CLASSES

Neuropathic Pain and Peripheral Neuropathy Agents
Serotonin Norepinephrine Reuptake Inhibitor Antidepressants, SNRIs

BOXED WARNING

Duloxetine is not recommended for use in pediatric patients less than 7 years of age; safety and efficacy have not been established. Duloxetine is FDA-approved for use in children and adolescents 7 years and older with generalized anxiety disorder (GAD) and is indicated for use in adolescents for pain associated with fibromyalgia. Efficacy for major depressive disorder (MDD) was not established in two 10-week controlled trials with 800 pediatric patients (7 years and older). In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of duloxetine may be necessary in patients with emerging suicidality or worsening depression. The potential for growth inhibition in pediatric patients should be monitored during duloxetine therapy. Monitor height and weight periodically while the patient is receiving duloxetine. Data are inadequate to determine whether the chronic use of SNRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving duloxetine.

DEA CLASS

Rx

DESCRIPTION

Oral serotonin norepinephrine reuptake inhibitor (SNRI) antidepressant
Indicated for depression, diabetic peripheral neuropathy, and chronic musculoskeletal pain in adults; approved for fibromyalgia in adults and adolescents 13 years and older and generalized anxiety disorder in adults and pediatric patients 7 years and older
Increased risk of suicidality during the initial stages of treatment in pediatric and young adult patients

COMMON BRAND NAMES

Cymbalta, Drizalma, Irenka

HOW SUPPLIED

Cymbalta/Drizalma/Duloxetine/Irenka Oral Cap DR Pellets: 20mg, 30mg, 40mg, 60mg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

120 mg/day PO.

120 mg/day PO.

120 mg/day PO for generalized anxiety disorder; 60 mg/day PO for fibromyalgia. Safety and efficacy for other indications have not been established.

7 to 12 years: 120 mg/day PO for generalized anxiety disorder. Safety and efficacy for other indications have not been established.
1 to 6 years: Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Avoid use in patients with any chronic hepatic disease or cirrhosis, due to an increased risk for hepatotoxicity.

CrCl 30 mL/minute or more: No dosage adjustments are required.
CrCl less than 30 mL/minute or eGFR less than 30 mL/min/1.73 m2: Avoid use in patients with severe renal impairment or renal failure.
 
Intermittent hemodialysis:
Avoid use in patients with end-stage renal disease receiving hemodialysis due to the risk of increased plasma concentrations of duloxetine and its metabolites.

ADMINISTRATION

May be administered without regard to meals.

STORAGE

Cymbalta:
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Drizalma:
- Store at 77 degrees F; excursions permitted to 68 to 77 degrees F
Irenka:
- Store at 77 degrees F; excursions permitted to 68 to 77 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Avoid abrupt discontinuation of duloxetine if possible. Gradual tapering is recommended during discontinuation of any serotonin-norepinephrine reuptake inhibitor (SNRI) drug to decrease or prevent the occurrence of potential withdrawal symptoms. Withdrawal symptoms have been reported with abrupt discontinuation or tapering of duloxetine and have included abnormal dreams, headache, insomnia, dizziness, nausea/vomiting, paresthesia, irritability, fatigue, diarrhea, anxiety, vertigo, hyperhidrosis, and a small increase in recumbent heart rate. More severe symptoms such as confusion, hypomanic episode, and seizures have been reported following discontinuation of other SNRIs and similar medications. Patients should be carefully monitored if abrupt discontinuation of duloxetine becomes necessary.

Duloxetine is contraindicated in patients with uncontrolled closed-angle glaucoma. Caution is recommended when prescribing duloxetine to patients with controlled closed-angle glaucoma. In clinical trials, duloxetine was associated with an increased risk of mydriasis. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

Duloxetine should be used cautiously in patients with a history of mania. All effective antidepressants can transform depression into mania in predisposed individuals. In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% of duloxetine-treated and placebo-treated patients. No activation of mania or hypomania was reported in placebo-controlled trials for the various indications for use. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. If a patient develops manic symptoms, duloxetine should be withheld, and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or suicidality. It should be noted that duloxetine is not approved for use in treating bipolar depression.

Duloxetine is not recommended for use in pediatric patients less than 7 years of age; safety and efficacy have not been established. Duloxetine is FDA-approved for use in children and adolescents 7 years and older with generalized anxiety disorder (GAD) and is indicated for use in adolescents for pain associated with fibromyalgia. Efficacy for major depressive disorder (MDD) was not established in two 10-week controlled trials with 800 pediatric patients (7 years and older). In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of duloxetine may be necessary in patients with emerging suicidality or worsening depression. The potential for growth inhibition in pediatric patients should be monitored during duloxetine therapy. Monitor height and weight periodically while the patient is receiving duloxetine. Data are inadequate to determine whether the chronic use of SNRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving duloxetine.

Duloxetine is contraindicated for concomitant use in patients receiving MAOI therapy, due to the risk for serotonin syndrome. Duloxetine is a serotonin norepinephrine reuptake inhibitor (SNRI) and should not be used concurrently with MAOI therapy or within 14 days of discontinuation of a MAOI intended to treat a psychiatric disorder. Similarly, treatment with such MAOIs should not be initiated for at least 5 days after stopping duloxetine. In addition, do not start duloxetine in a patient who is being treated with linezolid or intravenous methylene blue. Serotonin syndrome has been reported with SNRIs, including duloxetine, both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, selective serotonin reuptake inhibitors or SSRIs, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such symptoms occur, discontinue duloxetine and initiate supportive treatment. If concomitant use of duloxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% of patients treated with duloxetine and 0.01% of patients treated with placebo. Use with caution in patients with a history of a seizure disorder. Duloxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies.

Duloxetine has not been studied in patients with cardiac disease, including those with a recent history of myocardial infarction or unstable coronary artery disease. Blood pressure should be measured prior to initiating duloxetine treatment and periodically measured throughout treatment. Patients with preexisting hypotension should be cautioned appropriately and monitored closely if duloxetine therapy is initiated as orthostatic hypotension, syncope, and falls have been reported during duloxetine administration. Orthostatic hypotension and syncope are more likely during the first week of treatment or after dose increases. Other factors that may increase the risk of hypotension include use of duloxetine dosages above 60 mg/day and coadministration of potent CYP1A2 inhibitors or antihypertensive drugs. In an analysis of patients from all placebo-controlled trials, patients treated with duloxetine reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in blood pressure. Falls resulting in bone fractures and hospitalizations have occurred during treatment with duloxetine. Consideration should be given to reducing the dose or discontinuing treatment in patients who experience falls, syncope, or symptomatic orthostasis. Also use duloxetine with caution in patients with preexisting hypertension, as duloxetine use has been associated with mild increases in heart rate and blood pressure during clinical study of doses within the usual dosage range. Mean elevations of 0.5 mmHg in systolic blood pressure (SBP) and 0.8 mmHg in diastolic blood pressure (DBP) were noted in patients receiving duloxetine across all indications in clinical study.

Serotonin norepinephrine reuptake inhibitors (SNRIs), such as duloxetine, may cause hyponatremia which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SNRI. Elderly patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of duloxetine, as well as implementation of the appropriate medical interventions.

Avoid use of duloxetine in patients with chronic hepatic disease or cirrhosis. Postmarketing reports suggest patients with pre-existing hepatic disease who take duloxetine may be at an increased risk for hepatotoxicity. There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than 20 times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Duloxetine caused elevated liver function tests (LFTs) in clinical trials. Liver transaminase elevations resulted in drug discontinuation in 0.3% of treated patients. In most patients, the median time to detection of the transaminase elevation was about 2 months. In adult placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, ALT increased to more than 3 times the ULN occurred in 1.25% of duloxetine-treated patients compared to 0.45% for placebo. In adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of more than 3 times the ULN and more than 5 times the ULN, respectively. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, duloxetine should not be prescribed to patients with substantial alcohol use (alcoholism) or evidence of chronic hepatic disease.

Serious rash and other severe cutaneous reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with duloxetine. The reporting rate of SJS associated with duloxetine use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting. Duloxetine should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

Monitor patients taking duloxetine for signs and symptoms of bleeding. Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication. Bleeding events related to SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening GI bleeding and other hemorrhages. Concurrent use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking duloxetine should be instructed to promptly report any bleeding events to the practitioner.

Avoid use of duloxetine in patients with severe renal impairment (eGFR less than 30 mL/minute/1.73 m2). Increased plasma concentrations of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease and renal failure.

Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with duloxetine, consider the possibility that they might be drug-related. In postmarketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.

Monitor patients with diabetes mellitus for changes in glycemic control during duloxetine therapy. During long-term studies (up to 52 weeks) for the management of painful diabetic peripheral neuropathy, the mean blood glucose levels increased by 12 mg/dL in the duloxetine group and decreased by 11.5 mg/dL in the routine care group. In addition, the A1c increased by 0.5% in those treated with duloxetine and 0.2% in those receiving routine care. Additionally, the effects of altered motility on the stability of the enteric coating of duloxetine product is not known; however, rapid hydrolysis of the drug occurs in an acidic environment. Therefore, the manufacturer advises caution when using duloxetine in those with delayed gastric emptying, such as some patients with diabetes.

Because any psychoactive drug may impair judgment, thinking, or motor skills, patients should use caution when driving or operating machinery, until the full effect of duloxetine is determined. The use of other CNS-active agents may augment these effects. Duloxetine did not increase the impairment of mental and motor skills caused by alcohol. However, patients should be advised to limit ethanol ingestion while taking duloxetine, since excessive alcohol intake increases the risk for hepatotoxicity.

Sexual dysfunction can occur in individuals taking duloxetine. For males, these effects may present as ejaculatory failure or delay, decreased libido, and/or erectile dysfunction. Females may experience decreased libido and delayed or absent orgasm. Prescribers should discuss sexual function prior to initiating treatment with duloxetine and throughout treatment and obtain a detailed history and timeline of any changes in sexual function to determine whether the changes are medication-related or may be attributed to the underlying psychiatric disorder. Clinicians should also discuss management strategies and treatment options with patients.

There are no adequate and well-controlled studies on the use of duloxetine during human pregnancy; use in pregnancy only where the benefit clearly outweighs any potential risk to the fetus. In animal studies there was no evidence of teratogenicity; however, this data may not be reflective of human outcomes. Consider the risks of untreated depression during pregnancy as well as the potential risks of fetal exposure. When treating a pregnant individual with a serotonin norepinephrine reuptake inhibitor (SNRI) or other serotonergic agent during the third trimester, neonatal discontinuation symptoms may occur at birth. Neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery; symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with serotonin syndrome or a drug discontinuation syndrome. In terms of maternal risk, exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia and use near obstetric delivery may increase the risk for postpartum hemorrhage. A postmarketing study showed a higher incidence of postpartum hemorrhage in individuals taking duloxetine. If clinically feasible, gradual tapering of duloxetine prior to delivery may be considered. The National Pregnancy Registry for Antidepressants is dedicated to evaluating the safety of antidepressant medications that may be taken during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The pregnancy registry monitors pregnancy outcomes; information about the registry can be obtained at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants or by calling 1-866-961-2388.

Use caution when duloxetine is administered to a breast-feeding women. Duloxetine, a dual serotonin-norepinephrine reuptake inhibitor, is excreted into the breast milk of lactating women. The estimated daily infant dose is approximately 0.14% of the maternal dose. The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of duloxetine twice daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of duloxetine in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day. The estimated daily infant dose is approximately 0.14% of the maternal dose. The presence of metabolites in breast milk was not examined. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for duloxetine and any potential adverse effects on the milk-fed infant from the drug or from the underlying maternal condition. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Use duloxetine with caution in the geriatric patient. Therapeutic use of duloxetine has resulted in orthostatic hypotension, syncope, and falls that, in some cases, have resulted in bone fractures and hospitalizations. The risk of falls is associated with the degree of orthostasis, and any other factors that may increase the likelihood of falling (e.g., age-related risks, concomitant medications with orthostatic effects). Geriatric patients are more likely than younger adults to have a regimen of multiple medications, concomitant illnesses, and gait disturbances that may increase the underlying risk of falls. Also, serotonin-norepinephrine reuptake inhibitors (SNRIs) can cause or exacerbate hyponatremia, and the elderly may have an increased risk of developing low serum sodium levels compared to other age groups. Some geriatric patients may experience increased sensitivity to other adverse effects of antidepressants, including duloxetine.[29934] According to the Beers Criteria, SNRIs are considered potentially inappropriate medications (PIMs) in older adults and should be avoided in elderly patients with a history of falls or fractures, unless safer alternatives are not available since SNRIs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If duloxetine must be used in an elderly patient with a history of falls or fractures, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk. All SNRIs can cause or exacerbate hyponatremia and SIADH, and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages in older adults.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities; the duration of therapy is determined by pertinent literature and clinical practice guidelines for the condition being treated. Monitor closely for worsening of depression and suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Monitor for side effects of the antidepressant; some of these effects can increase the risk of falls. Review for continued need of the antidepressant at least quarterly and document the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated. Before discontinuation, many antidepressants, including SNRIs such as duloxetine, need a taper to avoid a withdrawal/discontinuation syndrome.[60742] Duloxetine has specific and limited uses for urinary incontinence based on the cause and categorization of incontinence. According to the OBRA guidelines, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after the time of initiating treatment with a urinary incontinence medication such as duloxetine. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability.[60742]

ADVERSE REACTIONS

suicidal ideation / Delayed / 0.1-1.0
myocardial infarction / Delayed / 0.1-1.0
visual impairment / Early / 0.1-1.0
GI bleeding / Delayed / 0.1-1.0
peptic ulcer / Delayed / 0-0.1
seizures / Delayed / 0-0.1
pancreatitis / Delayed / Incidence not known
hypertensive crisis / Early / Incidence not known
cardiomyopathy / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
vasculitis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
ocular hypertension / Delayed / Incidence not known
postpartum hemorrhage / Early / Incidence not known
hepatic failure / Delayed / Incidence not known
hyperkalemia / Delayed / Incidence not known
SIADH / Delayed / Incidence not known
serotonin syndrome / Delayed / Incidence not known
neonatal abstinence syndrome / Early / Incidence not known

constipation / Delayed / 9.0-11.0
impotence (erectile dysfunction) / Delayed / 4.0-4.0
blurred vision / Early / 3.0-3.0
ejaculation dysfunction / Delayed / 2.0-3.0
palpitations / Early / 0-2.0
elevated hepatic enzymes / Delayed / 1.1-1.1
dyskinesia / Delayed / 0.1-1.0
confusion / Early / 0.1-1.0
dehydration / Delayed / 0.1-1.0
teeth grinding (bruxism) / Delayed / 0.1-1.0
stomatitis / Delayed / 0.1-1.0
gastritis / Delayed / 0.1-1.0
sinus tachycardia / Rapid / 0.1-1.0
hypotension / Rapid / 0.1-1.0
orthostatic hypotension / Delayed / 0.1-1.0
contact dermatitis / Delayed / 0.1-1.0
erythema / Early / 0.1-1.0
hypothyroidism / Delayed / 0.1-1.0
hot flashes / Early / 0.1-1.0
dysuria / Early / 0.1-1.0
myoclonia / Delayed / 0.1-1.0
dysarthria / Delayed / 0-0.1
mania / Early / 0.1-0.1
withdrawal / Early / 1.0
trismus / Delayed / Incidence not known
hallucinations / Early / Incidence not known
depression / Delayed / Incidence not known
colitis / Delayed / Incidence not known
hypertension / Early / Incidence not known
supraventricular tachycardia (SVT) / Early / Incidence not known
bleeding / Early / Incidence not known
platelet dysfunction / Delayed / Incidence not known
hematoma / Early / Incidence not known
galactorrhea / Delayed / Incidence not known
vaginal bleeding / Delayed / Incidence not known
hyperprolactinemia / Delayed / Incidence not known
urinary retention / Early / Incidence not known
jaundice / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
cholestasis / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
hypokalemia / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known

nausea / Early / 4.0-25.0
headache / Early / 13.0-18.0
weight loss / Delayed / 0.1-15.0
xerostomia / Early / 2.0-14.0
abdominal pain / Early / 5.0-13.0
drowsiness / Early / 9.0-12.0
asthenia / Delayed / 5.0-11.0
insomnia / Early / 7.0-11.0
fatigue / Early / 5.0-11.0
dizziness / Early / 8.0-10.0
anorexia / Delayed / 7.0-10.0
diarrhea / Early / 6.0-9.0
vomiting / Early / 4.0-9.0
pharyngitis / Delayed / 4.0-9.0
infection / Delayed / 4.0-7.0
hyperhidrosis / Delayed / 0-6.0
agitation / Early / 4.0-5.0
myalgia / Early / 4.0-4.0
musculoskeletal pain / Early / 4.0-4.0
tremor / Early / 0-3.0
anxiety / Delayed / 0-3.0
flushing / Rapid / 0-3.0
libido decrease / Delayed / 3.0-3.0
back pain / Delayed / 3.0-3.0
cough / Delayed / 3.0-3.0
hypoesthesia / Delayed / 2.0-2.0
yawning / Early / 2.0-2.0
nightmares / Early / 0-2.0
abnormal dreams / Early / 0-2.0
dyspepsia / Early / 2.0-2.0
orgasm dysfunction / Delayed / 1.0-2.0
influenza / Delayed / 2.0-2.0
malaise / Early / 0.1-1.0
irritability / Delayed / 0.1-1.0
halitosis / Early / 0.1-1.0
polydipsia / Early / 0.1-1.0
eructation / Early / 0.1-1.0
syncope / Early / 0.1-1.0
photosensitivity / Delayed / 0.1-1.0
night sweats / Early / 0.1-1.0
otalgia / Early / 0.1-1.0
tinnitus / Delayed / 0.1-1.0
xerophthalmia / Early / 0.1-1.0
diplopia / Early / 0.1-1.0
increased urinary frequency / Early / 0.1-1.0
nocturia / Early / 0.1-1.0
polyuria / Early / 0.1-1.0
ecchymosis / Delayed / 0-0.1
menstrual irregularity / Delayed / 0-0.1
laryngitis / Delayed / 0-0.1
lethargy / Early / 1.0
dysgeusia / Early / 1.0
flatulence / Early / 1.0
weight gain / Delayed / 1.0
pruritus / Rapid / 1.0
vertigo / Early / 1.0
chills / Rapid / 1.0
urticaria / Rapid / Incidence not known
rash / Early / Incidence not known
mydriasis / Early / Incidence not known
petechiae / Delayed / Incidence not known
epistaxis / Delayed / Incidence not known
muscle cramps / Delayed / Incidence not known
restless legs syndrome (RLS) / Delayed / Incidence not known

DRUG INTERACTIONS

Abciximab: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) like duloxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving abciximab. Monitor the patient closely for signs and symptoms of bleeding.
Acebutolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of acebutolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Acetaminophen; Aspirin: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and duloxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Acetaminophen; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6.
Acetaminophen; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Acetaminophen; Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Acetaminophen; Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Adapalene; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Alfentanil: (Moderate) If concomitant use of alfentanil and duloxetine is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Aliskiren: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Alteplase: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Ambrisentan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Amiodarone: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with amiodarone. Concurrent use may result in increased duloxetine exposure. Duloxetine is a CYP1A2 and CYP2D6 substrate and amiodarone is a CYP1A2 and CYP2D6 inhibitor.
Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Amlodipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Amlodipine; Atorvastatin: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Amlodipine; Benazepril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Amlodipine; Celecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Amlodipine; Olmesartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Amlodipine; Valsartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Amphetamine; Dextroamphetamine Salts: (Moderate) Coadministration of amphetamines with serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release and act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Anagrelide: (Moderate) Anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with substrates of CYP1A2, including duloxetine, could lead to increases in the serum concentrations of these drugs and, thus, adverse effects. Patients receiving anagrelide and duloxetine concomitantly should be monitored for increased toxicity of duloxetine. Monitor the patient for signs of excessive serotonin activity. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, duloxetine and the concomitant serotonergic agent should be discontinued and symptomatic treatment should be initiated.
Angiotensin II receptor antagonists: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Angiotensin-converting enzyme inhibitors: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Antithrombin III: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Apixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like apixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Argatroban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like argatroban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Aripiprazole: (Major) Monitor for aripiprazole-related adverse reactions during concurrent use of duloxetine. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP3A inhibitor. Adults receiving a combination of a CYP3A inhibitor and duloxetine for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor alone. Aripiprazole is a substrate for CYP2D6 and CYP3A; duloxetine is a moderate CYP2D6 inhibitor.
Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and duloxetine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased duloxetine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
Asenapine: (Moderate) Duloxetine is an inhibitor of CYP2D6 and CYP1A2 and may decrease the clearance of atypical antipsychotics that are CYP2D6 and CYP1A2 substrates including asenapine. Decreased metabolism of asenapine may lead to adverse reactions such as extrapyramidal symptoms. In addition, asenapine is associated with a risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously with CYP2D6 and CYP1A2 inhibitors such as duloxetine. In vitro studies indicate that CYP1A2 is a primary metabolic pathway of asenapine.
Aspirin, ASA: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Caffeine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Carisoprodol: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Omeprazole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Aspirin, ASA; Pravastatin: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Atenolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of atenolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Atenolol; Chlorthalidone: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of atenolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Azilsartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Azilsartan; Chlorthalidone: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Benazepril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Bendroflumethiazide; Nadolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of nadolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Benzhydrocodone; Acetaminophen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and duloxetine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzoyl Peroxide; Clindamycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzoyl Peroxide; Erythromycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzoyl Peroxide; Sulfur: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin norepinephrine reuptake inhibitors. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Betaxolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of betaxolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Betrixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like betrixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Bismuth Subsalicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Bisoprolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of bisoprolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of bisoprolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Bivalirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like bivalirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Brexpiprazole: (Moderate) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. If duloxetine is used in combination with brexpiprazole and a moderate to strong CYP3A4 inhibitor, the brexpiprazole dose should be adjusted and the patient should be carefully monitored for brexpiprazole-related adverse reactions.
Brimonidine; Timolol: (Moderate) Monitor blood pressure during concomitant duloxetine and timolol use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Bupivacaine; Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Buprenorphine: (Moderate) Concurrent use of opioids, such as buprenorphine, with other drugs that modulate serotonergic function, such as duloxetine, has resulted in serotonin syndrome in some cases. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
Buprenorphine; Naloxone: (Moderate) Concurrent use of opioids, such as buprenorphine, with other drugs that modulate serotonergic function, such as duloxetine, has resulted in serotonin syndrome in some cases. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected.
Bupropion: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with bupropion. Concurrent use may result in increased duloxetine exposure. Duloxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Bupropion; Naltrexone: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with bupropion. Concurrent use may result in increased duloxetine exposure. Duloxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Buspirone: (Moderate) Coadministration of buspirone with serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk of serotonin syndrome. Both types of medications have serotonergic properties. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Calamine; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Calcium-channel blockers: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Candesartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Capsaicin; Metaxalone: (Moderate) Concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Captopril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Carteolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of carteolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Carvedilol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of carvedilol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Celecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with duloxetine is necessary. If duloxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and duloxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Central-acting adrenergic agents: (Moderate) Monitor blood pressure during concomitant duloxetine and central-acting adrenergic agent use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Chloroxylenol; Hydrocortisone; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Chlorpheniramine; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and duloxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Chlorpheniramine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Chlorpromazine: (Moderate) Caution is advisable during concurrent use of chlorpromazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of chlorpromazine may occur. Phenothiazines are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor. In addition, chlorpromazine is associated with a possible risk of QT prolongation; therefore, cardiac effects are possible.
Chlorthalidone; Clonidine: (Moderate) Monitor blood pressure during concomitant duloxetine and central-acting adrenergic agent use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Choline Salicylate; Magnesium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Cilostazol: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Cimetidine: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with cimetidine. Concurrent use may result in increased duloxetine exposure. Duloxetine is a CYP1A2 and CYP2D6 substrate and cimetidine is a CYP1A2 and CYP2D6 inhibitor.
Ciprofloxacin: (Major) Coadministration of duloxetine and potent inhibitors of CYP1A2, such as ciprofloxacin, should be avoided. Duloxetine is partially metabolized by CYP1A2. One study involving a potent CYP1A2 inhibitor in concomitant use with duloxetine showed that duloxetine exposure was significantly increased.
Citalopram: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) such as citalopram should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine.
Clevidipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Clomipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Clonidine: (Moderate) Monitor blood pressure during concomitant duloxetine and central-acting adrenergic agent use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Clopidogrel: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of duloxetine and clopidogrel. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Clozapine: (Moderate) Duloxetine is an inhibitor of CYP2D6 and CYP1A2, two of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP1A2, CYP3A4, or CYP2D6 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Cocaine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as cocaine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Codeine; Guaifenesin: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Codeine; Phenylephrine; Promethazine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Codeine; Promethazine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and duloxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of duloxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If duloxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Duloxetine is a moderate inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Cyclobenzaprine: (Major) Cautious use of cyclobenzaprine and drugs that increase serotonin concentrations such as serotonin norepinephrine reuptake inhibitors (SNRIs) is advised because of the possibility of serotonin syndrome. If these drugs must be used together, closely monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction develops, immediately discontinue cyclobenzaprine and the SSRI. A suspected case of serotonin syndrome was noted in a man who took duloxetine, opiates, and cyclobenzaprine. The man developed worsening confusion, hallucinations, diaphoresis, tachycardia, tremors, marked agitation, spontaneous sustained clonus, and multifocal myoclonus, but recovered after duloxetine and cyclobenzaprine discontinuation and cyproheptadine initiation.
Dabigatran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like dabigatran. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Dacomitinib: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with dacomitinib. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Dacomitinib is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Dalteparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like dalteparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Darifenacin: (Moderate) Duloxetine, a CYP2D6 inhibitor, may decrease the metabolism of darifenacin, a CYP2D6 substrate. Clinicians should monitor patients for increased anticholinergic effects when CYP2D6 inhibitors are coadministered with darifenacin; dosage adjustments of darifenacin may be necessary.
Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Desipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Desirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like desirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Desvenlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of desvenlafaxine and duloxetine should be avoided. Also, because both desvenlafaxine and duloxetine are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Bupropion: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with bupropion. Concurrent use may result in increased duloxetine exposure. Duloxetine is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Quinidine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with quinidine. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Quinidine is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Diazoxide: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Dibucaine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Diclofenac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Diclofenac; Misoprostol: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Diflunisal: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Diltiazem: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Diphenhydramine; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Dipyridamole: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Disulfiram: (Moderate) Co-administration of duloxetine and potent inhibitors of CYP1A2 should be avoided. Duloxetine is partially metabolized by CYP1A2. One study involving a potent CYP1A2 inhibitor in concomitant use with duloxetine showed that duloxetine exposure was significantly increased. Concurrent use of duloxetine and disulfiram, a CYP1A2 inhibitor, may result in excessive serotonin activity. Careful monitoring is recommended if concurrent therapy is considered necessary.
Diuretics: (Moderate) Monitor for signs and symptoms of hyponatremia during concomitant diuretic and serotonin norepinephrine reuptake inhibitor (SNRI) use; consider discontinuing the SNRI if symptomatic hyponatremia occurs and institute appropriate medical intervention. Concomitant use increases the risk for developing hyponatremia.
Dolasetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering dolasetron with other drugs that have serotonergic properties such as duloxetine. If serotonin syndrome is suspected, discontinue dolasetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Dorzolamide; Timolol: (Moderate) Monitor blood pressure during concomitant duloxetine and timolol use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Doxazosin: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Doxepin: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors including duloxetine may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if duloxetine is coadministered with doxercalciferol.
Doxorubicin Liposomal: (Major) Duloxetine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of duloxetine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Doxorubicin: (Major) Duloxetine is a CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of duloxetine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of duloxetine with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and duloxetine is a moderate CYP2D6 inhibitor.
Edoxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of duloxetine and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily; however, coadministration of eliglustat with both duloxetine and a strong or moderate CYP3A inhibitor is contraindicated. Duloxetine is a CYP2D6 substrate and moderate inhibitor; eliglustat is a CYP2D6 and CYP3A substrate and a CYP2D6 inhibitor. Coadministration with CYP2D6 inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). In addition, coadministration of eliglustat with CYP2D6 substrates (e.g., duloxetine) may result in increased concentrations of the concomitant drug; monitor patients closely for adverse events, and consider reducing the dosage of duloxetine and titrating to clinical effect.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Enalapril, Enalaprilat: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Enoxaparin: (Major) Whenever possible, discontinue agents which may enhance the risk of hemorrhage, including serotonin norepinephrine reuptake inhibitors (SNRIs), before initiation of enoxaparin therapy. If coadministration is essential, conduct close clinical and laboratory monitoring.
Eplerenone: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Epoprostenol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Eprosartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Eptifibatide: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Ergot alkaloids: (Moderate) Because of the potential risk and severity of serotonin syndrome, use caution when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties, such as the ergot alkaloids. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been coadministered with serotonin reuptake inhibitors, which may be indicative of serotonin excess. Inform patients of the potential risk and monitor for serotonin syndrome. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
Escitalopram: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) such as escitalopram should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine.
Esmolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of esmolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Ethyl Chloride: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Etodolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Felodipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Fenfluramine: (Moderate) Use fenfluramine and serotonin norepinephrine reuptake inhibitors with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Fenoldopam: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Fenoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Fentanyl: (Moderate) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering duloxetine with other drugs that have serotonergic properties such as fentanyl. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and institute appropriate medical treatment if serotonin syndrome occurs.
Finasteride; Tadalafil: (Moderate) Monitor blood pressure closely if duloxetine is coadministered with tadalafil due to the risk of additive hypotension. Orthostatic hypotension and syncope have been reported during duloxetine administration.
Fluoxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine.
Fluphenazine: (Moderate) Caution is advisable during concurrent use of fluphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of fluphenazine may occur. Phenothiazines are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor. In addition, fluphenazine is associated with a possible risk of QT prolongation; therefore, cardiac effects are possible.
Flurbiprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Fluvoxamine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, when fluvoxamine, a potent CYP1A2 inhibitor, was coadministered with duloxetine to male subjects (n=14) the duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine half-life was increased approximately 3-fold. The increased duloxetine exposure induced by fluvoxamine would potentially increase the risk of serotonin-related adverse effects; therefore, the manufacturer recommends avoiding concurrent use of these agents.
Fondaparinux: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Fosinopril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with duloxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and duloxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Givosiran: (Major) Avoid concomitant use of givosiran and duloxetine due to the risk of increased duloxetine-related adverse reactions. If use is necessary, consider decreasing the duloxetine dose. Duloxetine is a sensitive CYP1A2 substrate. Givosiran may moderately reduce hepatic CYP1A2 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
Granisetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as duloxetine. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Guaifenesin; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6.
Guanabenz: (Moderate) Monitor blood pressure during concomitant duloxetine and central-acting adrenergic agent use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Guanfacine: (Moderate) Monitor blood pressure during concomitant duloxetine and central-acting adrenergic agent use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Haloperidol: (Moderate) Duloxetine is a moderate inhibitor of CYP2D6. Substantial increases in concentrations of antipsychotics primarily metabolized via CYP2D6, such as haloperidol may also occur. Haloperidol is associated with a possible risk of QT prolongation and should be used cautiously with CYP2D6 inhibitors such as duloxetine.
Heparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Homatropine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6.
Hydralazine: (Moderate) Monitor blood pressure during concomitant duloxetine and hydralazine use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant duloxetine and hydralazine use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Monitor blood pressure during concomitant duloxetine and hydralazine use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor blood pressure during concomitant duloxetine and central-acting adrenergic agent use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6.
Hydrocodone; Ibuprofen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6. (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and duloxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with duloxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of duloxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If duloxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Duloxetine is a moderate inhibitor of CYP2D6.
Hydrocortisone; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued. (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ibuprofen; Famotidine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ibuprofen; Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Iloperidone: (Moderate) Duloxetine is a moderate inhibitor of CYP2D6 and may decrease the clearance of atypical antipsychotics that are CYP2D6 substrates including iloperidone. Decreased metabolism of iloperidone may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. In addition, iloperidone is associated with a risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously with CYP2D6 inhibitors such as duloxetine.
Iloprost: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Imipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Indomethacin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Iobenguane I 131: (Major) Discontinue serotonin norepinephrine reuptake inhibitors for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart serotonin norepinephrine reuptake inhibitors until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as serotonin norepinephrine reuptake inhibitors, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
Irbesartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Isoniazid, INH: (Moderate) Due to the risk of serotonin syndrome, concurrent use of duloxetine and medications with MAO-like activity, such as isoniazid, INH, should be approached with caution. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors (SNRIs). If serotonin syndrome is suspected, duloxetine and concurrent serotonergic agents should be discontinued.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Due to the risk of serotonin syndrome, concurrent use of duloxetine and medications with MAO-like activity, such as isoniazid, INH, should be approached with caution. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors (SNRIs). If serotonin syndrome is suspected, duloxetine and concurrent serotonergic agents should be discontinued.
Isoniazid, INH; Rifampin: (Moderate) Due to the risk of serotonin syndrome, concurrent use of duloxetine and medications with MAO-like activity, such as isoniazid, INH, should be approached with caution. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO and may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with serotonin norepinephrine reuptake inhibitors (SNRIs). If serotonin syndrome is suspected, duloxetine and concurrent serotonergic agents should be discontinued.
Isradipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Ketoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Ketorolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Labetalol: (Moderate) Monitor blood pressure during concomitant duloxetine and labetalol use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Lansoprazole; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and serotonin norepinephrine reuptake inhibitors. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Leflunomide: (Moderate) Closely monitor for reduced efficacy of duloxetine if coadministered with leflunomide. An adjustment of the duloxetine dose may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as duloxetine, may decrease duloxetine exposure and lead to a reduction in efficacy.
Lepirudin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like lepirudin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Levamlodipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Levomilnacipran: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of levomilnacipran and duloxetine should be avoided. Also, because both levomilnacipran and duloxetine are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
Linezolid: (Contraindicated) The use of linezolid with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine is contraindicated due to the potential for serotonin syndrome. Linezolid is an antibiotic that also possesses weak non-selective MAO-inhibiting activity which could have additive effects with SNRIs on central serotonin activity. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In a patient who requires urgent treatment of a psychiatric condition, interventions other than an SNRI, including hospitalization, should be considered. In some cases, a patient already receiving duloxetine may require urgent treatment with linezolid. If acceptable alternatives to linezolid are not available and the potential benefits of linezolid are determined to outweigh the risks of serotonin syndrome in an individual patient, duloxetine should be stopped promptly, and linezolid can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid, whichever comes first. Therapy with duloxetine may be resumed 24 hours after the last dose of linezolid.
Lisdexamfetamine: (Major) Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation or dosage increase, during concomitant lisdexamfetamine and serotonin norepinephrine reuptake inhibitor use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk of serotonin syndrome.
Lisinopril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Lithium: (Moderate) Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has central serotonin-enhancing effects and may increase the risk of serotonin syndrome when combined with SNRIs like duloxetine. Inform patients of the possible increased risk and monitor for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and symptomatic treatment should be initiated.
Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin norepinephrine reuptake inhibitors. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Losartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Macitentan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Magnesium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Maprotiline: (Major) Documentation is not available on the concurrent use of duloxetine with many CNS agents. Caution should be observed when administering duloxetine with other CNS-active drugs in the absence of clinical data regarding combined use. Examples of these drugs include the maprotiline. In addition, duloxetine is a moderate inhibitor of CYP2D6, and maprotiline appears to be metabolized by this isozyme. It is possible that duloxetine could increase the risk of cyclic-antidepressant-induced side effects or toxicity.
Mecamylamine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Meclofenamate Sodium: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Mefenamic Acid: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Menthol; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Meperidine: (Moderate) If concomitant use of meperidine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Meperidine; Promethazine: (Moderate) If concomitant use of meperidine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Metaxalone: (Moderate) Concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and metaxalone may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Methamphetamine: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as methamphetamine and serotonin norepinephrine reuptake inhibitors. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Methenamine; Sodium Salicylate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Methyldopa: (Moderate) Monitor blood pressure during concomitant duloxetine and central-acting adrenergic agent use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Methylene Blue: (Contraindicated) Concurrent use of methylene blue and serotonin norepinephrine reuptake inhibitors (SNRIs) (e.g., venlafaxine, duloxetine, desvenlafaxine, milnacipran) should generally be avoided due to the potential for serotonin syndrome. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with serotonergic agents such as SNRIs may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, SNRIs, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case report suggests that serotonin toxicity may have occurred post-operatively following administration of standard infusions of methylene blue in a patient receiving duloxetine. The patient experienced disorientation, a mildly elevated temperature, tachycardia, elevated blood pressure, mild agitation, and nystagmus. In a separate case, a patient who had been receiving venlafaxine developed expressive aphasia, confusion, and disinhibition following a methylene blue infusion. The authors concluded that methylene blue toxicity had occurred; however, they did not exclude the possibility of a drug interaction based upon previous reports of an interaction between injectable methylene blue and selective serotonin reuptake inhibitors (SSRIs). Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. If emergent treatment with methylene blue is required in a patient receiving an SNRI, the SNRI must be stopped immediately and the patient should be monitored for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, the SNRI should be stopped at least 2 weeks prior to methylene blue treatment, but also taking into consideration the half-life of the SNRI being discontinued.
Methylphenidate Derivatives: (Moderate) Caution should be observed when coadministering methylphenidate derivatives and serotonin norepinephrine reuptake inhibitors (SNRIs). There are postmarketing reports of serotonin syndrome during concurrent use of methylphenidate derivatives with other serotonergic medications. There is also a case of a neuroleptic malignant syndrome-like reaction occurring in a child on chronic methylphenidate therapy after ingesting methylphenidate with an SNRI. It is unclear if the reaction was the result of a drug interaction. Monitor patients for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical management should be implemented.
Metoclopramide: (Moderate) Concomitant use of metoclopramide and serotonin and norepinephrine reuptake inhibitors (SNRIs) may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary. In rare cases postmarketing, NMS-like symptoms, which may overlap with serotonin syndrome symptoms, have been reported with metoclopramide when used with serotonergic agents.
Metoprolol: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with duloxetine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and duloxetine is a CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with duloxetine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and duloxetine is a CYP2D6 inhibitor.
Milnacipran: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of milnacipran and duloxetine should be avoided. Also, because both milnacipran and duloxetine are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
Minoxidil: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as duloxetine may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) Coadministration of duloxetine and mirtazapine may increase the risk for serotonin syndrome. Cases of serotonin syndrome have been reported when mirtazapine has been administered with other serotonergic antidepressants. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
Moexipril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Monoamine oxidase inhibitors: (Contraindicated) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs). MAOIs should not be used within 5 days of discontinuing treatment with duloxetine or milnacipran or within 7 days of discontinuing treatment with other SNRIs. Conversely, SNRIs should not be initiated within 14 days of stopping an MAOI. Monitor the patient for serotonin-related effects during therapy transitions.
Morphine: (Moderate) If concomitant use of morphine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Morphine; Naltrexone: (Moderate) If concomitant use of morphine and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Nabumetone: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Nadolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of nadolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Naproxen; Esomeprazole: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Naproxen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with duloxetine; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and duloxetine is a moderate CYP2D6 inhibitor.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with duloxetine; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and duloxetine is a moderate CYP2D6 inhibitor. (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as nefazodone. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Netupitant, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as duloxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Nicardipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Nifedipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Nimodipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Nisoldipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
Nitroprusside: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Nortriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Olanzapine: (Moderate) Duloxetine is an inhibitor of CYP1A2 and CYP2D6 and should be used cautiously with atypical antipsychotics metabolized by CYP1A2 and CYP2D6 such as olanzapine. Plasma concentrations of atypical antipsychotics primarily metabolized via CYP1A2, such as olanzapine, may increase substantially during concurrent use. Decreased metabolism of olanzapine may lead to clinically important adverse reactions, such as orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with CYP1A2 and CYP2D6 inhibitors such as duloxetine.
Olanzapine; Fluoxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine. (Moderate) Duloxetine is an inhibitor of CYP1A2 and CYP2D6 and should be used cautiously with atypical antipsychotics metabolized by CYP1A2 and CYP2D6 such as olanzapine. Plasma concentrations of atypical antipsychotics primarily metabolized via CYP1A2, such as olanzapine, may increase substantially during concurrent use. Decreased metabolism of olanzapine may lead to clinically important adverse reactions, such as orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with CYP1A2 and CYP2D6 inhibitors such as duloxetine.
Olanzapine; Samidorphan: (Moderate) Duloxetine is an inhibitor of CYP1A2 and CYP2D6 and should be used cautiously with atypical antipsychotics metabolized by CYP1A2 and CYP2D6 such as olanzapine. Plasma concentrations of atypical antipsychotics primarily metabolized via CYP1A2, such as olanzapine, may increase substantially during concurrent use. Decreased metabolism of olanzapine may lead to clinically important adverse reactions, such as orthostatic hypotension, sedation, or extrapyramidal symptoms. In addition, olanzapine is associated with a possible risk of QT prolongation and should be used cautiously with CYP1A2 and CYP2D6 inhibitors such as duloxetine.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and duloxetine is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and duloxetine may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If duloxetine is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and duloxetine is a moderate CYP2D6 inhibitor. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Olmesartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Ondansetron: (Moderate) Because of the potential risk and severity of serotonin syndrome, use caution when administering ondansetron with other drugs that have serotonergic properties such as duloxetine. If serotonin syndrome is suspected, discontinue ondansetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Oritavancin: (Moderate) Duloxetine is metabolized by CYP2D6; oritavancin is a weak CYP2D6 inducer. Plasma concentrations and efficacy of duloxetine may be reduced if these drugs are administered concurrently.
Oxaprozin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Oxycodone: (Moderate) If concomitant use of oxycodone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Oxymorphone: (Moderate) If concomitant use of oxymorphone and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ozanimod: (Major) Coadministration of ozanimod with duloxetine is not recommended due to the potential for hypertensive crisis. If coadministration is necessary, closely monitor patients for hypertension and serotonergic effects. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Duloxetine may increase blood pressure by increasing serotonin and norepinephrine concentrations.
Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as duloxetine. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Paroxetine: (Moderate) Monitor patients for an increase in paroxetine-related adverse reactions and signs and symptoms of serotonin syndrome during concomitant use of paroxetine and duloxetine, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and duloxetine is a moderate CYP2D6 inhibitor.
Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to duloxetine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor, while duloxetine is a CYP1A2 and CYP2D6 substrate.
Penbutolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of penbutolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering serotonin norepinephrine reuptake inhibitors (SNRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Pentosan: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and pentosan, which has weak anticoagulant properties. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Perindopril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Perindopril; Amlodipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Perphenazine: (Moderate) Caution is advisable during concurrent use of perphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of perphenazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine are CYP2D6 inhibitors. In addition, perphenazine is associated with a possible risk of QT prolongation; therefore, cardiac effects are possible.
Perphenazine; Amitriptyline: (Moderate) Caution is advisable during concurrent use of perphenazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of perphenazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine are CYP2D6 inhibitors. In addition, perphenazine is associated with a possible risk of QT prolongation; therefore, cardiac effects are possible. (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Phenoxybenzamine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Phentermine: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phentermine; Topiramate: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
Phentolamine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Pimozide: (Moderate) Caution is advisable during concurrent use of pimozide and moderate CYP2D6 inhibitors such as duloxetine. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. While the manufacturer has provided no guidance regarding pimozide use with mild or moderate CYP2D6 inhibitors, concurrent use of the drug with more potent inhibitors of CYP2D6 is contraindicated. Elevated concentrations of pimozide can lead to QT prolongation, ventricular arrhythmias, and sudden death.
Pindolol: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of pindolol and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Piroxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Pramoxine; Zinc Acetate: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Prasugrel: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Prazosin: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Procarbazine: (Major) Concurrent use of procarbazine and serotonin norepinephrine reuptake inhibitors (SNRIs) should be avoided if possible. Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with an SNRI can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Prochlorperazine: (Moderate) Caution is advisable during concurrent use of prochlorperazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of prochlorperazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine are CYP2D6 inhibitors.
Promethazine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Propranolol: (Moderate) Monitor blood pressure during concomitant duloxetine and propranolol use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure during concomitant duloxetine and propranolol use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Protriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Quetiapine: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant duloxetine and quetiapine use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Quinapril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Quinidine: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with quinidine. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Quinidine is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Ramipril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including serotonin norepinephrine reuptake inhibitors (SNRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During post-marketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any antidepressant. Conversely, when discontinuing the antidepressant, it is advisable to wait the length of 4 to 5 half lives of the individual agent being discontinued prior to initiation with rasagiline.
Remifentanil: (Moderate) If concomitant use of remifentanil and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Reteplase, r-PA: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Riociguat: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Rivaroxaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like rivaroxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Rolapitant: (Major) Use caution if duloxetine and rolapitant are used concurrently, and monitor for duloxetine-related adverse effects. Duloxetine is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Sacubitril; Valsartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Safinamide: (Contraindicated) Safinamide is contraindicated for use with serotonin norepinephrine reuptake inhibitors (SNRIs) due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of safinamide and the initiation of an SNRI.
Salicylates: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Salsalate: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving aspirin, ASA or other salicylates which affect hemostasis. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Selegiline: (Contraindicated) Serotonin norepinephrine reuptake inhibitors (SNRIs) are contraindicated for use with selegiline, a selective monoamine oxidase type B inhibitor (MAO-B inhibitor). At least 14 days should elapse between discontinuation of selegiline and initiation of treatment with an SNRI. After stopping treatment with an SNRI, a time period equal to 4 to 5 half-lives of the SNRI or any active metabolite should elapse before starting therapy with selegiline. Serotonin syndrome has occurred in patients receiving selective MAO-B inhibitors and serotonin-augmenting antidepressants simultaneously. Monitor for serotonergic side effects during therapy transitions.
Selexipag: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Serotonin-Receptor Agonists: (Moderate) Monitor for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increase, during concomitant duloxetine and serotonin-receptor agonists use. If serotonin syndrome occurs, discontinue therapy. Concomitant use increases the risk for serotonin syndrome.
Sertraline: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) such as sertraline should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine.
Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with other drugs that have serotonergic properties such as serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving sibutramine in combination with an SNRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
Sildenafil: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. It is advisable to monitor blood pressure if the combination is necessary.
Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and antidepressants that are serotonin norepinephrine reuptake inhibitors. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
St. John's Wort, Hypericum perforatum: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Stiripentol: (Moderate) Consider a dose adjustment of duloxetine when coadministered with stiripentol. Coadministration may alter plasma concentrations of duloxetine resulting in an increased risk of adverse reactions and/or decreased efficacy. Duloxetine is a sensitive CYP1A2 substrate. In vitro data predicts inhibition or induction of CYP1A2 by stiripentol potentially resulting in clinically significant interactions.
Sulindac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Sumatriptan; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Tadalafil: (Moderate) Monitor blood pressure closely if duloxetine is coadministered with tadalafil due to the risk of additive hypotension. Orthostatic hypotension and syncope have been reported during duloxetine administration.
Tamsulosin: (Moderate) Use caution if coadministration of duloxetine with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and duloxetine is a moderate CYP2D6 inhibitor.
Tapentadol: (Moderate) If concomitant use of tapentadol and serotonin norepinephrine reuptake inhibitors is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tedizolid: (Minor) Use caution with the concurrent use of tedizolid and serotonin norepinephrine reuptake inhibitors (SNRIs) due to the theoretical risk of serotonin sydrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SNRIs were excluded from clinical trials. Additionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Telmisartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Telmisartan; Amlodipine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Tenecteplase: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Terazosin: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Terbinafine: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with terbinafine. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Terbinafine is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Teriflunomide: (Moderate) Use caution when administering teriflunomide and duloxetine concurrently. In vivo data suggest that teriflunomide is a weak inducer of CYP1A2. Coadministration of teriflunomide with CYP1A2 substrates, such as duloxetine, may decrease duloxetine exposure and lead to a reduction in efficacy.
Theophylline, Aminophylline: (Moderate) Close monitoring of theophylline levels is advisable during concurrent use of duloxetine and theophylline. Theophylline is a substrate for CYP1A2 and duloxetine is a CYP1A2 inhibitor. In two clinical studies, the average increase in the theophylline AUC was 7% (range: 1%-15%) and 20% (range: 13%-27%) when co-administered with duloxetine.
Thiethylperazine: (Moderate) Duloxetine is an inhibitor of CYP2D6, and concurrent use with CYP2D6 substrates, such as the phenothiazines, may result in increased plasma concentrations, and potential increased risk for phenothiazine-related side effects.
Thioridazine: (Contraindicated) Duloxetine is a moderate inhibitor of CYP2D6 and the use of thioridazine concomitantly with CYP2D6 inhibitors is contraindicated due to the possible risk of QT prolongation and subsequent arrhythmias, or other serious side effects, occurring from elevated serum concentrations of thioridazine.
Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving thrombolytic agents. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with medications which impair platelet function and to promptly report any bleeding events to the practitioner.
Ticagrelor: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Ticlopidine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Timolol: (Moderate) Monitor blood pressure during concomitant duloxetine and timolol use. Concomitant use increases the risk for hypotension, including orthostatic hypotension and syncope. Consider reducing the duloxetine dose or discontinuing duloxetine if symptomatic orthostatic hypotension, falls, or syncope occur during treatment.
Tipranavir: (Moderate) Monitor for increased duloxetine-related adverse effects if coadministered with tipranavir. Concurrent use may result in increased duloxetine exposure resulting in excessive serotonin activity. Tipranavir is a strong CYP2D6 inhibitor; duloxetine is a CYP2D6 substrate. Coadministration with another strong CYP2D6 inhibitor increased the duloxetine AUC by about 60%.
Tirofiban: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Tolmetin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with duloxetine is necessary. If duloxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and duloxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with duloxetine is necessary. If duloxetine is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and duloxetine is a CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Trandolapril: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Trandolapril; Verapamil: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Trazodone: (Moderate) Coadministration of trazodone and duloxetine may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Treprostinil: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Tretinoin; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Tricyclic antidepressants: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Trifluoperazine: (Moderate) Caution is advisable during concurrent use of trifluoperazine and serotonin norepinephrine reuptake inhibitors (SNRIs) since elevations in plasma concentrations of trifluoperazine may occur. Phenothiazines are CYP2D6 substrates, and SNRIs including duloxetine are CYP2D6 inhibitors.
Trimipramine: (Moderate) Monitor for an increase in tricyclic antidepressant-related adverse reactions and signs and symptoms of serotonin syndrome if coadministration with duloxetine is necessary, particularly during treatment initiation and dosage increases; a dose reduction of the tricyclic antidepressant may be necessary. If serotonin syndrome occurs, consider discontinuation of therapy. The concomitant use of serotonergic drugs increases the risk of serotonin syndrome. Concurrent use may increase exposure of the tricyclic antidepressant. Tricyclic antidepressants are CYP2D6 substrates and duloxetine is a CYP2D6 inhibitor.
Tryptophan, 5-Hydroxytryptophan: (Major) Since tryptophan is converted to serotonin (5-hydroxytryptamine), the use of tryptophan in patients receiving duloxetine could lead to serotonin excess and serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Concurrent use of SNRIs and tryptophan is not recommended. If combination theray is clinically warranted, patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, duloxetine and the concomitant serotonergic agent should be discontinued and symptomatic treatment should be initiated.
Valdecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant duloxetine and nonsteroidal antiinflammatory drug (NSAID) use due to increased risk for bleeding. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
Valerian, Valeriana officinalis: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents, may interact with the phytomedicinal valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
Valsartan: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and duloxetine may result in increased duloxetine concentrations. Vemurafenib is a CYP1A2 and CYP2D6 inhibitor and duloxetine is a substrate of these isoenzymes. Monitor the patient for signs of excessive serotonin activity.
Venlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, coadministration of venlafaxine and duloxetine should be avoided. Also, because both venlafaxine and duloxetine are serotonin norepinephrine reuptake inhibitors (SNRIs), coadministration is considered duplicative therapy. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SNRI to another SNRI.
Verapamil: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining serotonin norepinephrine reuptake inhibitors (SNRIs) with vilazodone. Interactions between vilazodone and serotonergic agents can lead to serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving vilazodone and an SNRI should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the SNRI should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
Viloxazine: (Contraindicated) Concomitant use of viloxazine and duloxetine is contraindicated due to the increased risk for duloxetine-related adverse effects and exposure. Duloxetine is a CYP1A2 and CYP2D6 substrate and viloxazine is a strong CYP1A2 inhibitor and weak CYP2D6 inhibitor. Coadministration with another strong CYP1A2 inhibitor increased duloxetine exposure by approximately 6-fold.
Vorapaxar: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome is suspected, vortioxetine and concurrent serotonergic agents should be discontinued.
Warfarin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of duloxetine and warfarin. Carefully monitor patients receiving warfarin therapy if duloxetine is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. Although both duloxetine and warfarin are highly protein bound, concurrent use did not significantly change INR or warfarin pharmacokinetics.
Zileuton: (Moderate) Co-administration of duloxetine and potent inhibitors of CYP1A2 should be avoided. Duloxetine is partially metabolized by CYP1A2. One study involving a potent CYP1A2 inhibitor in concomitant use with duloxetine showed that duloxetine exposure was significantly increased. Concurrent use of duloxetine and zileuton, a CYP1A2 inhibitor, may result in excessive serotonin activity. Careful monitoring is recommended if concurrent therapy is considered necessary.

PREGNANCY AND LACTATION

There are no adequate and well-controlled studies on the use of duloxetine during human pregnancy; use in pregnancy only where the benefit clearly outweighs any potential risk to the fetus. In animal studies there was no evidence of teratogenicity; however, this data may not be reflective of human outcomes. Consider the risks of untreated depression during pregnancy as well as the potential risks of fetal exposure. When treating a pregnant individual with a serotonin norepinephrine reuptake inhibitor (SNRI) or other serotonergic agent during the third trimester, neonatal discontinuation symptoms may occur at birth. Neonates exposed to serotonergic antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery; symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with serotonin syndrome or a drug discontinuation syndrome. In terms of maternal risk, exposure to SNRIs in mid to late pregnancy may increase the risk of eclampsia and use near obstetric delivery may increase the risk for postpartum hemorrhage. A postmarketing study showed a higher incidence of postpartum hemorrhage in individuals taking duloxetine. If clinically feasible, gradual tapering of duloxetine prior to delivery may be considered. The National Pregnancy Registry for Antidepressants is dedicated to evaluating the safety of antidepressant medications that may be taken during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The pregnancy registry monitors pregnancy outcomes; information about the registry can be obtained at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants or by calling 1-866-961-2388.

MECHANISM OF ACTION

Duloxetine inhibits the reuptake of both serotonin (5-HT) and norepinephrine (NE). The exact mechanism of its antidepressant effect is not known. The potency of duloxetine to inhibit reuptake is greater for 5-HT than for NE, however, inhibition of the NE reuptake process occurs at a considerably lower dose than for venlafaxine, a similar 5-HT/NE reuptake inhibitor. The ability of duloxetine to affect NE reuptake appears to occur at doses of at least 60 mg/day. Duloxetine also inhibits 5-HT uptake in human platelets, and this effect has been associated with potentiation of bleeding in some reports. Similar to the selective serotonin reuptake inhibitors (SSRIs), duloxetine does not exert significant activity at dopaminergic, histaminergic, muscarinic, alpha-1 adrenergic receptors, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, or opioid receptors in vivo or in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). The major circulating metabolites of duloxetine do not appear to contribute to its pharmacologic activity. In the treatment of stress urinary incontinence, inhibition of 5-HT and NE reuptake by duloxetine increases the activity of the bladder detrusor muscle and the urethral sphincter thereby promoting continence.

PHARMACOKINETICS

Duloxetine is administered orally. It is distributed widely throughout the body. Duloxetine is highly protein-bound (greater than 90%); however, plasma protein binding is not affected by renal or hepatic impairment. The drug undergoes extensive hepatic oxidation to numerous inactive metabolites with only 3% of the parent drug remaining in the plasma. Duloxetine is metabolized by CYP2D6 and CYP1A2, with a moderate potential for drug interactions involving CYP2D6. The mean elimination half-life is 12 hours (range: 8 to 17 hours). Only trace amounts are present in the urine; 70% of the dose appears as metabolites in the urine and 20% is excreted in the feces.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP1A2
Duloxetine is metabolized by CYP2D6 and CYP1A2. Duloxetine is a CYP1A2 inhibitor and a moderate CYP2D6 inhibitor. In two clinical studies, the average increase in AUC of the CYP1A2 substrate theophylline was 7% (range: 1% to 15%) and 20% (range: 13% to 27%) when coadministered with duloxetine 60 mg twice daily. When duloxetine was administered at a dose of 60 mg twice daily with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold.