sub-Q
therapy in patients at high risk of systemic embolization, and continue IV therapy in patients
at high risk for coronary reocclusion.322, 382, 439
>Sub-Q
Conjunctive therapy with non-fibrin-selective thrombolytic agents in patients who are at high
risk for thromboembolism: 12,500 units every 12 hours for 48 hours.445
Patients who did not receive thrombolytic therapy: 7500-12,500 units every 12 hours for 48
hours.322, 345, 369, 382, 439 Continue therapy until patient is ambulatory in patients with impaired
mobility.439
Cardiac and Vascular Surgery Thromboprophylaxis
>IV
Total body perfusion for open-heart surgery: Initially, 150 units/kg.373, 452, 453, 373, 466, 467, 468 469
Administer 300 units/kg for procedures estimated to last <1 hour.373, 452, 453, 466, 467, 468, 469
Administer 400 units/kg for those procedures estimated to last >1 hour.373, 452, 453, 466, 467, 468, 469
Vascular surgery patients with additional risk factors: 5000 or 7500 units twice daily
recommended by ACCP.437
Acute Ischemic Complications of PCI
>IV
PCI without concurrent antiplatelet therapy with a GP IIb/IIIa-receptor inhibitor: Dosage
adjusted to maintain an activated clotting time (ACT) of 250-300 seconds with the HemoTec
device or 300-350 seconds with the Hemochron device.380, 384, 447
PCI with concurrent GP IIb/IIIa-receptor inhibitors: A loading dose of 50-70 units/kg targeted
to an ACT of 200 seconds (using either the HemoTec or Hemochron device)
recommended.380, 381, 384, 447 Discontinue therapy immediately upon completion of an
uncomplicated procedure.380, 381, 384, 455
Acute Ischemic Complications of Unstable Angina and Non-ST-Segment Elevation MI
>IV
Adjusted-dose continuous therapy:70-80 units/kg loading dose followed by continuous IV
infusion to maintain the aPTT between 1.5-2 times the control value for 48 hours in addition
to aspirin and/or clopidogrel.322, 345, 348, 349, 418, 419 Continue for 48 hours or until anginal pain
resolves with pharmacologic therapy or with cardiac intervention (e.g., revascularization).345,
348, 349
Early treatment initiation appears to be necessary for beneficial effects.261, 262, 267, 268
Anticoagulant in Blood Transfusions and Blood Samples
>In vitro
In blood transfusions, add 7500 units to 100 mL of 0.9% sodium chloride injection and then
add 6-8 mL of this solution to each 100 mL of whole blood.453
When used as an in vitro anticoagulant for blood samples, add 70-150 units to each 10-20 mL
of whole blood.453
Prescribing Limits
Adults
Ischemic Complications of ST-Segment Elevation AMI
>IV
Conjunctive therapy with fibrin-selective thrombolytic agents: Maximum 4000 units loading
dose.382, 383, 439, 445, 455
Maintenance dosage: Maximum 1000 units/hour in patients weighing >70 kg, adjusted to
maintain a therapeutic aPTT for 48 hours.382, 383, 439, 445, 455
Special Populations
Geriatric Patients
Patients >60 years of age may require a lower dosage.107, 373, 452, 466, 469, 470, 471 Consider lower
dosages in geriatric patients undergoing PCI, particularly when combined with GP IIb/IIIareceptor inhibitors.455
Women
Consider lower dosages in women undergoing PCI, particularly when combined with GP
IIb/IIIa-receptor inhibitors.455
Cautions
Contraindications
Uncontrollable bleeding, unless such bleeding is secondary to disseminated intravascular
coagulation.e, 373
Severe thrombocytopenia.107
Inability to perform suitable blood coagulation tests at required intervals in patients receiving
full-dose therapy.101, 105, 106, 107, 234, 373, 452, 453, 454, 466, 467, 468, 469 Lack of such tests generally is not a
contraindication for fixed low-dose therapy, since monitoring of coagulation tests usually is
not required.101, 105, 106, 107, 234, 373, 452, 453, 454, 466, 467, 468, 469
Known hypersensitivity to heparin or bisulfites (in certain IV solutions).466, 467, 468
Hypersensitivity to corn products (solutions containing dextrose).469 (See Sensitivity
Reactions under Cautions.)
Warnings/Precautions
Warnings
Hematologic Effects
Hemorrhage can range from minor local ecchymoses to major hemorrhagic complications.e
Bleeding may occur at any site; some hemorrhagic complications may be difficult to
detect.107, 452
Use with extreme caution in patients with an increased risk of hemorrhage.373, 452, e, 464, 471 Such
patients include those with subacute bacterial endocarditis; ulcerative GI lesions;
hemorrhagic blood dyscrasias (e.g., hemophilia, some vascular purpuras, thrombocytopenia);
menstruation; hepatic disease with impaired hemostasis; severe hypertension; major surgery,
especially involving the eye, brain, or spinal cord; continuous tube drainage of the stomach or
small intestine; and spinal tap or spinal anesthesia.373, 452, 453, 454, 464 466, 467, 468, 469, 471 Screen
patients prior to treatment initiation to rule out bleeding disorders.373, 453, 471
Monitor patients with appropriate coagulation tests just prior to surgery.373, 453, 471 Discontinue
therapy immediately if hemorrhage occurs or if coagulation tests are unduly prolonged.373, 452,
453, 454, 466, 467, 468, 469
Nosebleed, hematuria, or tarry stools may be noted as the first sign of
bleeding or overdosage.107, 373, 452, 453, 454 466, 467, 468, 469 Easy bruising or petechiae may precede
frank bleeding.107, 373, 452, 453, 454 466, 467, 468, 469 If severe hemorrhage or overdosage occurs,
administer protamine sulfate immediately.e Blood transfusions may also be required
following massive blood loss.e
If signs and symptoms of acute adrenal hemorrhage and insufficiency occur, measure plasma
cortisol concentrations.e Initiate vigorous therapy with IV corticosteroids after
Because of the potential risk of bleeding, heparin lock flush solutions containing 100
units/mL should be avoided in neonates, particularly low birthweight neonates.374, 464 Some
manufacturers of heparin lock flush solutions recommend use with extreme caution in infants
with concomitant conditions associated with an increased risk of hemorrhage.374, 375, 461
Geriatric Use
Manufacturers state that risk of hemorrhage may be higher in patients >60 years of age,
particularly women.373, 453, 471 (See Geriatric Patients and see Women under Dosage and
Administration.)
Renal Impairment
Patients with renal failure may be at increased risk of bleeding complications.386
Common Adverse Effects
Hemorrhage.453
Interactions
Drugs Affecting Platelet Function
Potential pharmacodynamic interaction (increased risk of bleeding complications).453 Use
with caution.453
Specific Drugs and Laboratory Tests
Drug or Test
Anticoagulants, oral
Antihistamines
Interaction
Comments
Determine PT for oral anticoagulant
Potential for prolongation
effect 5 hours after IV heparin
of one-stage PT373, 452, 453,
sodium dose or 24 hours after sub-Q
454, 466, 467, 468, 469
dose373, 452, 453, 454, 466, 467, 468, 469
May partially counteract
anticoagulant effect373, 452,
453, 454, 466, 467, 468, 469
Antithrombin III
Dextran
Digitalis
Enhanced anticoagulant
Reduce heparin sodium dosage
effect, increased risk of
during concurrent treatment with
bleeding complications373
antithrombin III373, 454
454
May increase risk of
Use with cautione
hemorrhagee
May partially counteract
anticoagulant effect373, 452,
453, 454, 466, 467, 468, 469
Dipyridamole
Hydroxychloroquine
Nitroglycerin
NSAIAs
Thrombolytic agents
Pharmacokinetics
Absorption
Bioavailability
Peak plasma concentration achieved 2-4 hours following sub-Q administration.373, 452, 453, 454,
466, 467, 468, 469
Onset
Immediate following direct IV injection or IV infusion of full doses.e
Within 20-60 minutes following deep sub-Q injection.e
Duration
Heparin lock flush solutions: Anticoagulation maintained within the device for 4-24 hours.374,
376, 377, 458, 460, 461, 462, 463
Special Populations
Plasma heparin concentrations may be increased and aPTTs more prolonged in geriatric (>60
years of age) patients compared with younger adults.107, 377, 469, 471
Distribution
Extent
Does not cross the placenta and is not distributed into milk.291, 293, 359, 360, 387, 453
Plasma Protein Binding
Extensively bound to LDL, globulins, and fibrinogen.e May contribute to the lack of
relationship between duration of anticoagulant effect and blood concentration half-life.454
Elimination
Metabolism
Cleared from the circulation mainly by the reticuloendothelial system.e 373 May be partially
metabolized in the liver to uroheparin, which is partially desulfated heparin.e, 373
Elimination Route
Small fraction excreted in urine as unchanged drug.e
Half-life
1-2 hours in healthy adults.e Half-life increases with increasing doses.e Plasma half-life
averages 56, 96, and 152 minutes following IV heparin sodium doses of 100, 200, or 400
units/kg, respectively.e Shorter plasma half-life in patients with pulmonary embolism than in
healthy individuals or patients with other thrombotic disorders.e
Special Populations
Decreased plasma half-life in patients with liver impairment; half-life may be prolonged in
patients with cirrhosis.e
Half-life may be slightly prolonged in anephric patients or patients with severe renal
impairment.e
Stability
Storage
Parenteral
Solution for Injection
Heparin lock flush solutions: 15-30C463 or 25C (may be exposed to 15-30C).464, 465 Do not
freeze.106 374, 454, 458, 461, 465
Heparin sodium injections derived from beef lung: 20-25C.373
Heparin sodium injections derived from porcine intestinal mucosa: 20-25C.471
Heparin sodium injection in 5% dextrose or in 0.45 or 0.9% sodium chloride injection: 2025C (may be exposed to up to 40C).105, 134, 144, 373, 452, 457, 467
Heparin sodium injection in water for injection: 15-30C.453, 454, 468 Certain commercially
available heparin sodium in 5% dextrose injection: 15-30C.466
Premixed heparin sodium injection in Viaflex Plus containers: 25C (may be exposed to up
to 40C).469, 470
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution Compatibilitya
When administered in a venipuncture device with an incompatible drug, flush the entire
device with 0.9% sodium chloride injection, a compatible isotonic injection, or sterile water
prior to and immediately after administration of the incompatible drug.234, 374, 458, 460, 461, 462 463,
464, 465
Inject another dose of heparin lock flush solution (e.g., 1 mL of 10 units/mL) into the
device after the second flush.234, 458, 460, 461, 462, 463, 464, 465 A cartridge (Carpuject) containing 2
mL of 0.9% sodium chloride injection is supplied by one manufacturer for flushing before
and after administration of a drug incompatible with heparin.461
Compatible
Amino acids 4.25%, dextrose 25%
Dextran 40,000
Dextran 6% in dextrose 5%
Dextran 6% in sodium chloride 0.9%
Dextrose-Ringer's injection combinations
Dextrose-Ringer's injection, lactated, combinations
Dextrose 5% in Ringer's injection, lactated
Dextrose-saline combinations
Dextrose 2.5% in sodium chloride 0.45%
Dextrose 3.75% in sodium chloride 0.2%
Dextrose 5% in sodium chloride 0.45%
Dextrose 2 1/2% in water
Dextrose 25% in water
Fructose 10% in sodium chloride 0.9%
Fructose 10% in water
Ampicillin sodium
Ampicillin sodium-sulbactam sodium
Atracurium besylate
Atropine sulfate
Aztreonam
Betamethasone sodium phosphate
Bivalirudin
Bleomycin sulfate
Calcium gluconate
Cefazolin sodium
Cefotiam
Ceftazidime
Ceftriaxone sodium
Chlordiazepoxide HCl
Chlorpromazine HCl
Cimetidine HCl
Cisplatin
Cladribine
Clindamycin phosphate
Cyanocobalamin
Cyclophosphamide
Cytarabine
Daptomycin
Dexamethasone sodium phosphate
Dexmedetomidine HCl
Digoxin
Diphenhydramine HCl
Docetaxel
Dopamine HCl
Doxapram HCl
Doxorubicin HCl liposome injection
Edrophonium chloride
Enalaprilat
Epinephrine HCl
Ertapenem
Erythromycin lactobionate
Esmolol HCl
Estrogens, conjugated
Ethacrynate sodium
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Fentanyl citrate
Flecainide acetate
Fluconazole
Fludarabine phosphate
Fluorouracil
Foscarnet sodium
Furosemide
Gallium nitrate
Gemcitabine HCl
Granisetron HCl
Hetastarch in lactated electrolyte injection (Hextend)
Hydralazine HCl
Hydrocortisone sodium succinate
Hydromorphone HCl
Isoproterenol HCl
Kanamycin sulfate
Lansoprazole
Leucovorin calcium
Lidocaine HCl
Linezolid
Lorazepam
Magnesium sulfate
Melphalan HCl
Meperidine HCl
Meropenem
Methotrexate sodium
Methoxamine HCl
Methyldopate HCl
Methylergonovine maleate
Metoclopramide HCl
Metronidazole
Midazolam HCl
Milrinone lactate
Mitomycin
Morphine sulfate
Nafcillin sodium
Neostigmine methylsulfate
Nitroglycerin
Norepinephrine bitartrate
Ondansetron HCl
Oxacillin sodium
Oxaliplatin
Oxytocin
Paclitaxel
Pancuronium bromide
Pemetrexed disodium
Penicillin G potassium
Pentazocine lactate
Phytonadione
Piperacillin sodium-tazobactam sodium
Potassium chloride
Procainamide HCl
Prochlorperazine edisylate
Propofol
Propranolol HCl
Pyridostigmine bromide
Ranitidine HCl
Remifentanil HCl
Sargramostim
Scopolamine HBr
Sodium bicarbonate
Sodium nitroprusside
Succinylcholine chloride
Tacrolimus
Theophylline
Thiopental sodium
Thiotepa
Ticarcillin disodium-clavulanate potassium
Tirofiban HCl
Trimethobenzamide HCl
Vasopressin
Vecuronium bromide
Vinblastine sulfate
Vincristine sulfate
Warfarin sodium
Zidovudine
Incompatible
Alteplase
Amiodarone HCl
Amphotericin B cholesteryl sulfate complex
Amsacrine
Ciprofloxacin
Clarithromycin
Diazepam
Doxycycline hyclate
Ergotamine tartrate
Filgrastim
Gentamicin sulfate
Haloperidol lactate
Idarubicin HCl
Isosorbide dinitrate
Levofloxacin
Mexiletine HCl
Phenytoin sodium
Propafenone HCl
Tobramycin sulfate
Tramadol HCl
Triflupromazine HCl
Vancomycin HCl
Variable
Aldesleukin
Antithymocyte globulin (rabbit)
Dacarbazine
Diltiazem HCl
Dobutamine HCl
Doxorubicin HCl
Droperidol
Drotrecogin alfa (activated)
Labetalol HCl
Methylprednisolone sodium succinate
Nicardipine HCl
Promethazine HCl
Quinidine gluconate
Vinorelbine tartrate
Actions
Acts as a catalyst to markedly accelerate the rate at which antithrombin III (heparin cofactor)
neutralizes thrombin and activated coagulation factor X (Xa).e Low-dose therapy neutralizes
Xa which prevents the conversion of prothrombin to thrombin.452, e, 469 Low doses of heparin
have very little effect on thrombin and exert a measurable antithrombogenic effect only if
thrombin formation has not already occurred.e
Full-dose therapy neutralizes thrombin, which prevents the conversion of fibrinogen to
fibrin.452, e, 469 Also prevents the formation of a stable fibrin clot by inhibiting activation of
fibrin stabilizing factor.452, e, 469 Low-dose or full-dose therapy inhibits thrombus formation
when stasis is induced.e Full-dose therapy may prevent extension of existing thrombi.e
Full-dose therapy prolongs several coagulation assays including the ACT, aPTT, plasma
recalcification time, PT, thrombin time, and whole blood clotting time.373, 452, 453, 471, e Clotting
time is generally unaffected or only minimally prolonged by low-dose therapy.452, 453, 454, e A
single dose of heparin lock flush solution at a concentration of 10 units/mL does not induce
systemic anticoagulant effects.376, 377, 458, 460, 463 However, repeated flushing of a catheter device
with a heparin lock flush solution may result in a systemic anticoagulant effect.377, 461
Advice to Patients
Importance of reporting any unexplained bleeding or bruising to clinician.373, 453, 471
Importance of patients informing clinician of existing or contemplated concomitant therapy,
including prescription and OTC drugs, dietary and herbal supplements, and any concomitant
illnesses.373, 452, 453, 454, 457, 458, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470
Importance of women informing clinician if they are or plan to become pregnant or to breastfeed.373, 452, 453, 454, 457, 458, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469
Importance of informing patients of other important precautionary information.373, 453, 471 (See
Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects
in some individuals; consult specific product labeling for details.
Note: All multiple- and single-dose vials of heparin sodium injection and heparin flush
products manufactured by Baxter Healthcare Corporation were recalled from the US market
during 2008 as a result of reports of serious adverse events, including allergic or
hypersensitivity-type reactions and death, associated with a heparin-like contaminant
(oversulfated chondroitin sulfate) found in heparin injection.475, 477, 478, 480, 481, 482, 483, 484, 485, 486,
487
Strengths
Brand Names
1000 units/mL*
5000 units/mL*
10,000 units/mL*
Injection (porcine
1000 units/mL*
intestinal mucosa)
5000 units/mL*
10,000 units/mL*
20,000 units/mL*
Solution, lock
10 units/mL (10, 20,
flush (porcine
30, 50, 100, 300
intestinal mucosa) units)*
Manufacturer
Hospira
Brand Names
Manufacturer
Heparin Sodium
Injection
Heparin Sodium ADDHospira
Vantage
Heparin Sodium
10,000 units/mL* Injection (available in Hospira
Carpuject)
Solution, lock flush 10 units/mL (10,
(porcine intestinal
30, 50, or 100
HepFlush-10
Abraxis
mucosa)
units)*
Baxter
Hep-Lock U/P
Anesthesia
100 units/mL (100,
Baxter
Hep-Lock U/P
300 or 500 units)*
Anesthesia
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Heparin Sodium in Dextrose
Routes
Dosage Forms
Injection, for IV
Parenteral infusion (porcine
intestinal mucosa)
Strengths
Brand Names
Manufacturer
40 units/mL (20,000
Heparin Sodium
units) Heparin Sodium 20,000 units in 5%
in 5% Dextrose*
Dextrose Injection
50 units/mL (12,500
Heparin Sodium
units) Heparin Sodium 12,500 units in 5%
in 5% Dextrose*
Dextrose Injection
50 units/mL (25,000
Heparin Sodium
units) Heparin Sodium 25,000 units in 5%
in 5% Dextrose*
Dextrose Injection
100 units/mL (10,000 Heparin Sodium
units) Heparin Sodium 10,000 units in 5%
in 5% Dextrose*
Dextrose Injection
100 units/mL (25,000 Heparin Sodium
units) Heparin Sodium 25,000 units in 5%
in 5% Dextrose*
Dextrose Injection
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Heparin Sodium in Sodium Chloride
Routes
Dosage Forms
Strengths
Brand Names
Manufacturer
Injection, for IV
2 units/mL (1000 units) Heparin Sodium 1000
Parenteral infusion (porcine Heparin Sodium in 0.9% units in 0.9% Sodium
intestinal mucosa) Sodium Chloride*
Chloride Injection
2 units/mL (2000 units) Heparin Sodium 2000
Heparin Sodium in 0.9% units in 0.9% Sodium
Sodium Chloride*
Chloride Injection
50 units/mL (12,500
Heparin Sodium
units) Heparin Sodium 12,500 units in 0.45%
in 0.45% Sodium
Sodium Chloride
Chloride*
Injection
50 units/mL (25,000
Heparin Sodium
units) Heparin Sodium 25,000 units in 0.45%
in 0.45% Sodium
Sodium Chloride
Chloride*
Injection
100 units/mL (25,000
Heparin Sodium
units) Heparin Sodium 25,000 units in 0.45%
in 0.45% Sodium
Sodium Chloride
Chloride*
Injection
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
Metoclopramide (Systemic)
Introductory Information
Antiemetic; stimulant of upper GI motility (prokinetic agent);1, 2, 3, 4, 5, 6, 7, 8, 9, 263, 267 potent
dopamine-receptor antagonist.2, 4, 5, 7, 19, 28, 34, 52, 267
Class: 56:32 Prokinetic Agents; au300 (VA primary)
Brands*: Reglan
*
ASCO states that the combination of a 5-HT3 receptor antagonist, dexamethasone, and
aprepitant is preferred in patients receiving combination chemotherapy with an anthracycline
and cyclophosphamide; ASCO recommends combined therapy with a 5-HT3 receptor
antagonist and dexamethasone for other chemotherapy regimens of moderate emetic risk (i.e.,
31-90% incidence of emesis without antiemetics) and dexamethasone alone for chemotherapy
regimens of low emetic risk (i.e., 11-30% incidence).263
In patients experiencing nausea and vomiting despite recommended prophylaxis regimens,
ASCO recommends that clinicians consider adding a benzodiazepine (e.g., alprazolam,
lorazepam), butyrophenone, or phenothiazine to the regimen or substituting high-dose IV
metoclopramide for the 5-HT3 receptor antagonist in the regimen.263
Antiemetics can be prescribed on an as-needed basis for chemotherapy regimens with
minimal emetic risk (<10% incidence of emesis without antiemetics).263
Metoclopramide has been used orally
nausea and vomiting. 177, 218, 221, 224, 263, 264, 265, 266, 275 Some experts state that patients receiving
oral chemotherapy requiring only as-needed ("prn") antiemetic therapy or receiving an IV
chemotherapy regimen with low emetic risk may receive oral
metoclopramide.275
Oral
Gastroesophageal Reflux
Short-term (12 weeks) relief of symptomatic, documented gastroesophageal reflux in adults
who are unresponsive to conventional therapy (e.g., changes in lifestyle, habits, diet, weight
reduction) alone.5, 9, 30, 39, 40, 41, 42, 111, 112, 116, 117, 125, 129, 185, 186, 187, 188, 189, 190
Regular use for this purpose has declined; proton-pump inhibitors provide greater control of
acid reflux.258, 273, 274 Some experts recommend against use of metoclopramide for this
purpose based on the drug's adverse effect profile and lack of high-quality supporting data.273,
274
Pediatric Patients
Intubation of the Small Intestine
>IV
Children <6 years of age: Usually, one 0.1-mg/kg dose given by direct IV injection.267
Children 6-14 years of age: Usually, one 2.5- to 5-mg dose given by direct IV injection.267
Children >14 years of age: Usually, one 10-mg dose given by direct IV injection.267
Adults
Diabetic Gastric Stasis
Oral: 10 mg 4 times daily, given 30 minutes before meals and at bedtime.5 Continue for 2-8
weeks, depending on response and likelihood of continued well-being if drug is
discontinued.5 Reinstitute at earliest symptom recurrence.5
>IV
If symptoms are severe or oral use is not feasible, 10 mg 4 times daily, given by direct IV
injection 30 minutes before meals and at bedtime.5, 267 Continued use for up to 10 days may
be required until symptoms subside enough to allow oral administration;5, 267 however,
thoroughly assess the risks and benefits prior to continuing therapy.267
>IM
If symptoms are severe or oral use is not feasible, 10 mg 4 times daily, given 30 minutes
before meals and at bedtime.5, 267 Continued use for up to 10 days may be required until
symptoms subside enough to allow oral administration;5, 267 however, thoroughly assess the
risks and benefits prior to continuing therapy.267
Prevention of Postoperative Nausea and Vomiting
>IM
Manufacturer states that usual dose is 10 mg administered near the end of the surgical
procedure; 20 mg also may be used.267
Prevention of Cancer Chemotherapy-induced Emesis
>Oral
Some experts state that patients receiving IV chemotherapy regimens with low emetic risk
may receive 10-40 mg of metoclopramide before the chemotherapy dose and then every 4 or
6 hours as needed.275
Some experts state that patients receiving oral chemotherapy requiring only as-needed ("prn")
antiemetic therapy may receive 10-40 mg of metoclopramide before the chemotherapy dose
and then every 4 or 6 hours as needed.275
When given in combination with dexamethasone in clinical trials for the prevention of
delayed emesis (i.e., vomiting occurring 24 hours after chemotherapy), 20-40 mg (or 0.5
mg/kg) of metoclopramide has been given 2-4 times daily for 3 or 4 days.263, 264, 265, 266
>IV
Manufacturer states that metoclopramide usually is given by IV infusion 30 minutes before
administration of chemotherapy, and then repeated every 2 hours for 2 additional doses
followed by every 3 hours for 3 additional doses.267 Manufacturer states that initial 2 doses
should be 2 mg/kg if highly emetogenic chemotherapy used;267 for less emetogenic drugs or
regimens, initial 1-mg/kg dose may be sufficient.267 However, combinations of other
antiemetic agents generally are preferred as first-line regimens in patients receiving
chemotherapy of moderate or high emetic risk (see Prevention of Cancer Chemotherapyinduced Emesis under Uses). 263, 275
Some experts state that patients receiving IV chemotherapy regimens with low emetic risk
may receive 10-40 mg of metoclopramide before the chemotherapy dose and then every 4 or
6 hours as needed.275
Intubation of the Small Intestine
>IV
Usually, one 10-mg dose given by direct IV injection.267
Radiographic Examination of the Upper GI Tract
>IV
Usually, one 10-mg dose given by direct IV injection.267
Gastroesophageal Reflux
Oral: Usually, 10-15 mg up to 4 times daily (30 minutes before each meal and at bedtime) for
4-12 weeks, depending on symptoms and response.5 Patients sensitive to therapeutic and/or
adverse effects of metoclopramide may require initial dose of 5 mg.5
For intermittent symptoms or symptoms at specific times of the day, one 20-mg dose before
the provoking situation may be preferred to daily administration of multiple doses.5
In patients with esophageal erosion and ulceration, 15 mg 4 times daily for 12 weeks has
provided healing; monitor endoscopically because of the poor correlation between symptoms
and healing.5
Prescribing Limits
Adults
Avoid use of metoclopramide for >12 weeks in all but rare cases where therapeutic benefit is
thought to outweigh risk of developing tardive dyskinesia.5, 267 (See Boxed Warning and see
Tardive Dyskinesia under Cautions.)
Gastroesophageal Reflux
Oral: Safety and efficacy beyond 12 weeks not established; use beyond 12 weeks not
recommended.5
Special Populations
Hepatic Impairment
Dosage modification does not appear to be necessary.5, 267
Renal Impairment
Modify dosage according to degree of renal impairment.5, 54, 58, 59, 135, 142, 267
In patients with Clcr <40 mL/minute, manufacturers recommend an initial dosage of
approximately 50% of the usual dosage.5, 267 Subsequently, increase or decrease dosage
according to response and tolerance.5, 267
Geriatric Patients
Select dosage with caution, usually initiating therapy at the low end of the dosage range.5, 267
Administer lowest effective dosage.5, 267 In geriatric patients with gastroesophageal reflux,
initial 5-mg dose may be required due to possible sensitivity to therapeutic and/or adverse
effects of metoclopramide.5
Cautions
Contraindications
Most patients respond rapidly to treatment with diazepam4 or an agent with central
anticholinergic activity (e.g., diphenhydramine hydrochloride 20-50 mg orally, IM, or IV;5, 267,
275, 276
benztropine 1-2 mg IM5, 267).4, 5, 170, 206, 207, 267
Parkinsonian Symptoms
Parkinsonian symptoms (e.g., tremor, rigidity, bradykinesia, akinesia) occur rarely; may be
associated with usual160 or excessive metoclopramide doses62 or decreased renal function.9, 54
Possible exacerbation of parkinsonian symptoms;5, 9, 54, 62, 160, 267 use with caution, if at all, in
patients with parkinsonian syndrome.5, 267
More common during first 6 months of therapy but occur occasionally after longer periods.5,
267
Symptoms generally subside within 2-3 months following drug discontinuance.5, 267
Neuroleptic Malignant Syndrome (NMS)
NMS (characterized by hyperthermia, varying levels of consciousness, muscular rigidity, and
autonomic dysfunction) reported rarely.5, 208, 267
Important to determine whether untreated or inadequately treated extrapyramidal reactions
and serious medical illness (e.g., pneumonia, systemic infection) may coexist.5, 267 Also
consider the possibility of central anticholinergic toxicity, heat stroke, malignant
hyperthermia, drug fever, and primary CNS pathology.5, 267
Immediately discontinue metoclopramide and other drugs not considered essential, provide
intensive symptomatic treatment, monitor patient, and treat any concomitant serious medical
condition for which specific therapies are available.5, 267 Dantrolene and bromocriptine have
been used in the treatment of NMS, but their efficacy has not been established and there
currently is no specific drug therapy.5, 267
Depression
Mild to severe depression (including suicidal ideation and suicide) has occurred in patients
with or without prior history of depression.5, 210, 211, 215, 267
Use with extreme caution and only when anticipated benefits outweigh possible risks in
patients with a history of mental depression, especially those with suicidal tendencies.5, 267
Sensitivity Reactions
Procainamide Cross-sensitivity
Theoretical potential for patients who are allergic to procainamide to exhibit cross-sensitivity
to metoclopramide (since the drugs are structurally similar).11, 12
General Precautions
GI Anastomosis or Closure
When deciding whether to use metoclopramide or NG suction to prevent postoperative
nausea and vomiting, consider the possibility that metoclopramide theoretically could
produce increased pressure on suture lines following GI anastomosis or closure.267
Fluid and Electrolyte Effects
179, 182
Use with caution; incidence of extrapyramidal reactions is increased in children.5, 91, 125, 156, 267
Use with caution in neonates.5, 267 Neonatal susceptibility to methemoglobinemia is increased
due to prolonged clearance (may cause excessive serum concentrations) in combination with
decreased neonatal levels of cytochrome-b5 reductase.5, 267
Geriatric Use
Insufficient experience in patients 65 years of age to determine whether geriatric patients
repond differently than younger adults.5, 267
Possible increased risk of tardive dyskinesia.5, 267
Risk of adverse parkinsonian effects increases with increasing dosage; administer lowest
effective dosage in geriatric patients.5, 267 If parkinsonian symptoms develop, generally should
discontinue metoclopramide before initiating specific antiparkinsonian therapy.5, 267
Confusion and oversedation may occur.5, 267
Substantially eliminated by kidneys; risk of adverse reactions may be greater in patients with
impaired renal function.5, 267 (See Renal Impairment under Dosage and Administration.)
Select dosage with caution because of age-related decreases in renal function and
concomitant disease and drug therapy.5, 267 (See Geriatric Patients under Dosage and
Administration).
Hepatic Impairment
Possible increased risk of fluid retention and hypokalemia in patients with cirrhosis.3, 5, 69, 267
(See Fluid and Electrolyte Effects under Cautions.)
Discontinue if fluid retention or volume overload occurs at any time during therapy.5, 267
Renal Impairment
Clearance may be reduced.5, 54, 59, 142, 192, 267 Possible increased risk of adverse effects.5, 267 Use
with caution; reduce dosage during prolonged therapy in patients with renal impairment.5, 54,
58, 59, 69, 135, 142, 267
(See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Restlessness, drowsiness, fatigue, lassitude, nausea, bowel disturbances (principally
diarrhea).4, 5, 90, 125, 267
Interactions
Orally Administered Drugs
Possible decreased absorption of certain drugs that disintegrate, dissolve, and/or are absorbed
mainly in the stomach.4, 5, 119, 125, 267 Clinical importance not determined.c
Possible enhanced rate and extent of absorption of drugs mainly absorbed in the small
intestine.4, 5, 120, 125, 267 Clinical importance not determined.c
Specific Drugs
Drug
Acetaminophen
Anesthetic agents
Interaction
Comments
Possible enhanced rate and extent of
Clinical importance not
acetaminophen absorption4, 5, 120, 125,
determinedc
267
Acute hypotension reported with
Anticholinergic agents
(e.g., atropine)
Aspirin
Butyrophenones
Cholinergic agents
Concomitant use
contraindicated4, 5, 267
Clinical importance not
determinedc
Pharmacokinetics
Absorption
Bioavailability
Following oral administration, rapidly and almost completely absorbed;4, 5, 7, 53, 54, 55, 56, 133, 134,
135, 267
limited data indicate that 30-100% of an oral dose reaches systemic circulation as
unchanged metoclopramide.5, 54, 56, 133, 134, 135, 267 Peak plasma concentration usually attained at
1-2 hours.5, 55, 267
Following IM administration, absolute bioavailability is 74-96%.7
Onset
Following oral administration, 30-60 minutes for effects on GI tract.5, 7, 267
Following IM administration, 10-15 minutes for effects on GI tract.5, 7, 267
Following IV administration, 1-3 minutes for effects on GI tract.5, 7, 267
Duration
1-2 hours.5, 267
Special Populations
In patients with gastric stasis, absorption may be delayed or diminished.14
In infants, metoclopramide may accumulate in plasma after multiple doses; mean peak
plasma concentration was 2-fold higher after 10th dose compared with that after first dose in
infants (3.5 weeks-5.4 months of age) with gastroesophageal reflux receiving
metoclopramide oral solution.5, 267
Distribution
Extent
In mice, distributed into most body tissues and fluids; high concentrations in GI mucosa,
liver, biliary tract, and salivary glands, with lower concentrations in brain, heart, thymus,
adrenals, adipose tissue, and bone marrow.4, 7
Crosses the placenta138
Distributed into milk in humans;5, 139, 140, 267 milk concentrations are higher than plasma
concentrations 2 hours after oral administration.139, 140
Plasma Protein Binding
13-30% (principally albumin).5, 7, 267
Elimination
Metabolism
Minimally metabolized; not known whether major metabolite found in urine is active.5, 53, 267
Elimination Route
Excreted in urine (85%) as unchanged drug and metabolites5, 7, 53, 54, 133, 267 and also in feces
(about 5%).7, 53
Minimally removed by hemodialysis5, 129, 192, 267 or peritoneal dialysis.5, 129, 267
Half-life
Biphasic; terminal-phase half-life is 2.5-6 hours in adults.5, 53, 56, 57, 267
Elimination half-life is about 4.1-4.5 hours in children.5, 267
Special Populations
In patients with renal impairment, half-life may be prolonged and plasma concentrations
increased.5, 54, 59, 142, 192, 267
Reduced neonatal clearance, possibly associated with immature renal and hepatic functions
present at birth.5, 267
Stability
Storage
Oral
Tablets
Tight, light-resistant containers at 20-25C.5, 194, 216
Solution
Tight, light-resistant containers at 20-25C.194, 216, 268, 269
Parenteral
Injection
20-25C.267 Protect from light.267
Following dilution with 5% dextrose, 0.9% sodium chloride, 5% dextrose and 0.45% sodium
chloride, Ringer's, or lactated Ringer's injection, store for up to 48 hours (without freezing)
when protected from light or for up to 24 hours under normal light conditions (i.e.,
unprotected from light).267
May be stored frozen for up to 4 weeks following dilution with 0.9% sodium chloride
injection.267
Degradation occurs if metoclopramide is diluted in 5% dextrose injection and frozen.267
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution Compatibility267, HID
Compatible
Amino acids 2.75%, dextrose 25%, electrolytesHID
Dexmedetomidine HCl
Diltiazem HCl
Docetaxel
Doxapram HCl
Doxorubicin HCl
Droperidol
Etoposide phosphate
Famotidine
Fenoldopam mesylate
Fentanyl citrate
Filgrastim
Fluconazole
Fludarabine phosphate
Fluorouracil
Foscarnet sodium
Gallium nitrate
Gemcitabine HCl
Granisetron HCl
Heparin sodium
Hetastarch in lactated electrolyte injection (Hextend)
Hydromorphone HCl
Idarubicin HCl
Leucovorin calcium
Levofloxacin
Linezolid
Melphalan HCl
Meperidine HCl
Meropenem
Methadone HCl
Methotrexate sodium
Mitomycin
Morphine sulfate
Ondansetron HCl
Oxaliplatin
Pemetrexed disodium
Paclitaxel
Piperacillin sodium-tazobactam sodium
Quinupristin-dalfopristin
Remifentanil HCl
Sargramostim
Sufentanil citrate
Tacrolimus
Teniposide
Thiotepa
Topotecan HCl
Vinblastine sulfate
Vincristine sulfate
Vinorelbine tartrate
Zidovudine
Incompatible
Allopurinol sodium
Amphotericin B cholesteryl sulfate complex
Amsacrine
Cefepime HCl
Doxorubicin HCl liposome injection
Furosemide
Lansoprazole
Propofol
Actions
Complex pharmacology; mechanism(s) of action not fully elucidated; principal effects involve
the GI tract and CNS.3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 125, 267
At low concentrations in vitro, metoclopramide increases the resting tone and phasic
contractile activity of GI smooth muscle.8, 16, 21
Increases lower esophageal sphincter pressure.4, 125
Accelerates gastric emptying and intestinal transit from the duodenum to the ileocecal valve
by increasing the amplitude and duration of esophageal contractions,4 resting tone of the
lower esophageal sphincter,5, 7, 8, 30, 39, 40, 41, 42, 267 and amplitude and tone of gastric (especially
antral) contraction 5, 7, 9, 16, 25, 33, 37, 38, 43, 44, 267 and by relaxing the pyloric sphincter and the
duodenal bulb, while increasing peristalsis of the duodenum and jejunum.5, 7, 25, 33, 38, 43, 45, 48, 49,
267
Importance of informing patients that metoclopramide oral solution and tablets are
recommended for use in adults only.5, 268, 269
Risk of tardive dyskinesia.5, 267 Importance of contacting clinicians if new, abnormal,
involuntary, or uncontrollable muscle movements occur (e.g., lip smacking, chewing,
puckering mouth, frowning, scowling, tongue protrusion, blinking, eye movements, arm and
leg shaking).5, 267
Potential for metoclopramide to impair mental alertness or physical coordination; avoid
driving or operating machinery until effects on individual are known.5, 267
Potential for metoclopramide to enhance sedative effects of alcohol, barbiturates, or other
CNS depressants.5, 267
Importance of informing clinicians of existing or contemplated concomitant therapy, including
prescription and OTC drugs, as well as any concomitant illnesses.5, 267
Importance of women informing clinicians if they are or plan to become pregnant or plan to
breast-feed.5, 267
Importance of informing patients of other important precautionary information.5, 267 (See
Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects
in some individuals; consult specific product labeling for details.
Metoclopramide Hydrochloride
Dosage
Routes
Strengths
Forms
5 mg (of metoclopramide)
Oral
Solution
per 5 mL*
5 mg (of
Tablets
metoclopramide)*
Brand Names
Manufacturer
Metoclopramide
Hydrochloride Syrup
Metoclopramide
Hydrochloride Tablets
Reglan
Alaven
10 mg (of
Metoclopramide
metoclopramide)*
Hydrochloride Tablets
Reglan (scored)
Alaven
5 mg (of metoclopramide) Metoclopramide
Parenteral Injection
per mL*
Hydrochloride Injection
Reglan
Baxter
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 10/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
Aspirin (Systemic)
Introductory Information
Self-medication in fixed combination with acetaminophen and caffeine for the temporary
relief of mild to moderate pain associated with migraine headache;701, 702, 703 also can be used
for the treatment of severe migraine headache if previous attacks have responded to similar
non-opiate analgesics or NSAIAs.701, 702, 703, 778
Fever
Self-medication for reduction of fever associated with colds, sore throats, and teething.837, 841
(See Contraindications and see Pediatric Use under Cautions.)
Inflammatory Diseases
Symptomatic treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis,
spondyloarthropathies, and systemic lupus erythematosus (SLE).a, c, l, m
Rheumatic Fever
Symptomatic treatment of rheumatic fever
not indicated.691, 699, 700, 716, 818, 862 May be safely used with low-dose sub-Q heparin to prevent
DVT in such patients.818
prevention).573, 574, 575, 576, 658, 659, 660, 661, 666, 667, 668, 669, 670, 671, 783, 785, 786, 820, 848, 851 Balance of risks
and benefits is most favorable in patients at moderate to high risk of CHD783, 820 (based on age
and 10-year risk of cardiac event >10%).668, 669, 820, 832 Use of aspirin in such patients is
suggested over either warfarin or no antithrombotic therapy.820
Recommended by ADA for primary prevention in patients with type 1 or type 2 diabetes
mellitus who are at high risk for cardiovascular events (i.e., familial history of CHD,
May administer with clopidogrel in selected high-risk patients with chronic stable angina.820
Percutaneous Coronary Intervention and Revascularization Procedures
Reduction of cardiovascular risks (e.g., early ischemic complications, graft closure) in
patients undergoing percutaneous coronary intervention (PCI) including coronary
angioplastyc, 646, 686, 824, 865, 866 or stent implantation, 686, 824, 865, 866, 886, 887, 888, 889, m or CABG.c, 646,
683, 685, 781, 782, 823, m
Pretreatment with aspirin prior to PCI recommended by ACC and AHA.865, 867 Adjunctive
therapy with a loading dose of a thienopyridine derivative is preferred by ACCP over
systemic anticoagulant therapy prior to the procedure.771, 824, 865
For patients unable to tolerate aspirin, ACC and AHA suggest pretreatment with
clopidogrel,865, 866 while ACCP suggests pretreatment with clopidogrel or ticlopidine prior to
planned PCI.771, 824
Continue low-dose aspirin therapy indefinitely as secondary prevention against
cardiovascular events following PCI.824, 865, 867, 880 No evidence that such long-term therapy
affects the rate of restenosis.686, 771, 824
Recommended by ACCP for use in all patients undergoing saphenous vein or internal
mammary artery bypass grafting (regardless of effect on graft patency) based on indication in
all patients with CAD.823 ACC and AHA recommend use after saphenous vein CABG to
reduce risk of graft closure.867, 885
May be used in combination with oral anticoagulants in patients with saphenous vein bypass
grafts who have underlying conditions necessitating use of oral anticoagulants (e.g.,
prosthetic heart valves).768, 823
Embolism Associated with Atrial Fibrillation/Flutter
An alternative or adjunct to oral anticoagulation for reduction of the incidence of
thromboembolic episodes in selected patients with chronic atrial fibrillation
flutter
or atrial
Use of either aspirin or warfarin is suggested by ACC, AHA, and other clinicians in patients
with nonvalvular atrial fibrillation with intermediate risk of stroke.826, k, n, o
Recommended for use in patients with atrial fibrillation at low risk for stroke or who are poor
candidates for oral anticoagulation.744, 747, 748, 749, 767, 773, 774, 776, 826, 880, 881, k, n, o
Recommended for use in patients with "lone" atrial fibrillation (e.g., those younger than 75
years of age without prior stroke or TIA) over warfarin because relatively low risk of stroke
in these patients does not warrant risks of oral anticoagulation.
Embolism Associated with Valvular Heart Disease
Used as an alternative or adjunct to oral anticoagulation for reduction of the incidence of
thromboembolic episodes in selected patients with valvular heart disease
.746, 764, 827, 881
Recommend by ACCP for use in patients with mitral valve prolapse and unexplained
symptomatic TIAs.827
Used as an adjunct to warfarin in patients with mitral valve disease associated with rheumatic
fever and recurrent embolism despite warfarin therapy.827, 881
Thrombosis in Other Arteries and Arteriovenous Communications
Reduction of the risk of stroke and MI in patients undergoing peripheral percutaneous
transluminal angioplasty (PTA) with or without stenting.690, 828
Reduction of the risk of long-term cardiovascular morbidity and mortality in patients with
chronic limb ischemia (e.g., intermittent claudication) resulting from arteriosclerosis.690, 769, 828
Use of aspirin is suggested by ACCP over clopidogrel in these patients because of cost
considerations.828
Prolonging the patency of vascular grafts following peripheral bypass surgery (e.g., prosthetic
infrainguinal femoropopliteal).690, 769, 828 Prophylaxis used in selected patients undergoing
other bypass procedures and vascular reconstructions; consult specialized references for
additional information.690, 769, 828
Has been used following initial heparin therapy to reduce the risk of thrombotic occlusion in
children with Blalock-Taussig shunts
.662, 718, 825
In patients with a bioprosthetic valve in the aortic position, ACCP recommends aspirin or
warfarin for the first 3 months following valve insertion.827Follow-up long-term therapy
recommended to protect against thromboembolism in patients with bioprosthetic heart valves
who are in sinus rhythm and without risk factors.827
May be added to therapy with a low molecular weight heparin or unfractionated heparin in
pregnant women with prosthetic heart valves
who are at high risk for thrombosis.845
Has been used for prevention of thromboembolic complications following Fontan procedure
(definitive palliative surgical treatment for most congenital univentricular heart
lesions) in children.662, 825 Antithrombotic therapy effective in <50% of patients and many
prophylactic regimens in use; no consensus on optimal regimen.662, 825
Pericarditis
Drug of choice for the management of pain associated with acute pericarditis
Complications of Pregnancy
Has been used alone or in combination with other drugs (e.g., heparin, corticosteroids,
immune globulin) for prevention of complications of pregnancy
(e.g., preeclampsia,
pregnancy loss in women with a history of antiphospholipid syndrome and recurrent fetal
loss).594, 595, 596, 597, 599, 600, 601, 605, 626, 627, 628, 647, 648, 650, 651, 652, 653, 654, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714,
715, 726, 817, 845, 857
Prevention of Cancer
Limited data (observational studies) suggest that aspirin or other NSAIAs may reduce the risk
of various cancers
(e.g., colorectal, breast, gastric cancer);864, 870, 871, 872, 873 such
results generally not confirmed in randomized controlled trials.864, 874, 875, 876
Regular use (e.g., daily) associated with a reduction in the risk of recurrent colorectal
adenomas and colorectal cancer
in some studies.789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799,
800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815
Oral: ACCP suggests same treatment as for adults825 (75-100 mg daily long term in those in
sinus rhythm).827
Kawasaki Disease
Oral: Initially, 80-100 mg/kg daily given in 4 equally divided doses (in combination with
IVIG); initiate within 10 days of onset of fever.636, 637, 638, 639, 640, 662, 825 May be necessary to
monitor plasma salicylate concentrations.636, 637, 638 When fever subsides, decrease dosage to
3-5 mg/kg once daily.636, 637, 638, 639, 640, 641
Continue indefinitely in those with coronary artery abnormalities;636, 637, 638 in the absence of
such abnormalities, continue for 6-8 weeks after initial onset of illness or until platelet count
and erythrocyte sedimentation rate return to normal.636, 637, 638, 662, 825
Adults
Pain
Oral: For self-medication, 325-650 mg every 4 hours (maximum 4 g daily) or 0.5-1 g every 6
hours as necessary.836, e
For self-medication, 454 mg (as chewing gum pieces) every 4 hours as necessary (maximum
3.632 g daily).837
Adults <60 years of age for self-medication: 650 mg (as a highly buffered effervescent
solution [Alka-Seltzer Lemon-Lime or Original]) every 4 hours (maximum 2.6 g daily);
alternatively, 1 g (Alka-Seltzer Extra Strength) every 6 hours (maximum 3.5 g daily).838, 843,
844
Adults 60 years of age for self-medication: 650 mg (as a highly buffered effervescent
solution [Alka-Seltzer Lemon-Lime or Original]) every 4 hours (maximum 1.3 g daily);
alternatively, 1 g (Alka-Seltzer Extra Strength) every 6 hours (maximum 1.5 g daily).838, 843,
844
>Rectal
325-650 mg every 4 hours as necessary (maximum 4 g daily).a
>Pain Associated with Migraine Headache
Oral: For self-medication, 500 mg (combined with acetaminophen 500 mg and caffeine 130
mg) as a single dose.701
Fever
Oral: 325-650 mg every 4 hours as necessary (maximum 4 g daily).a
For self-medication, 454 mg (as chewing gum pieces) every 4 hours as necessary (maximum
3.632 g daily).837
>Rectal
325-650 mg every 4 hours as necessary (maximum 4 g daily).a
Inflammatory Diseases
>Rheumatoid Arthritis and Arthritis and Pleurisy of SLE
Oral: Initially, 3 g daily in divided doses.c, l, m Increase dosage as necessary for antiinflammatory efficacy; target plasma salicylate concentration is 150-300 mcg/mL.c, l, m
Plasma concentrations >200 mcg/mL associated with an increased incidence of toxicity.c, l, m
>Osteoarthritis
Oral: Up to 3 g daily in divided doses.c, m
>Spondyloarthropathies
Oral: Up to 4 g daily in divided doses.c, m
Rheumatic Fever
Oral: Initially, 4.9-7.8 g daily in divided doses given for maximal suppression of acute
inflammation.a Adjust dosage based on response, tolerance, and plasma salicylate
concentrations.a
Various regimens suggested depending on severity of initial manifestations.a Consult
published protocols for more information on specific dosages and schedules.a
TIAs and Acute Ischemic Stroke
>Secondary Prevention
Oral: 50-325 mg daily in patients who experienced a noncardioembolic stroke or TIA (i.e.,
atherothrombotic, lacunar, or cryptogenic stroke).a, m, 646, 691, 818
Alternatively, 25 mg (in combination with dipyridamole 200 mg) twice daily (morning and
evening) or clopidogrel (75 mg daily).738, 818
50-100 mg daily suggested by some clinicians for patients at moderate to high risk of
bleeding complications.818
Continue secondary prevention indefinitely.646, 691, 818, m
>Acute Treatment
of Ischemic Stroke
Oral: 160-325 mg daily, initiated within 48 hours of stroke onset in patients who are not
receiving thrombolytic therapy and continued for up to 2-4 weeks;691, 699, 700, 818 then aspirin,
dipyridamole and aspirin, or clopidogrel for secondary prevention.646, 691, 699, 700, 818
CAD and MI
>Suspected AMI or ACS
Oral: 160-325 mg as soon as AMI or ACS is suspected (no later than 24 hours after symptom
onset), continued daily after MI.c, m, 579, 635, 646, 669, 765, 819, 820, 821, 862 (See CAD and MI:
Secondary Prevention, under Dosage and Administration.)
Consider adjunctive therapy with clopidogrel (e.g., 300-mg loading dose, then 75 mg daily)
for acute ST-segment elevation MI, unless contraindicated.852, 853, 854, 855, 856, 862
75-325 mg daily initially for non-ST-segment elevation (NSTE) ACS also has been
recommended.820
>Rectal
300 mg daily may be considered for patients with severe nausea, vomiting, or upper GI tract
disorders.821, 862
>Secondary Prevention
Oral: 75-325 or 75-162 mg once daily, continued indefinitely, has been recommended;c, 635,
646, 668, 669, 736, 740, 765, 775, 820, 821, 822, 823, 828, 867, 881, m
current evidence suggests 75-81 mg daily
sufficient for long-term cardiovascular disease prevention and associated with less GI
bleeding risk.s
75-162 mg (possibly 75-81 mg)s daily in combination with long-term (up to 4 years),
moderate-intensity (target INR: 2-3) oral anticoagulation recommended in post-MI patients
where meticulous INR monitoring standard and routinely accessible.820
100 mg (possibly 75-81 mg)s daily in combination with short-term (3 months), moderateintensity (target INR: 2-3) oral anticoagulation suggested in high-risk post-MI patients.820
100 mg (possibly 75-81 mg)s daily recommended in patients with history of aspirin-induced
bleeding or risk factors for bleeding.820
>Primary Prevention
of MI
Oral: 75-162 mg once daily.669, 681, 682, 760, 765, 783, 820 Continue indefinitely, provided there are
no contraindications to aspirin.669, 681, 682, 760, 765, 783, 820
>Chronic Stable CAD
Oral: 75-162 mg daily; continue indefinitely.820 (See dosage for long-term cardiovascular
disease prevention under CAD and MI: Secondary Prevention, under Dosage and
Administration.)
75-162 mg daily in combination with long-term clopidogrel therapy in patients with high risk
of MI.820 (See dosage for long-term cardiovascular disease prevention under CAD and MI:
Secondary Prevention, under Dosage and Administration.)
>Angina
Oral: 75-325 mg once daily, continued indefinitely;740, 765, 775, 822, m 75-162 mg daily
recommended by ACCP for patients with chronic stable angina.820 (See dosage for long-term
cardiovascular disease prevention under CAD and MI: Secondary Prevention, under Dosage
and Administration.)
Unstable angina: 75-325 mg (possibly 75-81 mg)s once daily, continued indefinitely.m (See
dosage for long-term cardiovascular disease prevention under CAD and MI: Secondary
Prevention, under Dosage and Administration.)
>PCI and Revascularization Procedures
Oral: PCI in adults who are already receiving aspirin: 75-325 mg initiated 2 hours before
the procedure (e.g., PTCA, stent placement) in conjunction with a thienopyridine
derivative.646, 685, 686, 821, 824, 865, 867
PCI in patients not already receiving long-term aspirin therapy: 300-325 mg daily, initiated at
least 2 hours, preferably 24 hours, prior to PCIm in conjunction with a thienopyridine
derivative.824, 865, m
Following PCI and bare-metal stent placement: 325 mg daily for 1 month in conjunction
with a thienopyridine derivative; ideally, continue for 1 year in patients who are not at high
risk for bleeding.821, 824, 865, 867
Following PCI and drug-eluting stent placement: 75-100 mg daily for 12 months in
combination with a thienopyridine derivative (e.g., clopidogrel 75 mg daily).824, 886
Following PCI for prevention of myocardial ischemic events in patients requiring other
antithrombotic agents (e.g., clopidogrel, warfarin):<100 mg (possibly 75-81 mg)s daily
recommended.824, 878 (See dosage for long-term cardiovascular disease prevention under CAD
and MI: Secondary Prevention, under Dosage and Administration.)
Brachytherapy for restenosis following PCI and stent implantation
: 75-325 mg daily
in combination with clopidogrel (75 mg daily) suggested by ACC and AHA and other
clinicians.
Continue indefinitely for secondary prevention of cardiovascular events.c, 646, 686, 824, 865, 867, 880,
m
(See dosage for long-term cardiovascular disease prevention under CAD and MI:
Secondary Prevention, under Dosage and Administration.)
CABG: Some manufacturers recommend 325 mg daily, initiated 6 hours after surgery.c, m If
bleeding precludes earlier use, initiate as soon as possible thereafter .685, 768, 823
Saphenous vein CABG: 100-325 mg daily initiated within 48 hours after saphenous vein
CABG suggested by ACC and AHA.867, 885 75-325 mg daily initiated at 6 hours after surgery
recommended by ACCP.823
Internal mammary artery CABG: 75-162 mg daily, continued indefinitely, recommended by
ACCP.823 (See dosage for long-term cardiovascular disease prevention under CAD and MI:
Secondary Prevention, under Dosage and Administration.)
Following CABG: Manufacturer recommends 325 mg daily for 1 year after CABG.m ACCP
recommend 75-162 mg daily continued indefinitely.646, 685, 821, 823 ACC and AHA recommend
>162 mg daily for <1 year following saphenous vein CABG.867 (See dosage for long-term
cardiovascular disease prevention under CAD and MI: Secondary Prevention, under Dosage
and Administration.)
Carotid endarterectomy: ACCP recommends 75-325 mg daily initiated preoperatively and
continued indefinitely.690, 828 Manufacturer recommends 80 mg daily to 650 mg twice daily
initiated preoperatively and continued indefinitely.m (See dosage for long-term cardiovascular
disease prevention under CAD and MI: Secondary Prevention, under Dosage and
Administration.)
Lower-extremity balloon angioplasty with or without stenting: 75-162 mg daily continued
indefinitely.690, 828 (See dosage for long-term cardiovascular disease prevention under CAD
and MI: Secondary Prevention, under Dosage and Administration.)
Atrial Fibrillation/Flutter
Oral: Patients at high risk for stroke who decline or have contraindications to oral
anticoagulation: 325 mg daily.744, 773, 776, 826
Intermediate risk for stroke: 325 mg daily or warfarin.826
60 years of age and no other risk factors: 325 mg daily.773
Low risk for stroke: 325 mg daily.744, 747, 748, 749, 767, 773, 774, 776, 826
Mitral Valve Prolapse
Oral: 50-162 mg daily long-term in those with unexplained TIAs.764, 827
Thrombosis in Other Arteries and Arteriovenous Communications
>Carotid Stenosis
Oral: 75-162 mg daily indefinitely recommended by ACCP for patients who are not surgical
candidates.828 (See dosage for long-term cardiovascular disease prevention under CAD and
MI: Secondary Prevention, under Dosage and Administration.)
>Ischemic Events in Peripheral Arterial Occlusive Disease
Oral: 75-325 mg daily.690, 769, 828 Continue indefinitely.690, 769, 828 (See dosage for long-term
cardiovascular disease prevention under CAD and MI: Secondary Prevention, under Dosage
and Administration.)
>Vascular Grafts
Oral: 75-325 mg daily in patients undergoing prosthetic infrainguinal bypass; initiate
preoperatively.690, 769, 828
Use in combination with oral anticoagulation in patients at high risk of bypass occlusion or
limb loss.690, 769, 828
Continue life-long aspirin prophylaxis.690, 769, 828 (See dosage for long-term cardiovascular
disease prevention under CAD and MI: Secondary Prevention, under Dosage and
Administration.)
Prosthetic Heart Valves
>Mechanical Prosthetic Heart Valves
Oral: Optimal regimen not established.692 Consider low dosages (75-100 mg daily) of aspirin
in combination with oral anticoagulation for patients at increased risk of thromboembolism
(e.g., those with history of embolic event, atrial fibrillation, CHD, large left atrium,
endocardial damage, low ejection fraction, caged ball or caged disk valve, >1 mechanical
heart valve, mechanical valve in mitral position).692, 694, 717, 827
75-100 mg daily in combination with oral anticoagulation for patients who develop systemic
embolism with oral anticoagulation alone.692, 777, 827 Increase dosage to 325 mg daily and/or
titrate warfarin anticoagulation to a higher INR in patients who develop systemic embolism
despite receiving combined therapy with oral anticoagulation and low dosages of aspirin.741
80-100 mg daily recommended for patients with prosthetic heart valves in whom oral
anticoagulation must be discontinued.827
Consult specialized references for additional information.692, 694, 717
>Bioprosthetic Heart Valves
Oral: Bioprosthetic valve in the aortic position: 80-100 mg daily recommended for the first 3
months following valve insertion.827
75-100 mg daily long term for those in sinus rhythm with no other risk factors for
thromboembolism.692, 694, 744, 827
Pericarditis
>Acute Pericarditis
Following MI
Oral: 162-325 mg daily.635, 821 Higher dosages (e.g., 650 mg every 4-6 hours) may be
required.635, 821
Complications of Pregnancy
Oral: Congenital thrombophilic defect
Geriatric Patients
Highly buffered effervescent solution: Maximum 1.3 g (Alka-SeltzerLemon-Lime or
Original) or 1.5 g (Alka-Seltzer Extra Strength) in 24 hours.838, 843, 844
Cautions
Contraindications
Known hypersensitivity to aspirin or any ingredient in the formulation.c, m
History of asthma, urticaria, or other sensitivity reaction precipitated by other NSAIAs.c, m
Syndrome of asthma, rhinitis, and nasal polyps.c
Children or adolescents with viral infections (with or without fever) because of the possibility
that the infection may be one associated with an increased risk of Reye's syndrome.c, m (See
Pediatric Use under Cautions.)
Warnings/Precautions
Warnings
Alcohol
Long-term heavy alcohol use (3 alcoholic beverages daily) associated with an increased risk
of aspirin-induced bleeding.c, j, m (See Advice to Patients.)
Hematologic Effects
Inhibits platelet aggregation and may prolong bleeding time.c, m These effects may be
particularly important in patients with inherited (e.g., hemophilia) or acquired (e.g., liver
disease, vitamin K deficiency) bleeding disorders.c, m
Because of the increased risk of bleeding, avoid aspirin-containing chewing gum tablets or
gargles for 1 week after tonsillectomy or oral surgery.h
GI Effects
Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning
symptoms.c Increased risk in those with a history of GI bleeding or ulceration, geriatric
patients, those receiving an anticoagulant, receiving prolonged therapy, taking multiple
NSAIAs concomitantly, and consuming 3 alcohol-containing beverages daily.j
Avoid in patients with active peptic ulcer disease; can cause gastric mucosal irritation and
bleeding.c, m
Thrombosis Associated with Drug-eluting Stents
Stent thrombosis with potentially fatal sequelae, particularly with drug-eluting stents
(DES),886, 890, 891 associated with premature discontinuance (<12 months) of dual-drug therapy
with a thienopyridine derivative and aspirin.886, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900 (See
Percutaneous Coronary Intervention and Revascularization Procedures under Uses.) For nonelective procedures that mandate premature discontinuance of thienopyridine-derivative
therapy, continue aspirin therapy if at all possible.886 Restart thienopyridine therapy as soon as
possible after the procedure.886 (See Advice to Patients.)
Sensitivity Reactions
Anaphylactoid reactions, severe urticaria, angioedema, or bronchospasm reported.836, c, h, m
Immediate medical intervention and discontinuance for anaphylaxis.836
Contraindicated in patients with syndrome of asthma, rhinitis, and nasal polyps;c, m caution in
patients with asthma.c
General Precautions
Sodium Content
Avoid highly buffered aspirin preparations in patients with CHF, renal failure, or other
conditions in which high sodium content would be harmful.c, m
Individuals with Phenylketonuria
Some preparations contain aspartame (NutraSweet), which is metabolized in the GI tract to
phenylalanine.a, 838
Use of Fixed Combinations
When aspirin is used in fixed combination with other agents, consider the cautions,
precautions, and contraindications associated with the other agent(s).a
Specific Populations
Pregnancy
Category C (Category D in third trimester).
Use only if clearly needed.c, m Avoid use in the third trimester because of possible premature
closure of the ductus arteriosus.c, m Avoid 1 week prior to and during labor and delivery;
aspirin use prior to and during labor associated with excessive blood loss at delivery.c, m
Maternal and fetal hemorrhagic complications observed with maternal ingestion of large
doses (e.g., 12-15 g daily) of aspirin594, 595, 597, 611, 612 generally have not been observed in
studies in which low doses (60-150 mg daily) of the drug were used for prevention of
complications of pregnancy
.594, 595, 596, 597, 598, 599, 600, 601, 605, 626, 627, 629, 630, 631, 632, 647
Lactation
Distributed into milk; use not recommended.c, m High doses may result in adverse effects
(rash, platelet abnormalities, bleeding) in nursing infants.c, m
Pediatric Use
Dosing recommendations for juvenile rheumatoid arthritis based on well controlled clinical
studies.c, m High dosages that result in plasma concentrations >200 mcg/mL associated with
an increased incidence of toxicity.c, m
Use in children with varicella infection or influenza-like illnesses reportedly is associated
with an increased risk of developing Reye's syndrome.166, 167, 168, 169, 468, 538, 549, 638 US Surgeon
General, AAP Committee on Infectious Diseases, FDA, and other authorities advise that
salicylates not be used in children and teenagers with varicella or influenza, unless directed
by a clinician.466, 467, 554, 638 Generally avoid salicylates in children and teenagers with
suspected varicella or influenza and during presumed outbreaks of influenza, since accurate
diagnosis of these diseases may be impossible during the prodromal period;466 use of
salicylates in the management of viral infections in children or adolescents is contraindicated,
since the infection may be one associated with an increased risk of Reye's syndrome.646, m
Use with caution in pediatric patients who are dehydrated (increased susceptibility to
salicylate intoxication).h
Safety and efficacy of aspirin in fixed combination with extended-release dipyridamole not
established.738
Risk of overdosage and toxicity (including death) in children <2 years of age receiving
preparations containing antihistamines, cough suppressants, expectorants, and nasal
decongestants alone or in combination for relief of symptoms of upper respiratory tract
infection.b, d Limited evidence of efficacy for these preparations in this age group; appropriate
dosages not established.b Use such preparations in children <2 years of age with caution and
only as directed by clinician.b, d Clinicians should ask caregivers about use of OTC
cough/cold preparations to avoid overdosage.b
Hepatic Impairment
Avoid in patients with severe hepatic impairment.c, m
Renal Impairment
Avoid in patients with GFR <10 mL/minute.c, m
Common Adverse Effects
Minor upper GI symptoms (dyspepsia).c
Interactions
Protein-bound Drugs
Potential for salicylate to be displaced from binding sites by, or to displace from binding
sites, other protein-bound drugs.h, m Aspirin acetylates serum albumin, which may alter
binding of other drugs to the protein.a
Specific Drugs
Drug
Interaction
Reduced BP response to ACE
inhibitorsc
Possible attenuation of
hemodynamic actions of ACE
ACE inhibitors
inhibitors in patients with
CHFh
Reduced hyponatremic effect
of ACE inhibitorsc, m
Drugs that decrease urine pH
Acidifying agents may decrease salicylate
excretionh
Increased risk of bleedingc, m
Alcohol
(See Advice to Patients.)
Alkalinizing
Drugs that increase urine pH
agents
may increase salicylate
excretionh
Comments
Monitor BPc
discontinuedh
Increased risk of bleedingc, m
May displace warfarin from
Anticoagulants
protein-binding sites, leading
(warfarin, heparin)
to prolongation of PT and
bleeding timec, m
May displace phenytoin from
binding sites; possible
decrease in total plasma
phenytoin concentrations,
with increased free fractionc, m
Anticonvulsants May displace valproic acid
from binding sites; possible
increase in free plasma
valproic acid concentrations;c,
h, m
possible increased risk of
bleedingh
Antidiabetic drugs Potential for increased
(sulfonylureas)
hypoglycemic effectc, m
Reduced BP response to -adrenergic
adrenergic blocking agents c, m
blocking agents Potential for salt and fluid
retentionm
Increased risk of salicylate
Carbonic
toxicityh
anhydrase
Increased plasma
inhibitors
acetazolamide concentrations;
(acetazolamide) increased risk of
acetazolamide toxicityc, m
Decreased plasma salicylate
Corticosteroids
concentrationsh
Possible reduced natriuretic
Diuretics
effectc
Increased plasma
methotrexate concentrationsh
Inhibition of renal clearance
of methotrexate leading to
Methotrexate
bone marrow toxicity,
especially in geriatric patients
or patients with renal
impairmentm
NSAIAs
Increased risk of bleeding, GI
ulceration, decreased renal
function, or other
complications861, m, p, q, r
No consistent evidence that
low-dose aspirin mitigates
increased risk of serious
cardiovascular events
Monitor closelyh
Monitor BPc
Pyrazinamide
Tetracycline
Thrombolytic
agents
Uricosuric agents
(probenecid,
sulfinpyrazone)
Varicella virus
vaccine live
Salicylate: 90-95% bound at plasma salicylate concentrations <100 mcg/mL; 70-85% bound
at concentrations of 100-400 mcg/mL; 25-60% bound at concentrations >400 mcg/mL.h, m
Elimination
Metabolism
Partially hydrolyzed to salicylate by esterases in the GI mucosa.a Unhydrolyzed aspirin
subsequently undergoes hydrolysis by esterases mainly in the liver but also in plasma,
erythrocytes, and synovial fluid.a
Salicylate is metabolized in the liver by the microsomal enzyme system.h
Elimination Route
Excreted in urine via glomerular filtration and renal tubular reabsorption as salicylate and its
metabolites.h Urinary excretion of salicylate is pH dependent; as urine pH increases from 5 to
8, urinary excretion of salicylate is greatly increased.h
Half-life
Aspirin: 15-20 minutes.a
Half-life of salicylate increases with increasing plasma salicylate concentrations.h, m
Salicylate: 2-3 hours when aspirin administered in low doses (325 mg).h
Salicylate: 15-30 hours when aspirin administered in higher dosages.h
Special Populations
Salicylate and its metabolites readily removed by hemodialysis and, to a lesser extent, by
peritoneal dialysis.h
Stability
Storage
Oral
Capsules
Aspirin in fixed-combination with extended-release dipyridamole: 25C (may be exposed to
15-30C).738 Protect from excessive moisture.738
Gum
15-25C; protect from excessive moisture.837
Tablets
Room temperature (Bayer products, excluding Alka-Seltzer products);839, 840, 841, 842, m avoid
high humidity and excessive heat (40C).840
15-30C (Easprin).l
20-25C (Anacin Extra Strength); protect from moisture.836
Protect from excessive heat (Alka-Seltzer products).838, 843, 844
Rectal
Suppositories
2-15C.a
Actions
Inhibits COX-1 and COX-2 activity.677
Pharmacologic actions similar to those of prototypical NSAIAs; exhibits anti-inflammatory,
analgesic, and antipyretic activity.c
Irreversibly acetylates and inactivates COX-1 in platelets.677
The existence of 2 COX isoenzymes with different aspirin sensitivities and extremely different
recovery rates of their COX activity following inactivation by aspirin at least partially
explains the different dosage requirements and durations of aspirin effects on platelet
function versus the drug's analgesic and anti-inflammatory effects.677
Effects on urinary excretion of uric acid are dose related; large dosages (e.g., 1.3 g 4 times
daily) enhance urinary excretion and decrease serum concentrations of uric acid, intermediate
dosages (e.g., 650 mg to 1 g 3 times daily) usually do not alter uric acid excretion, and low
dosages (e.g., <325 mg 3 times daily) inhibit excretion and may increase serum uric acid
concentrations.h
Advice to Patients
When used for self-medication, importance of reading the product labeling.836, 841, e, 837, 838, 843, 844
When used for self-medication, importance of asking clinician whether to use aspirin or
another analgesic if alcohol consumption is 3 alcohol-containing drinks per day.836, e, 837, 838,
841, 843, 844
Importance of informing patients about risk of bleeding associated with chronic, heavy alcohol
use while taking aspirin.j, m
When used for self-medication in children, importance of basing the dose on the child's weight
or body surface area.841
In patients with drug-eluting stents (DES) receiving aspirin in combination with clopidogrel or
ticlopidine, importance of not discontinuing antiplatelet therapy without consulting
cardiologist, even if instructed to do so by other health-care professional (e.g., dentist).886
Importance of not using aspirin for chicken pox or flu symptoms in children or adolescents
without consulting a clinician.836, e, 837, 838, 841, 843, 844
Patients receiving anticoagulants and those with asthma, gout, diabetes, arthritis, peptic ulcers,
bleeding problems, or stomach problems that persist or recur should consult a clinician before
using aspirin for self-medication.836, e, 837, 838, 841, 843, 844
Discontinue and consult clinician if pain or fever persists or progresses, new symptoms occur,
redness or swelling is present in a painful area, or ringing in the ears or loss of hearing
occurs.836, e, 837, 838, 841, 843, 844
Risk of GI bleeding or ulceration, particularly with prolonged therapy,c, j, m and concomitant
therapy with another NSAIA.j
Risk of anaphylactoid and other sensitivity reactions.c
Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding or rash
develop.c
Importance of seeking immediate medical attention if an anaphylactic reaction occurs.c
Importance of women informing clinicians if they are or plan to become pregnant or to breastfeed.c Importance of avoiding aspirin in late pregnancy (third trimester) and during labor and
delivery.c
Tablets,
delayed-release 81 mg*
(enteric-coated)
Manufacturer
Heritage, Schering-Plough
Geri-Care, Magno-Humphries
Basic Vitamins
Chattem
Chattem
Bayer
AmerisourceBergen, Cardinal
Health, Chain Drug Marketing,
Eckerd, Ivax, Major, PDK, Prime
Marketing, Qualitest, Rugby, URL
Geri-Care
Halfprin
Kramer
Aspirin Regimen
Bayer Regular
325 mg* Strength Caplets
Bayer
(with propylene
glycol)
Ecotrin Regular
Strength (with
GlaxoSmithKline
propylene glycol)
Genacote
Ivax
Aspirin Enteric Coated
Time-Cap
Tablets
Aspirin for Arthritis Cardinal Health
Ecotrin Maximum
500 mg* Strength (with
GlaxoSmithKline
propylene glycol)
Aspirin Enteric Coated
Time-Cap
Tablets
Aspirin Extra Strength Medicine Shoppe
Aspirin Maximum
Chain Drug Marketing
Strength
Aspirin Enteric Coated
650 mg*
Time-Cap, United Research
Tablets
975 mg Easprin
Rosedale
Aspirin Enteric Coated
Time-Cap
Tablets
162 mg
Tablets,
800 mg ZORprin
Par
extended-release
Tablets, filmGenuine Bayer
325 mg*
Bayer
coated
AspirinTablets
Aspirin Lite Coated
AmerisourceBergen
Aspirin Micro Coated
Time-Cap
Tablets
Aspirin Microthin
Cardinal Health
Coating
Extra Strength Bayer
500 mg Aspirin Caplets (with Bayer
propylene glycol)
Rectal Suppositories 60 mg* Aspirin Suppositories Consolidated Midland
120 mg* Aspirin Suppositories Consolidated Midland
200 mg* Aspirin Suppositories Consolidated Midland
300 mg*
Aspirin Suppositories Consolidated Midland
600 mg*
Aspirin Suppositories Consolidated Midland
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Brand Names
Manufacturer
GlaxoSmithKline
Brand Names
Manufacturer
GlaxoSmithKline
Gelpirin (combination)
Alra
250 mg Acetaminophen,
Aspirin 250 mg, and
Caffeine 65 mg
Goody'sTablets
(combination) (with
povidone)
GlaxoSmithKline
Vanquish Caplets
(combination) (with buffers Bayer
and propylene glycol)
Excedrin Extra-Strength
Caplets (combination)
Bristol-Myers
(with povidone and
propylene glycol)
Excedrin Extra-Strength
Geltabs (combination) (with
Bristol-Myers
povidone and propylene
glycol)
Excedrin Extra-Strength
Tablets (combination) (with
Bristol-Myers
povidone and propylene
glycol)
Excedrin Migraine
Caplets (combination)
Bristol-Myers
(with povidone and
Squibb
propylene glycol)
Excedrin Migraine Geltabs
(combination) (with
Bristol-Myers
povidone and propylene
Squibb
glycol)
Excedrin Migraine Tablets
(combination) (with
Bristol-Myers
povidone and propylene
Squibb
glycol)
Brand Names
Manufacturer
Oral
Tablets
Percodan-Demi
(combination) (C-II;
scored)
Endo
Endodan
(combination) (C-II)
Endo
Percodan
(combination) (C-II; Endo
scored)
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Propoxyphene Hydrochloride, Aspirin, and Caffeine
Dosage
Routes
Strengths
Brand Names
Manufacturer
Forms
65 mg Propoxyphene
Darvon Compound
Oral Capsules Hydrochloride, Aspirin 389 mg, Pulvules (combination) aaiPharma
and Caffeine 32.4 mg*
(C-IV)
PC-CAP (combination)
Alra
(C-IV)
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Other Aspirin Combinations
Routes Dosage Forms
Strengths
Oral
Capsules
Brand Names
Manufacturer
Fiorinal
325 mg with Butalbital
(combination) (C-III;
50 mg and Caffeine 40
Watson
with benzyl alcohol
mg*
and parabens)
Lanorinal
Lannett
(combination)
Aspirin and Caffeine
Actavis
with Butalbital
Butalbital, Aspirin,
West Ward
and Caffeine
Fiorinal with
325 mg with Butalbital
Codeine
50 mg, Caffeine 40 mg,
(combination) (C-III; Watson
and Codeine Phosphate
with benzyl alcohol
30 mg
and parabens)
Ascomp with
Codeine
Breckenridge
(combination)
Butalbital, Aspirin.
Anabolic, Stevens,
Caffeine, and Codeine
Watson
Phosphate
356.4 mg with Caffeine Synalgos-DC
Leitner
30 mg and
(combination) (C-III)
Dihydrocodeine
Bitartrate 16 mg
Capsules,
extended-release 25 mg with
core (dipyridamole Dipyridamole 200 mg
only)
650 mg/packet with
Caffeine 33.3
For solution
mg/packet and
Salicylamide 195
mg/packet
650 mg/packet with
Caffeine 32 mg/packet
and Salicylamide 200
mg/packet
742 mg/packet with
Caffeine 38 mg/packet
and Salicylamide 222
mg/packet
325 mg with Butalbital
Tablets
50 mg and Caffeine 40
mg*
325 mg with
Carisoprodol 200 mg
Aggrenox
(combination) (with
povidone)
Boehringer
Ingelheim
BC Powder
(combination)
GlaxoSmith Kline
Stanback Powder
(combination)
GlaxoSmithKline
BC Powder Arthritis
Strength
GlaxoSmithKline
(combination)
Butal Compound
(combination)
Fortabs
(combination) (C-III)
Carisoprodol
Compound
Soma Compound
(combination)
325 mg with
Soma Compound
Carisoprodol 200 mg,
with Codeine
and Codeine Phosphate
(combination)
16 mg
Equagesic
325 mg with
(combination) (CMeprobamate 200 mg
IV;scored)
Micrainin
(combination) (C-IV)
385 mg with Caffeine
Norgesic
30 mg, and
(combination) (with
Orphenadrine Citrate
povidone)
25 mg
Orphenadrine Citrate,
Aspirin, and Caffeine
Tablets
P-A-C Analgesic
400 mg with Caffeine
(combination) (with
32 mg
tartrazine)
500 mg with
Damason-P
Sandoz
United Research
Consolidated
Midland
Medpointe
MedPointe
Leitner
Wallace
3M
Sandoz
Lee
Pharmaceuticals
Mason
Hydrocodone Bitartrate
(combination) (C-IV)
5 mg
770 mg with Caffeine
Norgesic Forte
60 mg, and
(combination) (with 3M
Orphenadrine Citrate
povidone; scored)
50 mg
Orphenadrine Citrate,
Aspirin, and Caffeine Sandoz
Tablets
Tablets, film400 mg with Caffeine Anacin Caplets
Wyeth
coated
32 mg
(combination)
Anacin Tablets
Wyeth
(combination)
421 mg with Caffeine
Lee
Cope (combination)
32 mg and buffers
Pharmaceuticals
Anacin Maximum
500 mg with Caffeine
Strength
Wyeth
32 mg
(combination)
Extra Strength Bayer
500 mg with Caffeine Back and Body Pain
Bayer
32.5 mg
(with propylene
glycol)
Tablets, for
500 mg with Caffeine Alka Seltzer Morning
Bayer
solution
65 mg
Relief (combination)
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Aspirin is also commercially available in combination with other drugs such as analgesics,
antihistamines, antimuscarinics, antitussives, barbiturates, decongestants, and expectorants.
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
Clopidogrel (Systemic)
Introductory Information
Platelet-aggregation inhibitor; thienopyridine derivative.1
Class: 20:12.18 Platelet-Aggregation Inhibitors; atc
Brands: Plavix
Generic Name: Clopidogrel Bisulfate
Boxed Warning
Clopidogrel is a prodrug; requires activation by CYP enzyme system (principally by
CYP2C19) to produce its pharmacologically active metabolite.1, 2, 6, 8, 11, 121
Genetic variations of CYP2C19 can result in impaired metabolism and reduced effectiveness
of clopidogrel.1, 121 (See Reduced Efficacy Associated with Impaired CYP2C19 Function
under Cautions.) Higher rates of major adverse cardiovascular events (e.g., death, MI, stroke)
have been reported in poor metabolizers of CYP2C19 receiving clopidogrel at recommended
dosages following acute coronary syndrome or PCI compared with those who have normal
CYP2C19 function.1, 121
Genetic tests are available to determine a patient's CYP2C19 genotype; results of such tests
may be used to guide treatment decisions.1, 20, 121, 122
Consider use of other antiplatelet agents or alternative dosing strategies for clopidogrel in
patients with variant CYP2C19 genotypes.1, 121
REMS:
FDA approved a REMS for clopidogrel to ensure that the benefits of a drug outweigh the
risks. However, FDA later rescinded REMS requirements. See the FDA REMS page ([Web])
or the ASHP REMS Resource Center ([Web]).
Uses
Cardiovascular Risk Reduction Following Recent Myocardial Infarction or Stroke or in
Established Peripheral Arterial Disease
Reduction of the risk of cardiovascular or cerebrovascular events (new MI, new ischemic
stroke, and vascular death) in patients with a history of recent MI, recent ischemic stroke, or
established peripheral arterial disease.1, 2, 6, 8, 15, 23, 25, 27 Recommended as an alternative to
aspirin in those with aspirin allergy.10, 14, 17, 21, 25, 26, 28, 30
Clopidogrel monotherapy or aspirin in combination with dipyridamole may be preferable to
aspirin monotherapy for secondary prevention of stroke based on a somewhat greater
absolute risk reduction for stroke; weigh benefit against additional costs of therapy.25, 63
In patients with peripheral arterial disease, clopidogrel recommended over ticlopidine or no
antiplatelet therapy for prevention of death and disability from stroke or MI.29
In children who have recurrent arterial ischemic strokes or TIAs despite aspirin therapy,
ACCP suggests changing from aspirin therapy to clopidogrel or an anticoagulant, such as a
low molecular weight heparin or warfarin.63
Use of aspirin rather than clopidogrel for most patients requiring long-term antiplatelet
therapy is suggested by many clinicians because of lower cost and modest additional benefit
of clopidogrel over aspirin.5, 8, 10, 20, 23, 29, 66, 71
Acute Coronary Syndromes: Unstable Angina or Non-ST-Segment Elevation MI
Used in combination with aspirin for reduction of the risk of cardiovascular or
cerebrovascular events in patients with non-ST-segment elevation (NSTE) acute coronary
syndromes (NSTE ACS), including unstable angina and non-ST-segment-elevation MI
(NSTEMI).1, 5, 10, 14, 17, 18, 21, 26, 28, 30, 34, 35, 39, 64, 65, 66 Used in patients who are managed medically
or with coronary intervention (e.g., PCI with or without coronary artery stenting, CABG).1, 5,
10, 18, 21, 26, 28, 30, 34, 35, 39, 40
Recommended by ACC/AHA and other clinicians as an adjunct to acute therapy with heparin
and aspirin in patients with NSTE ACS who are managed medically and in those undergoing
PCI who are not at high risk for bleeding.18, 21, 34, 39
Dual-drug antiplatelet therapy (aspirin plus clopidogrel or prasugrel) recommended by
ACC/AHA for patients with definite or likely NSTEMI in whom an invasive approach is
selected.134 Begin treatment as early as possible before or at the time of PCI and continue for
1 month, ideally 1 year in patients who are not at high risk for bleeding.134
Balance potential benefit of pretreatment with clopidogrel in patients undergoing PCI against
increased risk of bleeding should emergency CABG be needed.28, 34, 35 Temporarily
discontinue therapy 5-10 days prior to CABG and reinitiate therapy in conjunction with
aspirin after the procedure.26, 30, 35, 40, 66, 69
In patients undergoing PCI with an absolute contraindication to aspirin
, ACCP states
Recommended by ACCP, ACC, AHA, and other clinicians for 14-28 days in addition to
aspirin, with or without reperfusion therapy (i.e., thrombolytic therapy, primary PCI), in
patients with suspected acute STEMI.67, 68 ACCP suggests continuance of clopidogrel and
aspirin beyond 28 days and up to 1 year in patients with STEMI who have not undergone
stent implantation.67
In patients in whom CABG is planned, withhold clopidogrel for at least 5 days and preferably
for 7-10 days prior to surgery unless urgency of revascularization outweighs risks of excess
bleeding.69, 134
Suggested as adjunct to thrombolytic therapy in patients with acute STEMI who are allergic
to aspirin or in whom aspirin is otherwise contraindicated.10, 23, 27
In patients with STEMI in whom PCI is planned, ACC/AHA and ACCP recommend
pretreatment with a loading dose of a thienopyridine derivative (e.g., clopidogrel, prasugrel)
before or at the time of PCI in conjunction with aspirin therapy.67, 134
Recommended by ACC/AHA in combination with aspirin as short-term prophylaxis ( 1
month) in patients with STEMI who have undergone PCI with bare-metal coronary artery
stent implantation.39, 134
Ideally, use long term (12 months) in conjunction with aspirin therapy in patients with
STEMI who have undergone PCI with bare-metal stent implantation and are at low risk of
bleeding.134
Recommended as short-term (minimum of 2 weeks) therapy with aspirin in patients with
STEMI who have undergone PCI with bare-metal stent implantation and are at high risk of
bleeding.134
Prolonged (12 months) prophylaxis in combination with aspirin strongly recommended in
patients who have undergone PCI with DES implantation and are not at high risk of
bleeding.43, 44, 45, 46, 50, 51, 52, 54, 134 (See Compliance with Therapy in Patients with Drug-eluting
Stents under Cautions.) Consider continuation of thienopyridine therapy beyond 15 months in
patients with drug-eluting stents; may use abbreviated period of thienopyridine therapy (less
than 12 months) in patients with STEMI and a drug-eluting stent in whom the risk of
morbidity due to bleeding outweighs the anticipated benefit of such therapy.134
Triple antithrombotic therapy with clopidogrel, low-dose aspirin, and warfarin
anticoagulation
(target INR 2-2.5) recommended, based on case studies or expert
opinion, in patients who have indications for anticoagulation (e.g., atrial fibrillation, left
ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical
heart valves) and who require clopidogrel and aspirin after PCI.23, 42, 65 In patients who have
undergone stent placement and have indications for anticoagulation, warfarin (INR 2-3) and
aspirin suggested in addition to clopidogrel;23, 42, 66 continue clopidogrel therapy for 4 weeks
or 1 year following bare-metal or drug-eluting stent implantation, respectively, in addition to
warfarin and aspirin.66 Such triple antithrombotic regimens are associated with an increased
risk of bleeding; monitor closely.65, 70
who are at high risk for cardiovascular events (i.e., family history of CHD, smoking,
hypertension, obesity, albuminuria, and elevated blood cholesterol or triglyceride
concentrations).95 Recommended by ACCP for primary prevention of cardiovascular events
as an alternative to aspirin for aspirin-allergic patients who are at moderate to high risk for
cardiovascular events.66
Chronic Stable Angina
Use in combination with aspirin suggested by ACCP for reduction of the risk of AMI in highrisk patients with symptomatic chronic stable angina
.26
Used as an alternative to aspirin in patients with symptomatic chronic stable angina who
cannot tolerate aspirin
.96
Other Uses
Aspirin generally recommended for all clinical conditions in which antiplatelet prophylaxis
has a favorable benefit-to-risk profile.5, 8, 10, 11 However, use recommended by ACCP as
alternative and/or adjunctive antithrombotic therapy in selected patients with a number of
atherosclerotic and ischemic conditions,13, 14 15, 16, 17 including rheumatic mitral valve disease
13, 24
and saphenous vein CABG
.14, 26, 30 40
Considered a reasonable choice for antiplatelet therapy in high-risk patients with prosthetic
heart valves in whom aspirin cannot be used
or in patients with prosthetic heart
.41
risk for bleeding.134 In patients in whom a high risk of bleeding is deemed to outweigh
anticipated benefit, administer clopidogrel with aspirin for a minimum of 2 weeks.134
Following drug-eluting stent (DES) implantation: 75 mg once daily with aspirin for 12
months in patients not at high risk for bleeding.43, 44, 45, 46, 50, 51, 52, 54, 66, 134 (See Compliance
with Therapy in Patients with Drug-eluting Stents under Cautions.)
>ST-Segment Elevation MI
Oral: Usual recommended dosage: 75 mg once daily with or without a loading dose in
combination with aspirin.1, 39, 67, 134 ACCP recommends a clopidogrel loading dose of 300 mg
in patients 75 years of age;67 loading dose for patients >75 years of age not established.134
ACC/AHA state that clopidogrel should be continued as the thienopyridine of choice in
patients with STEMI who will undergo PCI and have already received clopidogrel and
thrombolytic therapy.134
Patients with STEMI who have received any thrombolytic agent (fibrin-specific or not) and
in whom PCI is planned within 24 hours: ACC/AHA recommend a clopidogrel loading dose
of 300 mg.134
Patients with STEMI receiving a non-fibrin-specific thrombolytic agent who will undergo
PCI within 24-48 hours: ACC/AHA recommend a clopidogrel 300-mg loading dose.134
Patients with STEMI who have received a fibrin-specific thrombolytic agent and will
undergo PCI >24 hours later: ACC/AHA recommend a clopidogrel loading dose of 300-600
mg.134
Patients with STEMI who have received a non-fibrin-specific thrombolytic agent and will be
undergoing PCI >48 hours later: ACC/AHA recommend a clopidogrel loading dose of 300600 mg.134
Patients with STEMI who have not received thrombolytic or thienopyridine therapy and who
will undergo nonprimary PCI: ACC/AHA recommend a clopidogrel loading dose of 300-600
mg.134
Patients allergic to or intolerant of aspirin
: 75 mg of clopidogrel once daily
indefinitely as an adjunct to thrombolytic therapy.66
Planned PCI: ACC/AHA recommend a loading dose of 300-600 mg as early as possible
before or at the time of PCI in conjunction with aspirin therapy.134 Larger loading doses (e.g.,
900 mg) have been used to achieve higher level of antiplatelet activity more rapidly, but
efficacy and safety not established.67, 134
Following bare-metal stent implantation: 75 mg once daily with aspirin for 1 month.66, 134
Ideally, continue for 12 months in conjunction with daily aspirin therapy in patients at low
risk for bleeding.66, 134 In patients at high risk for bleeding, administer clopidogrel and aspirin
for a minimum of 2 weeks.134
Following DES implantation: 75 mg once daily with aspirin for 1 month.66, 134 Continue for
12 months with aspirin in patients not at high risk for bleeding.28, 43, 44, 45, 46, 50, 51, 52, 54, 66, 134
Special Populations
Geriatric Patients
No dosage adjustment necessary.1
Hepatic Impairment
No dosage adjustment necessary.1
Cautions
Contraindications
Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).1, 6
Known hypersensitivity to clopidogrel or any ingredient in the formulation.1
Warnings/Precautions
Warnings
Compliance with Therapy in Patients with Drug-eluting Stents
Stent thrombosis with potentially fatal sequelae, particularly with DES, associated with
premature discontinuance of therapy with a thienopyridine derivative and aspirin.43, 44, 45, 46, 47,
48, 49, 54
(See Acute Coronary Syndromes: Unstable Angina or Non-ST-Segment Elevation MI
under Uses.)
Before implantation of a DES, carefully assess patients for likelihood of compliance with
prolonged dual-drug antiplatelet therapy.45, 59 Consider avoiding use of a DES in patients who
are not expected to comply.45, 59 (See Advice to Patients.) In patients who are likely to require
invasive or surgical procedures 12 months after DES implantation, consider implantation of
a bare-metal stent or use of balloon angioplasty with provisional stent implantation instead.45
Clinicians performing invasive procedures must understand the consequences of premature
discontinuance of thienopyridine derivative therapy in patients with DES.45 If issues about a
patient's antiplatelet therapy are unclear (e.g., concern about periprocedural bleeding), such
professionals should contact the patient's cardiologist.45 Defer elective procedures with
substantial bleeding risk until completion of dual-drug antiplatelet therapy.45 For non-elective
procedures that mandate discontinuance of thienopyridine-derivative therapy, continue
aspirin therapy if at all possible.45 Restart thienopyridine therapy as soon as possible after the
procedure.45
Reduced Efficacy Associated with Impaired CYP2C19 Function
Possible reduced efficacy of clopidogrel (i.e., increased risk of cardiovascular events) due to
genetic polymorphism of CYP2C19 or concurrent use of drugs (e.g., omeprazole) that inhibit
CYP2C19.1, 72, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 100, 101, 121 Consider use of other antiplatelet agents or
alternative dosing strategies for clopidogrel in patients with variant CYP2C19 genotypes.1, 121,
123
(See Boxed Warning.)
Specific variant alleles of CYP2C19 (e.g., CYP2C19*2, CYP2C19*3) associated with
reduced metabolism of and diminished antiplatelet response to clopidogrel; data on clinical
outcomes are conflicting, but higher rates of major adverse cardiovascular events (e.g., death,
MI, stroke, stent thrombosis) reported in patients receiving recommended dosages of
clopidogrel who possess such alleles.1, 76, 78, 79, 80, 82, 83, 88, 89, 90, 92, 104, 117, 118, 121 (See Actions.)
Genetic tests (e.g., Plavitest) are available to identify patients with variant CYP2C19
genotypes.1, 20, 121, 122 While such tests are appropriate for any patient currently receiving or
considering treatment with clopidogrel, the need for pharmacogenetic testing should be
determined individually.121, 122, 123 Genetic variants of other CYP isoenzymes (e.g.,
CYP2C19*17, CYP2B6) also may affect response to clopidogrel.1, 78, 123, 131 Role of either
pharmacogenomic testing or platelet function testing in managing therapy with
thienopyridines and proton-pump inhibitors not established.136
Concurrent use of clopidogrel and omeprazole, a potent inhibitor of CYP2C19, also shown to
reduce antiplatelet effects of clopidogrel.1, 72, 79, 84, 88, 89, 98, 100, 101, 102, 103, 109 (See Proton-Pump
Inhibitors under Interactions.) Clinical importance not fully elucidated, but reduced
effectiveness in preventing cardiovascular events possible.1, 73, 74, 81, 89, 91, 92, 98, 100, 101, 102, 103, 115
Concomitant use of other drugs that inhibit CYP2C19 also may decrease response to
clopidogrel.1, 100, 101 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
under Interactions.) Avoid concomitant therapy with known inhibitors of CYP2C19 activity.1,
20, 101
Pediatric Use
Manufacturer states that safety and efficacy not established in patients <21 years of age.1, 20
In neonates and infants
shunts or other cardiac conditions predisposing to thrombosis, clopidogrel 0.2 mg/kg daily for
1-4 weeks achieved similar inhibition of platelet aggregation as a 75-mg daily dosage in
adults; no serious hemorrhagic events reported.97
Geriatric Use
In patients 75 years of age, no difference in platelet aggregation observed compared with
younger healthy individuals.1 In a clinical trial, geriatric patients were at greater risk for
thrombotic events and major bleeding than younger patients.1
Hepatic Impairment
Inhibition of ADP-induced platelet aggregation in patients with severe hepatic impairment
appears to be similar to that observed in healthy individuals.1
Renal Impairment
Experience limited in patients with moderate or severe renal impairment.1
Inhibition of ADP-induced platelet aggregation is decreased in patients with moderate (Clcr
30-60 mL/minute) or severe (Clcr 5-15 mL/minute) renal impairment.1
Common Adverse Effects
Chest pain,1, 6 accidental injury,1, 6 influenza-like symptoms,1, 6 pain,1, 6 headache,1, 6
dizziness,1, 6 abdominal pain,1, 6, 8 dyspepsia,1, 2, 3, 6, 8 diarrhea,1, 2, 3, 6, 8, 10, 11 nausea,1, 2, 3, 6
arthralgia,1, 6 back pain,1, 6 purpura,1, 6 upper respiratory tract infection,1, 6 rash,1, 2, 3, 6, 8, 10, 11
pruritus.1, 6
Interactions
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Appears to inhibit CYP2C9 isoenzyme in vitro at high concentrations.1, 8, 20
Converted to active metabolite by CYP2C19.1, 72, 78, 80, 81, 82, 83 (See Metabolism under
Pharmacokinetics.) Potential pharmacokinetic (decreased concentrations of active metabolite)
and pharmacodynamic (reduced antiplatelet effects) interaction with inhibitors of CYP2C19.1,
72, 76, 81, 88, 89
Avoid concomitant use of drugs (e.g., omeprazole) known to be potent inhibitors
of CYP2C19.1, 20, 101
Proton-Pump Inhibitors
Potential for reduced systemic exposure to clopidogrel's active metabolite and reduced
antiplatelet effects with certain proton-pump inhibitors (via inhibition of CYP2C19 by
proton-pump inhibitor).1, 20, 72, 73, 74, 84, 86, 88, 89, 91, 100, 101, 102, 103, 106, 107, 109 (See Reduced Efficacy
Associated with Impaired CYP2C19 Function under Cautions and see Drugs Affecting or
Metabolized by Hepatic Microsomal Enzymes under Interactions.) Interaction demonstrated
with omeprazole, but not consistently observed with other proton-pump inhibitors.1, 20, 72, 79, 84,
88, 102, 103, 106, 109
Conflicting data on clinical outcomes reported, but increased risk of adverse
cardiovascular events possible.1, 72, 73, 74, 81, 91, 98, 102, 103, 104, 105, 107, 108, 110, 111, 112, 113, 115, 119
Based on currently available information, FDA and manufacturer of clopidogrel state that
concomitant use (including separation of administration times) of clopidogrel and omeprazole
should be avoided.1, 100, 101, 113 FDA also states that esomeprazole should be avoided in patients
receiving clopidogrel because of its potent CYP2C19-inhibitory activity.101 Extent to which
other proton-pump inhibitors, which differ in CYP2C19-inhibitory potency, also may
interfere with clopidogrel's effects is unknown.100, 106, 114 If concomitant proton-pump inhibitor
therapy is considered necessary, pantoprazole (which appears to be the weakest inhibitor of
CYP2C19 among proton-pump inhibitors) has been suggested by some clinicians.81, 89, 92, 102,
103, 109, 111, 112, 114
However, weigh risks and benefits of concomitant use of any proton-pump
inhibitor in individual patients.102, 103, 112, 119 American College of Cardiology
Foundation/American College of Gastroenterology/American Heart Association
(ACCF/ACG/AHA) states that use of a proton-pump inhibitor concomitantly with dual
antiplatelet therapy may provide the optimal balance of risk and benefit in patients with acute
coronary syndrome (ACS) who have a history of upper GI bleeding.136 Risk/benefit tradeoff
may favor concomitant use of dual antiplatelet therapy and a proton-pump inhibitor in stable
patients with a history of GI bleeding who undergo coronary revascularization and receive a
coronary stent.136 ACCF/ACG/AHA states that the risk reduction with proton-pump inhibitors
is substantial in patients with risk factors for GI bleeding (e.g., advanced age; concomitant
use of warfarin, corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIDs); H. pylori
infection) and may outweigh potential reduction in cardiovascular efficacy of antiplatelet
treatment associated with a drug-drug interaction.136 In patients without such risk factors for
GI bleeding, risk/benefit balance may favor use of antiplatelet therapy without a concomitant
proton-pump inhibitor.136 Alternatively, consider concomitant therapy with antacids or H2receptor antagonists (i.e., ranitidine, famotidine, nizatidine), except for cimetidine (also a
potent CYP2C19 inhibitor).1, 81, 89, 92, 100, 103, 112
Specific Drugs
Drug
Antacids
Cilostazol
Dexlansoprazole
Esomeprazole
Interaction
Currently no evidence that
antacids interfere with
antiplatelet effects of
clopidogrel101
Potential additive antiplatelet
effects93, 94
Pharmacokinetic interaction
unlikely19, 93
Reduced efficacy observed with
concomitant clopidogrel and
omeprazole; extent to which
other proton-pump inhibitors
also may interfere with
clopidogrel's effects is
unknown1, 100, 101, 106, 114
Possible decreased plasma
concentrations of clopidogrel's
Comments
Lansoprazole
NSAIAs
Omeprazole
Pantoprazole
Rabeprazole
Warfarin
Use caution6, 8
Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed after oral administration;1 at least 50% of an oral dose is absorbed.1 Peak
plasma concentrations of the active metabolite occur approximately 30-60 minutes following
an oral dose.1
Onset
Brand
Names
Manufacturer
Plavix
300 mg (of
clopidogrel)
Plavix
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 10/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
Plavix 300MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$749.95 or
90/$2,199.95
Plavix 75MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$195.99 or 90/$565.97
Use is not currently included in the labeling approved by the US Food and Drug
Administration.
Ticlopidine (Systemic)
Introductory Information
Platelet-aggregation inhibitor;1, 2 thienopyridine derivative.1, 2, 48 49, 50, 52, 71
Class: 20:12.18 Platelet-Aggregation Inhibitors
Brands: Ticlid
Generic Name: Ticlopidine Hydrochloride
CAS Number: 53885-35-1
Chemical Name: 5-[(2-Chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
hydrochloride
Molecular Formula: C14H14ClNSClH
Investigational Drug Number: 4-C-32, 53-32C
Synonym: Panaldine
Boxed Warning
Possible life-threatening adverse hematologic effects (e.g., neutropenia1, 3, 4, 7, 8, 9, 10, 11, 14, 71
and/or agranulocytosis,1, 7, 9, 10, 20, 71 thrombotic thrombocytopenic purpura [TTP],1, 7, 11, 23, 30, 32,
71
aplastic anemia1, 7, 16, 17, 20, 22, 24, 25, 26, 27, 71).
Neutropenia occurred in 2.4% of stroke patients in clinical trials;1, 71 TTP and aplastic anemia
reported rarely.1, 71
Incidence of neutropenia, TTP, or aplastic anemia peaks about 4-6, 3-4, or 4-8 weeks,
respectively, following initiation of therapy and declines thereafter.1, 71 Adverse hematologic
effects occur infrequently >3 months after initiation of therapy.1, 71
Risk factors for development of adverse hematologic effects not identified.1, 71
Careful clinical and hematologic monitoring required, especially during the first 3 months of
Because of potentially life-threatening adverse effects (see Boxed Warning), reserve for
patients who are unable to tolerate or have hypersensitivity to aspirin or those who have
failed to respond to aspirin therapy where indicated to prevent stroke.1, 71
The American College of Chest Physicians (ACCP) does not recommend use of ticlopidine
for stroke prevention;59 instead, clopidogrel is recommended as alternative therapy to aspirin
for stroke prevention because of a more favorable adverse effect profile.59
Prevention of Coronary Artery Stent Thrombosis
Used as an adjunct to aspirin therapy to reduce the incidence of subacute stent thrombosis
after percutaneous coronary intervention (PCI) with successful coronary artery stent
placement.1, 46, 48, 49, 62, 71
ACCP and other clinicians currently recommend use of a thienopyridine derivative (i.e.,
clopidogrel, ticlopidine) as an adjunct to aspirin therapy in patients undergoing PCI and
intracoronary stenting.49, 57, 69 However, clopidogrel is preferred over ticlopidine because of a
more favorable adverse effect profile.48, 49, 57, 62, 66, 69 Some clinicians suggest ticlopidine may
be used in clopidogrel-intolerant patients undergoing PCI.66 In patients undergoing stent
implantation, ACCP suggests use of ticlopidine or clopidogrel over cilostazol in conjunction
with aspirin.69
Acute Coronary Syndromes
Has been used as an alternative to aspirin in patients with unstable angina or non-ST38, 47, 50, 58, 60 62
segment-elevation MI
(i.e., non-ST-segment-elevation acute coronary
syndrome) when aspirin therapy has failed, cannot be tolerated, or is contraindicated.37, 38, 41,
42, 68
elevation MI
, ACCP
suggests administration of a ticlopidine loading dose at least 24 hours prior to planned PCI.62,
68
ACCP suggests 250 mg twice daily for 2 weeks in addition to aspirin when ticlopidine is used
instead of clopidogrel following PCI for placement of a bare-metal stent.48, 62, 66
Some clinicians suggest that a shorter duration of therapy (i.e., 10-14 days) may reduce the
incidence of adverse effects while maintaining efficacy in PCI.49, 68
Geriatric Patients
No specific dosage recommendations at this time.1, 71
Cautions
Contraindications
Known hypersensitivity to ticlopidine.1, 9, 11, 71
Preexisting hematopoietic disorders (e.g., neutropenia, thrombocytopenia, history of TTP or
aplastic anemia).1, 9, 10, 11, 71 (See Hematologic Toxicity under Cautions.)
Hemostatic disorders or active pathologic bleeding (e.g., bleeding peptic ulcer, intracranial
bleeding).1, 9, 10, 11, 71 (See Conditions Predisposing to Bleeding under Cautions.)
Severe hepatic impairment.1, 6, 9, 11, 71
Warnings/Precautions
Warnings
Concomitant Anticoagulant Therapy
Tolerance and long-term safety of concomitant heparin, oral anticoagulants, or fibrinolytic
agents not established; manufacturer recommends discontinuing anticoagulants and
fibrinolytic drugs prior to initiating ticlopidine.1, 71
Metabolic Effects
Possible increased total serum cholesterol concentrations without changes in lipoprotein
subfractions;1, 4, 7, 9, 11, 71 not associated with liver dysfunction or an increase in vascular
ischemic events.4 Also, possible increases in triglyceride concentrations.1, 71
Major Toxicities
Possible life-threatening adverse effects; carefully weigh potential benefit of therapy against
possible risks involved.1, 11, 71 All adverse hematologic effects potentially fatal.1, 71 Reserve
therapy for patients who are unable to tolerate or do not respond adequately to aspirin therapy
where indicated to prevent stroke.1, 11, 59, 71
Hematologic Toxicity
Possible life-threatening adverse hematologic effects including neutropenia (ANC
<1200/mm3)1, 3, 4, 7, 8, 9, 10, 11, 14, 71 and/or agranulocytosis,1, 7, 9, 10, 20, 71 thrombocytopenia
(platelet count <80,000/mm3),1, 7, 10, 11, 14, 71 TTP (i.e., fever, weakness, pallor, petechiae or
purpura, dark urine, jaundice, neurologic changes, and/or acute, unexplained decreases in
hemoglobin or platelet count),1, 7, 11, 23, 30, 32, 71 and aplastic anemia (i.e., anemia,
thrombocytopenia, and neutropenia together with evidence of depression of myeloid
precursors on bone marrow examination).1, 7, 16, 17, 20, 22, 24, 25, 26, 27, 71
Pancytopenia or leukemia, sometimes fatal, reported rarely during postmarketing
experience.1, 71
Perform CBCs (including platelet count) and leukocyte differentials prior to initiation of
therapy and every 2 weeks to the end of the third month of therapy;1, 4, 7, 8, 10, 71 continue
monitoring for at least two weeks following discontinuance of ticlopidine within the first 3
months of therapy.1, 71 Monitor more frequently or continue monitoring after the first 3
months of therapy if clinical manifestations (e.g., suggestive of or consistent with infection)
or laboratory evidence (e.g., neutrophil count <70% of baseline count, decrease in hematocrit
or platelet count) suggest incipient adverse hematologic effects.1, 71 Discontinue therapy
immediately if laboratory testing confirms neutropenia (<1200/mm3), TTP, aplastic anemia,
or thrombocytopenia (platelet count <80,000/mm3).1, 8, 11, 71 Initiate prompt treatment for TTP
(e.g., plasmapheresis) and aplastic anemia (i.e., hematopoietic agents).1, 71
Use contraindicated in patients with preexisting hematopoietic disorders such as neutropenia
and thrombocytopenia or a history of either TTP or aplastic anemia.1, 9, 10, 11, 71
Compliance with Therapy in Patients with Drug-eluting Stents
Stent thrombosis with potentially fatal sequelae, particularly with DES, associated with
premature discontinuance of therapy with a thienopyridine derivative and aspirin.70, a, b, c, d, e, f,
g
Before implantation of a DES, carefully assess patients for likelihood of compliance with
prolonged dual-drug antiplatelet therapy.70, h Consider avoiding use of a DES in patients who
are not expected to comply.70, h (See Advice to Patients.) In patients who are likely to require
invasive or surgical procedures 12 months after DES implantation, consider implantation of
a bare-metal stent or use of balloon angioplasty with provisional stent implantation instead.70
Clinicians performing invasive procedures must understand the consequences of premature
discontinuance of thienopyridine derivative therapy in patients with DES.70 If issues about a
patient's antiplatelet therapy are unclear (e.g., concern about periprocedural bleeding), such
professionals should contact the patient's cardiologist.70 Defer elective procedures with
substantial bleeding risk until completion of dual-drug antiplatelet therapy.70 For non-elective
procedures that mandate discontinuance of thienopyridine-derivative therapy, continue
aspirin therapy if at all possible.70 Restart thienopyridine therapy as soon as possible after the
procedure.70
General Precautions
Trauma, Surgery, or Other Pathologic Conditions
Use with caution in patients at risk for increased bleeding from trauma, surgery, or other
pathologic conditions.1, 71 Discontinue therapy 10-14 days prior to elective surgery to
minimize excessive surgical bleeding.1, 28, 33, 71 Administer IV methylprednisolone (20 mg) to
normalize prolonged bleeding time1, 10, 28, 71 or platelet transfusions to reverse effect on
bleeding.1, 33, 71 Avoid administering platelets in patients who have had TTP secondary to
ticlopidine therapy; such transfusions may accelerate thrombosis.1, 33, 71
Interaction
Decreased plasma ticlopidine
concentrations1, 71
Aspirin, other
NSAIAs
Digoxin
Phenobarbital
Phenytoin
Propranolol
Theophylline
Thrombolytic
agents
1, 71
Comments
Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed (>80%) following oral administration.1 Peak plasma concentrations at 2
hours.1, 71
Food
Increases bioavailability by 20%.1, 71
Distribution
Plasma Protein Binding
Binds reversibly (98%), mainly to serum albumin and lipoproteins.1, 71
Elimination
Metabolism
Extensively metabolized by the liver.1, 71
Elimination Route
Excreted in urine (60%) and feces (23%).1, 71
Special Populations
Increased plasma concentrations in patients with advanced cirrhosis.1, 71 Decreased plasma
clearance in patients with mild to moderate renal impairment.1, 71
Stability
Storage
Oral
Tablets
15-30C1 or 20-25C.71
Actions
Structurally and pharmacologically related to clopidogrel.1, 2, 48 49, 50, 52, 71
Time- and dose-dependent inhibition of platelet aggregation and release of platelet granule
constituents; also prolongs bleeding time.1, 71
Inhibits ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet
interactions.1, 71
Platelet effects irreversible for the life of the platelet.1, 71
Advice to Patients
Importance of routine laboratory monitoring (e.g., CBCs, leukocyte differential, platelet
counts).1, 3, 9, 11, 33, 71
Importance of informing patients of potential adverse effects and toxicities.1, 71 Importance of
immediately informing clinician of signs or symptoms of these adverse effects.1, 8, 9, 11, 71
Importance of immediately discontinuing therapy and contacting clinician if any
manifestations suggestive of aplastic anemia (e.g., fever, weakness, pallor, bruising, bleeding
from gums or nose, excessive fatigue) or TTP (e.g., fever, weakness, difficulty speaking,
seizures, jaundice, dark or bloody urine, pallor, petechiae) occur.1, 71
Before implantation of drug-eluting stent (DES), determine likelihood of patient compliance
with 12 months of aspirin-ticlopidine combination therapy.70
Importance of informing patients prior to hospital discharge about risks associated with
premature discontinuance of such combination therapy.70 Importance of informing patient not
to discontinue therapy without consulting their prescribing clinician, even if instructed to do
so by another health-care professional (e.g., dentist).70
Importance of patients informing clinicians and dentists that they are receiving ticlopidine
prior to scheduling of any surgery or prescription of any new drug.1, 9, 11, 71
Importance of informing clinicians of existing or contemplated concomitant therapy, including
prescription and OTC drugs.1, 71
Importance of women informing clinicians if they are or plan to become pregnant or plan to
breast-feed.1, 71
Importance of informing patients of other important precautionary information. (See
Cautions.)1, 3, 9, 11, 33, 71
Preparations
Excipients in commercially available drug preparations may have clinically important effects
in some individuals; consult specific product labeling for details.
Ticlopidine Hydrochloride
Routes Dosage Forms
Oral
Tablets, film-coated
Strengths
250 mg
Brand Names
Ticlid (with povidone)
Manufacturer
Roche
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
Ticlopidine HCl 250MG Tablets (TEVA PHARMACEUTICALS USA): 100/$179.99 or
300/$509.96
Use is not currently included in the labeling approved by the US Food and Drug
Administration.
Gemfibrozil (Systemic)
Introductory Information
Antilipemic agent; fibric acid derivative.2
Class: 24:06.06 Fibric Acid Derivatives; cv350 (VA primary)
Brands*: Lopid
*
Uses
Prevention of Cardiovascular Events
Adjunct to dietary therapy to reduce the risk of developing CHD in patients with type IIb
hyperlipoproteinemia without clinical evidence of CHD (primary prevention) who have an
inadequate response to dietary management, weight loss, exercise, and drugs known to
reduce LDL-cholesterol and increase HDL-cholesterol (e.g., bile acid sequestrants, niacin)
and who have low HDL-cholesterol concentrations in addition to elevated LDL-cholesterol
and triglycerides.1, 67, 68, 104, 105, 110, 127
Because of potential toxicity, including malignancy, gallbladder disease, abdominal pain
leading to appendectomy and other abdominal surgeries, and an increased incidence of
noncardiovascular and all-cause mortality associated with the chemically and
pharmacologically similar drug, clofibrate (no longer commercially available in the US), the
potential benefit of gemfibrozil in treating patients with type IIa hyperlipoproteinemia and
elevations of LDL-cholesterol only is unlikely to outweigh the risks of such therapy.1
Manufacturer states that gemfibrozil is not indicated for use in the management of patients
with low HDL-cholesterol as their only lipid abnormality (isolated low HDL-cholesterol).1
Reduction of recurrent coronary events
and stroke in men with clinical evidence of CHD who have low HDL-cholesterol and
moderately elevated LDL-cholesterol concentrations.137
Dyslipidemias
Adjunct to dietary therapy in the management of severe hypertriglyceridemia in patients at
risk of developing pancreatitis (typically those with serum triglyceride concentrations >2000
mg/dL and elevated concentrations of VLDL-cholesterol and fasting chylomicrons) who do
not respond adequately to dietary management.1
Also may be used in patients with triglyceride concentrations of 1000-2000 mg/dL who have
a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis;1 however,
efficacy in patients with type IV hyperlipoproteinemia and triglyceride concentrations >1000
mg/dL who exhibit type V patterns subsequent to dietary or alcoholic indiscretion has not
been adequately studied.1
Manufacturer states that gemfibrozil is not indicated for use in patients with type I
hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but
normal VLDL-cholesterol concentrations.1
Effective in a very limited number of patients with type III hyperlipoproteinemia
17, 18,
Interaction
Possible increase in serum
triglyceride and decreases in
HDL-cholesterol
concentrations30, 74
Comments
HMG-CoA
reductase
inhibitors
(Statins)
Methyldopa
Repaglinide
Increased repaglinide
concentrations and half-life,
resulting in enhanced and
prolonged blood glucoselowering effects.138, 139
Potential for severe
hypoglycemia.138
Rate and extent of absorption increased when administered 30 minutes before meals.1
Distribution
Extent
Highest tissue concentrations observed in the liver and kidneys in animals.2
Gemfibrozil crosses the placenta;2 not known if it is distributed into milk.1, 102
Plasma Protein Binding
About 95%.2
Elimination
Metabolism
Appears to be metabolized in the liver to 4 major metabolites produced via 3 metabolic
pathways.2, 7, 102 A phenol derivative (metabolite I)2, 7 is pharmacologically active.102
Elimination Route
Excreted in urine (70%) in the form of metabolites and in feces (approximately 6%).1
Half-life
1.3-1.5 hours.1, 7, 9, 10
Stability
Storage
Oral
Tablets
20-25C.1 Protect from light and humidity.1
Actions and Spectrum
Decreases serum concentrations of triglycerides,1, 15, 16, 17, 18, 19, 21, 22, 23, 24, 26, 27, 28, 29, 30, 32, 33, 37, 38,
45, 48, 76, 91, 104
VLDL-cholesterol,1, 15, 17, 18, 19, 25, 33, 37, 38, 45, 48, 76 and, to a lesser extent, LDLcholesterol.1, 15, 33, 37, 38, 45, 76 Increases HDL-cholesterol.1, 15, 16, 19, 21, 22, 24, 25, 26, 31, 32, 33, 36, 38, 45, 88,
91
Causes a variable reduction in serum total cholesterol,1, 15, 16, 17, 18, 19, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32,
33, 37, 38, 48, 68, 105, 106
because the decrease in serum cholesterol is a net result of a decrease in
VLDL-cholesterol,18, 19, 21, 25, 26, 28, 32, 33, 38, 45 an increase in HDL-cholesterol,37, 68 and an
increase15, 21, 30, 33, 37, 45, 91 or decrease in LDL-cholesterol.21, 24, 26, 32, 37, 38, 45
Generally increases LDL-cholesterol in patients with type IV or V hyperlipoproteinemia and
decreases LDL-cholesterol in type IIa or IIb disorder.21, 25, 28, 45, 91
Inhibits lipolysis of fat in adipose tissue1, 54, 56, 75, 76, 91 and decreases hepatic uptake of plasma
free fatty acids1, 54, 75, 76 (i.e., free fatty acid turnover is decreased),51, 54, 75 thereby reducing
hepatic triglyceride production1, 54, 75, 76 (triglyceride turnover rate is decreased).51, 75 Also
inhibits production1, 15, 54, 75, 91 and increases clearance1, 75, 102 of VLDL carrier apolipoprotein
B (VLDL-apo B), leading to a decrease in VLDL production,1, 15, 45, 54, 75 enhanced clearance
of VLDL,15 and, subsequently, a decrease in serum triglyceride concentrations.2, 54, 91
Advice to Patients
Manufacturer
Mylan, Sandoz, Teva,
Watson
Hg) is 62, 80, or 85% with valsartan alone, amlodipine alone, or amlodipine combined with
valsartan, respectively.113
Administration
Oral Administration
Administer amlodipine orally without regard to meals.1, 2, 3, 5
Dosage
Amlodipine is available as amlodipine besylate; dosage expressed in terms of amlodipine.1
Pediatric Patients
Hypertension
>Amlodipine Therapy for Hypertension
Oral: Children 6 years of age: Usual effective amlodipine dosage is 2.5-5 mg once daily.1,
105
Adults
Hypertension
>Amlodipine Therapy for Hypertension
Oral: Initially as monotherapy, amlodipine 2.5-5 mg once daily.1, 2, 4, 6, 49 In small or frail
individuals, initiate therapy with 2.5 mg once daily.1
When adding amlodipine to an existing antihypertensive regimen, use initial dosage of 2.5
mg once daily.1
Increase amlodipine dosage gradually over 7-14 days until optimum control of BP is obtained
(up to a maximum dosage of 10 mg daily).1 May increase more rapidly if symptoms so
warrant and patient's tolerance and response are frequently assessed.1
Usual maintenance dosage of amlodipine is 5-10 mg once daily.1, 2, 6, 12, 49
>Amlodipine/Benazepril Fixed-combination Therapy for Hypertension
Oral: In studies using amlodipine/benazepril fixed combination in dosages of amlodipine 2.510 mg daily and benazepril hydrochloride 10-40 mg daily, BP response increased with
increasing amlodipine dosage in all patient groups and increased with increasing benazepril
dosage in nonblack patient groups.21
If BP is not adequately controlled by monotherapy with amlodipine (or another
dihydropyridine-derivative calcium-channel blocker) or benazepril (or another ACE
inhibitor), can switch to amlodipine/benazepril fixed combination.21
If BP is adequately controlled by monotherapy with amlodipine, but edema has developed,
can switch to amlodipine/benazepril fixed combination to achieve similar or better BP control
without edema.21 May be prudent to reduce amlodipine dosage, especially in nonblack
patients, when benazepril is initiated to avoid excessive antihypertensive response.21
If BP is controlled with amlodipine and benazepril (administered separately), can switch to
the fixed-combination preparation containing the corresponding individual doses for
convenience.21
Adjust dosage of amlodipine/benazepril fixed combination according to patient's response;
consider that steady-state plasma concentrations of amlodipine and benazepril are reached
after 7 and 2 days, respectively.21
In small or frail patients, initial amlodipine dosage of 2.5 mg (available in fixed combination
with benazepril hydrochloride 10 mg) once daily.21
CAD
>Amlodipine Therapy for Angina
Oral: Usual amlodipine dosage is 5-10 mg once daily;1, 2 adequate control usually requires a
maintenance dosage of 10 mg daily.1
>Amlodipine Therapy for Angiographically Documented CAD
Oral: Recommended amlodipine dosage is 5-10 mg once daily;1 adequate control usually
requires a maintenance dosage of 10 mg daily.1
>Amlodipine/Atorvastatin Fixed-combination Therapy for CAD (Amlodipine) and for
Dyslipidemias and Prevention of Cardiovascular Events (Atorvastatin)
Oral: Use the fixed combination as a substitute for the individually titrated drugs.107 Can
switch to the fixed-combination preparation containing the corresponding individual doses of
amlodipine and atorvastatin; alternatively, can increase the dosage of one or both components
for additional antianginal and/or antilipemic effects.107
Use the fixed combination to provide additional therapy for patients currently receiving one
component of the preparation.107 Select initial dosage of the fixed combination based on the
current dosage of the component being used and the recommended initial dosage for the
added monotherapy.107
Use the fixed combination to initiate treatment in patients requiring therapy for angina and
dyslipidemias.107 Select initial dosage of the fixed combination based on recommended
dosages of the individual components.107
Prescribing Limits
Pediatric Patients
Hypertension
Oral: Children 6 years of age: Safety and efficacy of amlodipine dosages >5 mg daily not
established.1
Adults
Hypertension
Oral: Maximum 10 mg of amlodipine once daily.1, 107, 112, 113
Special Populations
The following information addresses dosage of amlodipine in special populations. Dosages of
drugs administered in fixed combination with amlodipine also may require adjustment in
certain patient populations; the need for such dosage adjustments must be considered in the
context of cautions, precautions, and contraindications specific to that population and drug.21,
107, 112, 113
Hepatic Impairment
Hypertension
Initially, amlodipine 2.5 mg daily (as initial or add-on therapy).1, 21, 107, 112
Angina
Initially, amlodipine 5 mg daily.1, 107
Renal Impairment
Amlodipine dosage modification not necessary.1, 2, 3, 5, 112, 113
Safety and efficacy of amlodipine in children <6 years of age not established.1
Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril,
olmesartan, or valsartan not established in children.21, 107, 112, 113
Geriatric Use
Select amlodipine dosage with caution; initiate with dosage at lower end of recommended
range.1, 21, 112, 113 (See Geriatric Patients under Dosage and Administration and see Special
Populations under Pharmacokinetics.)
Amlodipine in fixed combination with benazepril, olmesartan, or valsartan: No substantial
differences in safety and efficacy relative to younger adults, but increased sensitivity cannot
be ruled out.21, 112, 113
Amlodipine in fixed combination with atorvastatin: Safety and efficacy not established in
geriatric patients.107
Hepatic Impairment
Use amlodipine with caution and consider dosage reduction in patients with severe hepatic
impairment.1, 21, 112, 113 (See Hepatic Impairment under Dosage and Administration and see
Special Populations under Pharmacokinetics.)
Common Adverse Effects
Amlodipine: Headache, edema.1 Edema may be less frequent with concomitant benazepril or
olmesartan therapy.21 112
Interactions
The following information addresses potential interactions with amlodipine. When
amlodipine is used in fixed combination with atorvastatin, benazepril, olmesartan, or
valsartan, consider interactions associated with the concomitant agent.21, 107, 112, 113
Specific Drugs and Food
Drug or Food
Alcohol
Antacids (e.g., aluminum hydroxide
and magnesium hydroxide)
Atorvastatin
Cimetidine
Digoxin
Grapefruit juice
Sildenafil
Warfarin
Interaction
No change in alcohol pharmacokinetics1
Pharmacokinetic interaction unlikely1
No clinically important change in atorvastatin
pharmacokinetics1
Pharmacokinetic interaction unlikely1
No effects on serum digoxin concentrations or
clearance1
Altered bioavailability possible;64, 65, 74, 75 no clinically
important changes in another study1
Pharmacokinetic interaction unlikely; additional
reduction of BP possible1
No change in PT1
Pharmacokinetics
Absorption
Bioavailability
Peak plasma amlodipine concentrations attained 6-12 hours after oral administration.1
Absolute bioavailability ranges from 64-90%.1
Duration
Antihypertensive effects of amlodipine persist for at least 24 hours after administration.1
Food
Food does not affect bioavailability of amlodipine besylate tablets.1
Distribution
Extent
Not known whether amlodipine is distributed into milk.1
Plasma Protein Binding
Amlodipine: Approximately 93%.1
Elimination
Metabolism
Amlodipine is extensively metabolized to inactive metabolites in the liver.1
Elimination Route
Amlodipine is excreted in urine as metabolites (60%) and unchanged drug (10%).1
Half-life
Terminal elimination half-life of amlodipine is 30-50 hours.1
Special Populations
In geriatric patients, amlodipine clearance decreased and AUC increased about 40-60%.1
In patients with hepatic impairment, amlodipine clearance decreased and AUC increased
about 40-60%.1
In patients with moderate to severe heart failure, amlodipine clearance decreased and AUC
increased about 40-60%.1
Stability
Storage
Oral
Tablets
Amlodipine: Tight, light-resistant containers at 15-30C.1
Amlodipine/atorvastatin, amlodipine/olmesartan, and amlodipine/valsartan fixed
combinations: 25C (may be exposed to 15-30C).107, 112, 113
Capsules
Amlodipine/benazepril fixed combination: Tight container at 25C (may be exposed to 1530C).21
Actions
Amlodipine inhibits transmembrane influx of extracellular calcium ions across the membranes
of myocardial cells and vascular smooth muscle cells, without changing serum calcium
concentrations.1
Amlodipine is a peripheral arterial vasodilator; acts directly on vascular smooth muscle
causing reduction in peripheral vascular resistance and BP.1
Amlodipine reduces total peripheral resistance (afterload) and rate pressure product and thus
myocardial oxygen demand at any given level of exercise in patients with exertional angina.1
Amlodipine blocks constriction and restores blood flow in coronary arteries in response to
calcium, potassium, epinephrine, serotonin, and thromboxane A2 analog in animal studies and
human vessels in vitro.1
Advice to Patients
When amlodipine is used in fixed combination with atorvastatin, benazepril, olmesartan, or
valsartan, importance of informing patients of important cautionary information about the
concomitant agent.21, 107, 112, 113
Importance of informing clinicians of existing or contemplated concomitant therapy, including
prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to
breast-feed.1
Importance of advising patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects
in some individuals; consult specific product labeling for details.
Amlodipine Besylate
Routes Dosage Forms Strengths
Brand Names
Oral Tablets
2.5 mg (of amlodipine)* Amlodipine Besylate Tablets
Norvasc
5 mg (of amlodipine)* Amlodipine Besylate Tablets
Norvasc
10 mg (of amlodipine)* Amlodipine Besylate Tablets
Norvasc
Amlodipine Besylate Combinations
Dosage
Routes
Strengths
Forms
2.5 mg (of amlodipine) with
Oral Capsules Benazepril Hydrochloride
10 mg*
Brand Names
Amlodipine Besylate and
Benazepril Hydrochloride
Capsules (combination)
Manufacturer
Pfizer
Pfizer
Pfizer
Manufacturer
Lotrel (combination)
Amlodipine Besylate and
Benazepril Hydrochloride
Capsules (combination)
Lotrel (combination)
Amlodipine Besylate and
Benazepril Hydrochloride
Capsules (combination)
Lotrel (combination)
Novartis
Lotrel (combination)
Novartis
Novartis
Lotrel (combination)
Novartis
Azor (combination)
DaiichiSankyo
Azor (combination)
DaiichiSankyo
Azor (combination)
DaiichiSankyo
Azor (combination)
DaiichiSankyo
Caduet (combination)
Pfizer
Caduet (combination)
Pfizer
Caduet (combination)
Pfizer
Caduet (combination)
Pfizer
Caduet (combination)
Pfizer
Caduet (combination)
Pfizer
Novartis
Novartis
(of atorvastatin)
5 mg (of amlodipine) with
Atorvastatin Calcium 80 mg Caduet (combination)
Pfizer
(of atorvastatin)
5 mg (of amlodipine) with
Exforge (combination)
Novartis
Valsartan 160 mg
5 mg (of amlodipine) with
Exforge (combination)
Novartis
Valsartan 320 mg
10 mg (of amlodipine) with
Atorvastatin Calcium 10 mg Caduet (combination)
Pfizer
(of atorvastatin)
10 mg (of amlodipine) with
Atorvastatin Calcium 20 mg Caduet (combination)
Pfizer
(of atorvastatin)
10 mg (of amlodipine) with
Atorvastatin Calcium 40 mg Caduet (combination)
Pfizer
(of atorvastatin)
10 mg (of amlodipine) with
Atorvastatin Calcium 80 mg Caduet (combination)
Pfizer
(of atorvastatin)
10 mg (of amlodipine) with
Exforge (combination)
Novartis
Valsartan 160 mg
10 mg (of amlodipine) with
Exforge (combination)
Novartis
Valsartan 320 mg
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Atorvastatin (Systemic)
Introductory Information
Atorvastatin is an antilipemic agent; hydroxymethylglutaryl-CoA (HMG-CoA) reductase
inhibitor (i.e., statin).1, 18
Class: 24:06.08 HMG-CoA Reductase Inhibitors; cv350 (VA primary)
Brands: Caduet (combination), Lipitor
Generic Name: Atorvastatin Calcium
CAS Number: 134523-03-08
Molecular Formula: C33H35O5 1/2Ca
Investigational Drug Number: CI-981
Special Alerts:
[Posted 09/30/2008] An FDA analysis provides new evidence that the use of statins does not
increase incidence of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease often
referred to as "Lou Gehrig's Disease." The FDA analysis, undertaken after the agency
received a higher than expected number of reports of ALS in patients on statins, is based on
data from 41 long-term controlled clinical trials. The results showed no increased incidence
of the disease in patients treated with a statin compared with placebo.
The FDA is anticipating the completion of a case-control or epidemiological study of ALS
and statin use. Results from this study should be available within 6-9 months. FDA is also
examining the feasibility of conducting additional epidemiologic studies to examine the
incidence and clinical course of ALS in patients taking statins.
Based on currently available information, health care professionals should not change their
prescribing practices for statins and patients should not change their use of statins. For more
information visit the FDA website at: [Web].
Pending revision, the material in this section should be considered in light of more recently
available information in the MEDWATCH notification at the beginning of this monograph.
Uses
Pending revision, the material in this section should be considered in light of more recently
available information in the MEDWATCH notification at the beginning of this monograph.
Prevention of Cardiovascular Events
Atorvastatin is used to reduce the risk of MI, stroke, or angina and the risk of undergoing
revascularization procedures in patients without clinical evidence of CHD who have multiple
risk factors (e.g., age, smoking, hypertension, low HDL-cholesterol concentrations, family
history of early CHD).1, 65
Atorvastatin is used to reduce the risk of MI or stroke in patients without clinical evidence of
CHD who have type 2 diabetes mellitus and other risk factors (e.g., smoking, hypertension,
retinopathy, microalbuminuria, macroalbuminuria).1, 65
Atorvastatin is used to reduce the risk of nonfatal MI, fatal and nonfatal stroke, angina, or
hospitalization for CHF, and the risk of undergoing revascularization procedures in patients
with clinical evidence of CHD.1, 65
Atorvastatin has been used to slow the progression of coronary atherosclerosis
in
composite risk of death or major cardiovascular events for atorvastatin compared with
8, 38, 39
.21, 37
Pediatric Patients
Dyslipidemias
>Atorvastatin Therapy for Heterozygous Familial Hypercholesterolemia
Oral: Children 10 years of age: Initially, atorvastatin 10 mg once daily.1
Adjust atorvastatin dosage at intervals 4 weeks until the desired effect on lipoprotein
concentrations is observed or a daily dosage of 20 mg is reached.1
Adults
Dyslipidemias and Prevention of Cardiovascular Events
>Atorvastatin Therapy for Primary Hypercholesterolemia (Heterozygous Familial and
Nonfamilial) and Mixed Dyslipidemia
Oral: Initially, atorvastatin 10 or 20 mg once daily; patients who require a large reduction in
LDL-cholesterol concentration (>45%) may receive 40 mg once daily.1 Determine serum
lipoprotein concentrations within 2-4 weeks after initiating and/or titrating therapy and adjust
dosage accordingly.1 Usual maintenance dosage of atorvastatin is 10-80 mg once daily.1
>Atorvastatin Therapy for Homozygous Familial Hypercholesterolemia
Oral: Atorvastatin 10-80 mg once daily.1
Pending revision, the material in this section should be considered in light of more recently
available information in the MEDWATCH notification at the beginning of this monograph.
Fetal/Neonatal Morbidity and Mortality
Suppression of cholesterol biosynthesis could cause fetal harm.1 Congenital anomalies
following intrauterine exposure to statins reported rarely.1
Administer atorvastatin to women of childbearing age only when such patients are highly
unlikely to conceive and have been informed of the potential hazards.1 If the patient becomes
pregnant while taking the drug, discontinue therapy and apprise the patient of the potential
hazard to the fetus.1
Hepatic Effects
Atorvastatin is associated with increases in serum aminotransferase (AST, ALT)
concentrations.1
Possible pancreatitis,1 hepatitis,1 cholestatic jaundice,1 and biliary pain.1 Fatty change in liver,
increased serum alkaline phosphatase concentrations, increased serum -glutamyl
transpeptidase concentrations, increased bilirubin concentrations, and, rarely, cirrhosis,
fulminant hepatic necrosis, and hepatoma have been reported with other statins.
Perform liver function tests before and at 12 weeks after initiation of atorvastatin therapy or
any increase in dosage and periodically (e.g., semiannually) thereafter.1
Patients who develop increased serum AST/ALT concentrations or manifestations of liver
disease should receive frequent liver function tests thereafter until the abnormalities return to
normal.1 If increases in AST or ALT concentrations of >3 times the upper limit of normal
(ULN) persist, reduce atorvastatin dosage or discontinue therapy.1
The National Lipid Association (NLA) statin safety assessment task force recommends that
clinicians be alert to signs and symptoms of hepatotoxicity (e.g., jaundice, malaise, fatigue,
lethargy, hepatomegaly, increased indirect bilirubin concentrations, elevated PT). If
substantial hepatotoxicity is suspected, discontinue statin therapy, determine etiology, and
refer patient to a gastroenterologist or hepatologist if indicated.
Musculoskeletal Effects
Myopathy (manifested as muscle pain, tenderness, or weakness and CK [CPK] concentration
increases >10 times the ULN) has been reported with atorvastatin.1
Rhabdomyolysis (characterized by muscle pain or weakness with marked increases [>10
times the ULN] in serum CK concentrations and increases in Scr [usually accompanied by
brown urine and urinary myoglobinuria]) with acute renal failure secondary to myoglobinuria
has been reported with atorvastatin.1
Risk of myopathy increased in patients receiving higher doses of statins; in patients with
multisystem disease (e.g., renal or hepatic impairment); in patients with concurrent serious
infections or hypothyroidism; in patients (particularly women) of advanced age (especially
>80 years of age); in patients with small body frame and frailty; and in patients undergoing
surgery (i.e., during perioperative periods). Risk also may be increased by concomitant
administration of cyclosporine, niacin, fibric acid derivatives, macrolide antibiotics (e.g.,
clarithromycin, erythromycin), certain azole antifungals, HIV protease inhibitors (e.g.,
ritonavir plus saquinavir, lopinavir plus ritonavir), alcohol, and large quantities (>1 quart
daily) of grapefruit juice.1 (See Interactions.)
Measure baseline serum CK concentrations prior to initiation of therapy, particularly in
patients at high risk of developing musculoskeletal toxicity (e.g., geriatric patients, black
men, patients receiving concomitant therapy with myotoxic drugs).
Obtain serum CK concentrations and compare with baseline concentrations in patients
presenting with musculoskeletal symptoms suggestive of myopathy; because hypothyroidism
may be a predisposing factor, TSH concentrations also should be obtained in such patients.
Discontinue atorvastatin if serum CK concentrations become markedly elevated or if
myopathy is diagnosed or suspected.1
Monitor patients weekly if myalgia (muscle pain, tenderness) is present with either no CK
elevation or a moderate elevation (3-10 times the ULN) until manifestations improve;
discontinue statin therapy if manifestations worsen.
Dosage reduction or temporary discontinuance of statin therapy may be prudent in patients
with muscle discomfort and/or weakness in the presence of progressive elevation of CK
concentrations on serial measurements.
Temporarily withhold or discontinue atorvastatin therapy in any patient experiencing an acute
or serious condition suggestive of myopathy or predisposing to the development of renal
failure secondary to rhabdomyolysis (e.g., severe acute infection; hypotension; major
surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; uncontrolled
seizures).1 Initiate IV hydration therapy (in a hospital setting) in patients experiencing
rhabdomyolysis as needed.
General Precautions
Role as Adjunct Therapy
Prior to institution of antilipemic therapy, vigorously attempt to control serum cholesterol by
appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying
disorder that might be the cause of lipid abnormality.1
Renal Effects
NLA recommends performing renal function tests prior to initiating statin therapy; routine
monitoring of Scr and proteinuria is not necessary. If Scr is elevated in the absence of
rhabdomyolysis, may continue statin therapy but dosage adjustment may be necessary per
labeling recommendations. If unexpected proteinuria develops, determine etiology; may
continue therapy but dosage adjustment may be necessary per labeling recommendations.
Peripheral Neuropathy
If manifestations of peripheral neuropathy occur, NLA recommends evaluating patient to rule
out secondary causes (e.g., diabetes mellitus, renal impairment, alcohol abuse, vitamin B12
deficiency, cancer, hypothyroidism, acquired immunodeficiency syndrome [AIDS], Lyme
disease, heavy metal intoxication). If a secondary cause is not identified, discontinue statin
therapy for 3-6 months.
If neurologic manifestations improve over this period, a presumptive diagnosis of statininduced peripheral neuropathy may be made; however, consider reinitiating therapy with a
different statin and dosage.
If neurologic manifestations do not improve during period of discontinuance, reinitiate statin
therapy, taking into consideration the risks and benefits of such therapy.
CNS Effects
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear
cell infiltration of perivascular spaces, have been observed in animals with other statins.1
If manifestations of impaired cognition occur, NLA recommends evaluating patient to rule
out secondary causes. If a secondary cause is not identified, discontinue statin therapy for 1-3
months. If no improvement, reinitiate statin therapy, taking into consideration the risks and
benefits of such therapy.
Ocular Effects
Optic nerve degeneration observed in animals with other statins.1
Use of Fixed Combinations
When atorvastatin is used in fixed combination with amlodipine, consider cautions,
precautions, contraindications, and interactions associated with amlodipine.65 Consider
cautionary information applicable to specific populations (e.g., pregnant or nursing women,
individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed
combination.65
Specific Populations
Pregnancy
Category X.1, 65 (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality,
under Cautions.)
Lactation
Atorvastatin is distributed into milk in animals; may distribute into milk in humans.1 Use not
recommended.1
Pediatric Use
Safety and efficacy of atorvastatin not established in prepubertal children or in children <10
years of age.1 Advise adolescent girls to use effective and appropriate contraceptive methods
during therapy to reduce the likelihood of unintended pregnancy.1
Safety and efficacy of atorvastatin in fixed combination with amlodipine not established in
children.65
Geriatric Use
Mean reductions in LDL-cholesterol concentrations with atorvastatin therapy were slightly
higher in patients 65 years of age compared to younger adults.1 However, no clinically
relevant differences in laboratory abnormalities or rates of discontinuance were reported.1
Caution in patients (particularly women) of advanced age (especially >80 years of age) and in
those with small body frame and frailty.
Safety and efficacy of atorvastatin in fixed combination with amlodipine not established in
geriatric patients.65
Hepatic Impairment
Use atorvastatin with caution in patients who consume substantial amounts of alcohol and/or
have a history of liver disease.1
Atorvastatin is contraindicated in patients with active liver disease or unexplained, persistent
increases in liver function test results.1
Renal Impairment
Atorvastatin dosage modification is not necessary in patients with renal impairment.1
Atorvastatin not studied in patients with end-stage renal disease; hemodialysis not expected
to substantially enhance clearance of the drug.1
Common Adverse Effects
Atorvastatin: GI disturbances (e.g., constipation, flatulence, dyspepsia, abdominal pain,
diarrhea), headache, infection, sinusitis, myalgia, arthralgia, accidental injury, back pain, flu
syndrome, asthenia, allergic reaction (e.g., rash), pharyngitis.1
Interactions
The following information addresses potential interactions with atorvastatin. When
atorvastatin is used in fixed combination with amlodipine, consider interactions associated
with amlodipine.65
Atorvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity.1
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4: Potential pharmacokinetic interaction (variable increases in plasma
atorvastatin concentrations); increased risk of myopathy.1 Carefully monitor patients for
manifestations of unexplained muscle pain, tenderness, or weakness, particularly following
initiation of atorvastatin therapy or an increase in dosage of either drug.1 (See Specific Drugs
under Interactions.)
Inducers of CYP3A4: Potential pharmacokinetic interaction (variable reductions in plasma
atorvastatin concentrations).1 (See Specific Drugs under Interactions.)
Specific Drugs
Drug
Amlodipine
Antacids
Anticoagulants, oral
(e.g., warfarin)
Azole antifungals
Interaction
Modest increase in
atorvastatin exposure1
Decreased plasma
atorvastatin
concentrations1
Pharmacologic interaction
(e.g., increased PT)
unlikely1
Itraconazole: 2.5 to
threefold increase in
Comments
Not clinically relevant1
Cyclosporine
Digoxin
Diltiazem
Efavirenz
atorvastatin AUC1
Increased risk of
myopathy1
Decreased plasma
atorvastatin
concentrations1
Combination of ritonavir
plus saquinavir: Threefold
increase in atorvastatin
HIV protease inhibitors
AUC and increased risk of
(combination of ritonavir
myopathy1
plus saquinavir,
Combination of lopinavir
combination of lopinavir
plus ritonavir: 5.9-fold
plus ritonavir)
increase in atorvastatin
AUC and increased risk of
myopathy1
Macrolide antibiotics
(i.e., clarithromycin,
erythromycin)
Clarithromycin: 4.4-fold
increase in atorvastatin
AUC and increased risk of
myopathy1
Erythromycin: Increased
plasma atorvastatin
concentrations and
increased risk of
myopathy1
Niacin (antilipemic
dosages)
Increased risk of
myopathy1
Oral contraceptives
Increased bioavailability
of norethindrone and
ethinyl estradiol1
Rifampin
Possible variable
reductions in plasma
atorvastatin
concentrations1, 2
Pharmacokinetics
Absorption
Bioavailability
Atorvastatin is rapidly absorbed following oral administration; undergoes extensive first-pass
metabolism in the liver.1
Peak plasma atorvastatin concentrations are attained at 1-2 hours.1
Absolute bioavailability of atorvastatin is 14%.1
Evening administration of atorvastatin is associated with a decrease in the extent of
absorption;1 however, antilipemic activity remains unchanged.1
Onset
A therapeutic response to atorvastatin usually is apparent within 2 weeks; maximal response
occurs within 4 weeks.1
Food
Food decreases rate and extent of absorption of atorvastatin but does not alter antilipemic
effects.1
Distribution
Extent
Statins are distributed mainly to the liver.
Atorvastatin distributes into milk in animals; may distribute into human milk.1
Plasma Protein Binding
Atorvastatin: About 98% (principally albumin).1
Elimination
Metabolism
Atorvastatin is extensively metabolized in the liver,1 mainly by CYP3A4,1 to active
metabolites.1
Elimination Route
Atorvastatin is excreted principally in feces; <2% of a dose excreted in urine.1
Half-life
Atorvastatin: 14 hours.1
Special Populations
Increased plasma atorvastatin concentrations in patients with hepatic impairment (Child-Pugh
class A and B).1
Stability
Storage
Oral
Tablets
Atorvastatin: 20-25C.1
Atorvastatin/amlodipine fixed combination: 25C (may be exposed to 15-30C).65
Actions
Atorvastatin inhibits HMG-CoA reductase, causing subsequent reduction in hepatic cholesterol
synthesis.1 Reduces serum concentrations of total cholesterol, LDL-cholesterol, VLDLcholesterol, apo B, and triglycerides.1
Statins may slow progression of and/or induce regression of atherosclerosis in coronary and/or
carotid arteries; modulate BP in hypercholesterolemic patients with hypertension; and possess
anti-inflammatory activity.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently
available information in the MEDWATCH notification at the beginning of this monograph.
When atorvastatin is used in fixed combination with amlodipine, importance of informing
patients of important cautionary information about amlodipine.65
Strengths
10 mg (of atorvastatin)
20 mg (of atorvastatin)
40 mg (of atorvastatin)
80 mg (of atorvastatin)
Brand Names
Lipitor
Lipitor
Lipitor
Lipitor
Manufacturer
Pfizer
Pfizer
Pfizer
Pfizer
Brand Names
Manufacturer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
amlodipine)
40 mg (of atorvastatin) with
Amlodipine Besylate 2.5 mg (of
amlodipine)
40 mg (of atorvastatin) with
Amlodipine Besylate 5 mg (of
amlodipine)
40 mg (of atorvastatin) with
Amlodipine Besylate 10 mg (of
amlodipine)
80 mg (of atorvastatin) with
Amlodipine Besylate 5 mg (of
amlodipine)
80 mg (of atorvastatin) with
Amlodipine Besylate 10 mg (of
amlodipine)
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer
Caduet
(combination)
Pfizer