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BuSpar (busPIRone) and pristiq (desvenlafaxine) (Major Drug-Drug)
MONITOR CLOSELY: Concomitant use of agents with serotonergic activity such as serotonin
reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, 5-HT1 receptor
agonists, ergot alkaloids, lithium, St. John's wort, phenylpiperidine opioids, dextromethorphan,
and tryptophan may potentiate the risk of serotonin syndrome, which is a rare but serious and
potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A
receptors. Symptoms of the serotonin syndrome may include mental status changes such as
irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction
such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis;
neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and
gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.
MANAGEMENT: In general, the concomitant use of multiple serotonergic agents should be
avoided if possible, or otherwise approached with caution if potential benefit is deemed to
outweigh the risk. Patients should be closely monitored for symptoms of the serotonin syndrome
during treatment. Particular caution is advised when increasing the dosages of these agents. The
potential risk for serotonin syndrome should be considered even when administering
serotonergic agents sequentially, as some agents may demonstrate a prolonged elimination halflife. For example, a 5-week washout period is recommended following use of fluoxetine before
administering another serotonergic agent. If serotonin syndrome develops or is suspected during
the course of therapy, all serotonergic agents should be discontinued immediately and supportive
care rendered as necessary. Moderately ill patients may also benefit from the administration of a
serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed
under consultation with a toxicologist and may require sedation, neuromuscular paralysis,
intubation, and mechanical ventilation in addition to the other measures.
Plavix (clopidogrel) and pristiq (desvenlafaxine) (Moderate Drug-Drug)
MONITOR: Serotonin reuptake inhibitors (SRIs) may potentiate the risk of bleeding in patients
treated with agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin
inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The tricyclic
antidepressant, clomipramine, is also a strong SRI and may interact similarly. Serotonin release
by platelets plays an important role in hemostasis, thus SRIs may alter platelet function and
induce bleeding. Published case reports have documented the occurrence of bleeding episodes in
patients treated with psychotropic agents that interfere with serotonin reuptake. Additional
epidemiological studies have confirmed the association between use of these agents and the
occurrence of upper gastrointestinal bleeding, and concurrent use of NSAIDs or aspirin was
found to potentiate the risk. Preliminary data also suggest that there may be a pharmacodynamic
interaction between SSRIs and oral anticoagulants that can cause an increased bleeding diathesis.
Concomitant administration of paroxetine and warfarin, specifically, has been associated with an
increased frequency of bleeding without apparent changes in the disposition of either drug or
changes in the prothrombin time. Bleeding has also been reported with fluoxetine and warfarin,
while citalopram and sertraline have been reported to prolong the prothrombin time of patients
taking warfarin by about 5% to 8%.
MANAGEMENT: Caution is advised if SRIs or clomipramine are used in combination with
other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic
complications is recommended. Patients should be advised to promptly report any signs of
bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged
bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums
from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.
flomax (tamsulosin) and pristiq (desvenlafaxine) (Moderate Drug-Drug)
MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives,
hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit
hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration
with antihypertensive agents, in particular vasodilators and alpha-blockers, may result in additive
effects on blood pressure and orthostasis.
MANAGEMENT: Caution is advised during coadministration of these agents. Close monitoring
for development of hypotension is recommended. Patients should be advised to avoid rising
abruptly from a sitting or recumbent position and to notify their physician if they experience
dizziness, lightheadedness, syncope, orthostasis, or tachycardia.
hydrocodone (Ingredient of vicodin) and pristiq (desvenlafaxine) (Moderate Drug-Drug)
MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or
synergistically increased in patients taking multiple drugs that cause these effects, especially in
elderly or debilitated patients.
MANAGEMENT: During concomitant use of these drugs, patients should be monitored for
potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should
be counseled to avoid hazardous activities requiring complete mental alertness and motor
coordination until they know how these agents affect them, and to notify their physician if they
experience excessive or prolonged CNS effects that interfere with their normal activities.
cardizem (diltiazem) and pristiq (desvenlafaxine) (Moderate Drug-Drug)
MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives,
hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit
hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration
with antihypertensive agents, in particular vasodilators and alpha-blockers, may result in additive
effects on blood pressure and orthostasis.
MANAGEMENT: Caution is advised during coadministration of these agents. Close monitoring
for development of hypotension is recommended. Patients should be advised to avoid rising
abruptly from a sitting or recumbent position and to notify their physician if they experience
dizziness, lightheadedness, syncope, orthostasis, or tachycardia.
coumadin (warfarin) and pristiq (desvenlafaxine) (Moderate Drug-Drug)
MONITOR: Serotonin reuptake inhibitors (SRIs) may potentiate the risk of bleeding in patients
treated with agents that affect hemostasis such as anticoagulants, platelet inhibitors, thrombin
inhibitors, thrombolytic agents, or agents that commonly cause thrombocytopenia. The tricyclic
antidepressant, clomipramine, is also a strong SRI and may interact similarly. Serotonin release
by platelets plays an important role in hemostasis, thus SRIs may alter platelet function and
induce bleeding. Published case reports have documented the occurrence of bleeding episodes in
patients treated with psychotropic agents that interfere with serotonin reuptake. Additional
epidemiological studies have confirmed the association between use of these agents and the
occurrence of upper gastrointestinal bleeding, and concurrent use of NSAIDs or aspirin was
found to potentiate the risk. Preliminary data also suggest that there may be a pharmacodynamic
interaction between SSRIs and oral anticoagulants that can cause an increased bleeding diathesis.
Concomitant administration of paroxetine and warfarin, specifically, has been associated with an
increased frequency of bleeding without apparent changes in the disposition of either drug or
changes in the prothrombin time. Bleeding has also been reported with fluoxetine and warfarin,
while citalopram and sertraline have been reported to prolong the prothrombin time of patients
taking warfarin by about 5% to 8%.
MANAGEMENT: Caution is advised if SRIs or clomipramine are used in combination with
other drugs that affect hemostasis. Close clinical and laboratory observation for hematologic
complications is recommended. Patients should be advised to promptly report any signs of
bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged
bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums
from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.
lipitor (atorvastatin) and Plavix (clopidogrel) (Moderate Drug-Drug)
MONITOR: The concomitant administration of atorvastatin may reduce the metabolic activation
of the prodrug clopidogrel and its antiplatelet effects. The proposed mechanism is competitive
inhibition of CYP450 3A4 enzymatic activity, which is responsible for the conversion of
clopidogrel to its active metabolite. However, data have been conflicting. In a trial with coronary
stent implant patients receiving clopidogrel 75 mg/day (n=44), the percent platelet aggregation
was 34% with no atorvastatin, 58% with atorvastatin 10 mg, 74% with 20 mg, and 89% with 40
mg. Results from an in vitro study suggest that equimolar concentrations of atorvastatin inhibit
clopidogrel metabolism by more than 90 %. However, in a post hoc analysis of a trial with
percutaneous coronary intervention patients, no statistical differences in the incidence of
bleeding, stroke, myocardial infarction, or death were found at 1 year with concomitant
administration of clopidogrel 75 mg/day and CYP450 3A4-metabolized HMG-CoA reductase
inhibitors (n=1001, atorvastatin, lovastatin, simvastatin, cerivastatin) or other statins (n=158,
pravastatin, fluvastatin).
MANAGEMENT: Until more information is available, monitoring for altered efficacy of
clopidogrel may be advisable if atorvastatin is coadministered with clopidogrel. Pravastatin,
fluvastatin, and rosuvastatin are not metabolized by CYP450 3A4 and are theoretically not
expected to interact with clopidogrel.
coumadin (warfarin) and Plavix (clopidogrel) (Moderate Drug-Drug)
MONITOR: The coadministration of oral anticoagulants with clopidogrel may increase the risk
for bleeding. The safety of these agents in combination has not been established. A study of 43
patients with atrial fibrillation reported that average INR, R- and S-warfarin levels did not
change significantly and bleeding did not occur when clopidogrel 75 mg/day was added to a
stable warfarin regimen for 8 days.
MANAGEMENT: The manufacturer recommends to use caution if these two drugs are given
concomitantly. The clinician may consider closer INR and clinical monitoring in patients
receiving clopidogrel and oral anticoagulants. Patients should be advised to promptly notify their
physician if they experience pain, swelling, headache, dizziness, weakness, prolonged bleeding
from cuts, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or
brown urine, or red or black stools.
hydrocodone (Ingredient of vicodin) and flomax (tamsulosin) (Moderate Drug-Drug)
MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives,
hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit
hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration
with antihypertensive agents, in particular vasodilators and alpha-blockers, may result in additive
effects on blood pressure and orthostasis.
MANAGEMENT: Caution is advised during coadministration of these agents. Close monitoring
for development of hypotension is recommended. Patients should be advised to avoid rising
abruptly from a sitting or recumbent position and to notify their physician if they experience
dizziness, lightheadedness, syncope, orthostasis, or tachycardia.
BuSpar (busPIRone) and flomax (tamsulosin) (Moderate Drug-Drug)
MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives,
hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit
hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration
with antihypertensive agents, in particular vasodilators and alpha-blockers, may result in additive
effects on blood pressure and orthostasis.
MANAGEMENT: Caution is advised during coadministration of these agents. Close monitoring
for development of hypotension is recommended. Patients should be advised to avoid rising
abruptly from a sitting or recumbent position and to notify their physician if they experience
dizziness, lightheadedness, syncope, orthostasis, or tachycardia.
cardizem (diltiazem) and lipitor (atorvastatin) (Moderate Drug-Drug)
MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma
concentrations of HMG-CoA reductase inhibitors that are metabolized by the isoenzyme.
Lovastatin and simvastatin are particularly susceptible because of their low oral bioavailability,
but others such as atorvastatin and cerivastatin may also be affected. High levels of HMG-CoA
reductase inhibitory activity in plasma is associated with an increased risk of musculoskeletal
toxicity. Myopathy manifested as muscle pain and/or weakness associated with grossly elevated
creatine kinase exceeding ten times the upper limit of normal has been reported occasionally.
Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure
secondary to myoglobinuria and may result in death. Clinically significant interactions have been
reported with potent CYP450 3A4 inhibitors such as macrolide antibiotics, azole antifungals,
protease inhibitors and nefazodone, and moderate inhibitors such as amiodarone, cyclosporine,
danazol, diltiazem and verapamil.
MANAGEMENT: Caution is advised if atorvastatin, cerivastatin, lovastatin, simvastatin, or red
yeast rice (which contains lovastatin) is prescribed in combination with a CYP450 3A4 inhibitor.
All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report
any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or
fever. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of
strenuous exercise or if myopathy is otherwise suspected or diagnosed. Fluvastatin, pravastatin,
and rosuvastatin are not expected to interact with CYP450 3A4 inhibitors.
BuSpar (busPIRone) and hydrocodone (Ingredient of vicodin) (Moderate Drug-Drug)
MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or
synergistically increased in patients taking multiple drugs that cause these effects, especially in
elderly or debilitated patients.
MANAGEMENT: During concomitant use of these drugs, patients should be monitored for
potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should
be counseled to avoid hazardous activities requiring complete mental alertness and motor
coordination until they know how these agents affect them, and to notify their physician if they
experience excessive or prolonged CNS effects that interfere with their normal activities.
cardizem (diltiazem) and BuSpar (busPIRone) (Moderate Drug-Drug)
MONITOR: The concomitant administration of diltiazem may increase buspirone levels and the
risk of adverse effects. In one study (n=9), buspirone AUC increased by 5.5-fold and maximum
plasma concentrations increased 4.1-fold after 5 doses of diltiazem. The proposed mechanism is
inhibition of CYP450 3A4 first pass metabolism by diltiazem.
MANAGEMENT: The patient should be monitored carefully for signs of buspirone toxicity
(e.g., drowsiness, dizziness, nervousness, insomnia, headache, nausea, vomiting). Alternatively,
use of a dihydropyridine calcium channel blocker or an anxiolytic which is not a substrate of
CYP450 3A4 may be appropriate.
coumadin (warfarin) and flomax (tamsulosin) (Minor Drug-Drug)
Studies evaluating a potential drug interaction between warfarin and tamsulosin have provided
inconclusive results. The manufacturer recommends caution if these agents are used together.
Clinical and INR/PT monitoring is recommended. Patients should be advised to promptly report
any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness,
prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding
of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.
coumadin (warfarin) and lipitor (atorvastatin) (Minor Drug-Drug)
The manufacturer reports that atorvastatin had no clinically significant effect on prothrombin
time when given to patients also receiving chronic warfarin therapy. The clinical utility of the
lack of this interaction has not been fully evaluated, and caution should still be exercised if these
drugs are coadministered. Lovastatin has been shown to alter the hypoprothrombinemic response
to warfarin. Theoretically, no interaction should occur with other oral anticoagulants and
atorvastatin, although data is lacking.
coumadin (warfarin) and acetaminophen (Ingredient of vicodin) (Minor Drug-Drug)
Acetaminophen (APAP) may potentiate the hypoprothrombinemic effect of warfarin and other
oral anticoagulants, although data are somewhat conflicting and the mechanism of interaction is
unknown. The interaction has generally been associated with prolonged ingestion of relatively
high APAP dosages (greater than 1.3 g/day continuously for greater than 1 week) but not with
brief, intermittent exposures of average doses. Reported increases in prothrombin time or INR
from most studies were often small but statistically significant, although there have been isolated
case reports citing bleeding episodes and clinically significant alterations in coagulation
parameters. In contrast, one retrospective study found no significant effect of APAP 2000 to
2500 mg/day on the anticoagulant effect of phenprocoumon, and another study reported no effect
of APAP 4 g/day for 2 weeks on single-dose warfarin pharmacokinetics and pharmacodynamics
in healthy volunteers. Due to the lack of safer alternatives, acetaminophen is considered the
analgesic and antipyretic drug of choice for patients receiving oral anticoagulant therapy.
However, caution is recommended during concomitant therapy, particularly if high dosages of
APAP are used for a prolonged period. Patients should be advised to promptly report any signs
of bleeding to their physician, including pain, swelling, headache, dizziness, weakness,
prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding
of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.