Side Effects of Cymbalta (duloxetine)

Cymbalta (duloxetine) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant used to treat

• major depressive disorder,
• generalized anxiety disorder,
• diabetic peripheral neuropathic pain,
• fibromyalgia, and
• chronic musculoskeletal pain. 

Cymbalta affects neurotransmitters, the chemicals that nerves within the brain make and release in order to communicate with one another. Neurotransmitters either travel across the space between nerves and attach to receptors on the surface of nearby nerves or they attach to receptors on the surface of the nerves that produce them, to be taken up by the nerve and released again (a process referred to as re-uptake). 

Many experts believe that an imbalance among neurotransmitters is the cause of depression as well as other psychiatric disorders. Serotonin and norepinephrine are two neurotransmitters released by nerves in the brain. 

Cymbalta works by preventing the reuptake of serotonin and epinephrine by nerves after they have been released. Since uptake is an important mechanism for removing released neurotransmitters and terminating their actions on adjacent nerves, the reduced uptake caused by Cymbalta increases the effect of serotonin and norepinephrine in the brain. 

The mechanism responsible for its effectiveness treating pain is not known but also is thought to involve its effects on serotonin and norepinephrine in the brain. 

Common side effects of Cymbalta include

• nausea,
• dry mouth,
• constipation,
• diarrhea,
• fatigue,
• difficulty sleeping, and dizziness, and
• sexual dysfunction (decreased sex drive and delayed orgasm and ejaculation).

Some patients may experience withdrawal reactions upon stopping Cymbalta. Symptoms of withdrawal include

• dizziness,
• anxiety,
• nausea,
• vomiting,
• nervousness,
• diarrhea,
• irritability, and
• insomnia.

Serious side effects of Cymbalta include increased blood pressure, seizures, and increased risk of suicidal thinking and behavior (suicidality) in children and adolescents with depression and other psychiatric disorders. 

Drug interactions of Cymbalta include monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing the MAOI.

• Because combinations of SNRIs and MAOIs may lead to serious, sometimes fatal, reactions including
  • very high body temperature,
  • muscle rigidity,
  • rapid fluctuations of heart rate and blood pressure,
  • extreme agitation progressing to delirium, and
  • coma.
• Similar reactions may occur if Cymbalta is combined with antipsychotics, tricyclic antidepressants or other drugs that affect serotonin in the brain such as
  • tryptophan,
  • sumatriptan,
  • lithium,
  • linezolid,
  • tramadol, and
  • St. John’s wort.
• Fluoxetine, paroxetine, fluvoxamine, and quinidine increase blood levels of Cymbalta by reducing its metabolism in the liver.
• Such combinations may increase adverse effects of Cymbalta.
• Combining Cymbalta with aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin or other drugs that are associated with bleeding may increase the risk of bleeding, because Cymbalta itself is associated with bleeding.
• Cymbalta has an enteric coating that prevents dissolution until it reaches a segment of the gastrointestinal that has a pH higher than 5.5.
• In theory, drugs that raise the pH in the gastrointestinal system (for example, Prilosec) may cause Cymbalta to be released early while conditions that slow gastric emptying (for example, diabetes) may cause premature breakdown of Cymbalta.
• Cymbalta may reduce the breakdown of desipramine, leading to increased blood concentrations of desipramine and potential side effects. 

Cymbalta use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. There is a pregnancy exposure registry that monitors the pregnancy outcomes in women exposed to Cymbalta during pregnancy. 

Cymbalta is excreted into the milk of lactating women. Because the safety of Cymbalta in infants is not known, breastfeeding while on Cymbalta is not recommended.

The most common side effects of Cymbalta (duloxetine) are

• nausea,
• dry mouth,
• constipation,
• diarrhea,
• fatigue,
• difficulty sleeping, and
• dizziness.

Increased blood pressure can occur and should be monitored. Seizures have been reported. Sexual dysfunction (decreased sex drive and delayed orgasm and ejaculation) has been associated with Cymbalta (duloxetine).

Some patients may experience withdrawal reactions upon stopping Cymbalta (duloxetine). Symptoms of withdrawal include:

• dizziness,
• anxiety,
• nausea,
• vomiting,
• nervousness,
• diarrhea,
• irritability, and
• insomnia.

The Cymbalta (duloxetine) dosage should be gradually reduced when therapy is discontinued to prevent symptoms of withdrawal.

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with depression and other psychiatric disorders.

Anyone considering the use of Cymbalta (duloxetine) or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be closely observed for clinical worsening, suicidality, or unusual changes in behavior.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults
• Hepatotoxicity
• Orthostatic Hypotension, Falls and Syncope 
• Serotonin Syndrome 
• Abnormal Bleeding 
• Severe Skin Reactions
• Discontinuation of Treatment with Cymbalta 
• Activation of Mania/Hypomania
• Angle-Closure Glaucoma
• Seizures
• Effect on Blood Pressure 
• Clinically Important Drug Interactions 
• Hyponatremia 
• Urinary Hesitation and Retention

Clinical Trial Data Sources

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
• The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed.
• A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
• Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

Adults

• The data described below reflect exposure to Cymbalta in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294).
• The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively.
• Most patients received doses of a total of 60 to 120 mg per day.
• The data below do not include results of the trial examining the efficacy of Cymbalta in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population.

Children And Adolescents

• The data described below reflect exposure to Cymbalta in pediatric, 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135).
• The population studied (N=476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age, 50.6% female, and 68.6% white.
• Patients received 30-120 mg per day during placebo-controlled acute treatment studies.
• Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to Cymbalta in MDD and GAD clinical trials up to 36-weeks in length, in which most patients received 30-120 mg per day.

Adverse Reactions Reported As Reasons For Discontinuation Of Treatment In Adult Placebo-Controlled Trials

Major Depressive Disorder

• Approximately 8.4% (319/3779) of the patients who received Cymbalta in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo.
• Nausea (Cymbalta 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).

Generalized Anxiety Disorder

• Approximately 13.7% (139/1018) of the patients who received Cymbalta in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo.
• Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Cymbalta 3.3%, placebo 0.4%), and dizziness (Cymbalta 1.3%, placebo 0.4%).

Diabetic Peripheral Neuropathic Pain

• Approximately 12.9% (117/906) of the patients who received Cymbalta in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo.
• Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included
  • nausea (Cymbalta 3.5%, placebo 0.7%),
  • dizziness (Cymbalta 1.2%, placebo 0.4%), and
  • somnolence (Cymbalta 1.1%, placebo 0.0%).

Fibromyalgia

• Approximately 17.5% (227/1294) of the patients who received Cymbalta in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo.
• Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included
  • nausea (Cymbalta 2.0%, placebo 0.5%),
  • headache (Cymbalta 1.2%, placebo 0.3%),
  • somnolence (Cymbalta 1.1%, placebo 0.0%), and
  • fatigue (Cymbalta 1.1%, placebo 0.1%).

Chronic Pain due To Osteoarthritis

• Approximately 15.7% (79/503) of the patients who received Cymbalta in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo.
• Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (Cymbalta 2.2%, placebo 1.0%).

Chronic Low Back Pain

• Approximately 16.5% (99/600) of the patients who received Cymbalta in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo.
• Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included
  • nausea (Cymbalta 3.0%, placebo 0.7%), and
  • somnolence (Cymbalta 1.0%, placebo 0.0%).

Most Common Adult Adverse Reactions

Pooled Trials For All Approved Indications

• The most commonly observed adverse reactions in Cymbalta-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were
  • nausea,
  • dry mouth,
  • somnolence,
  • constipation,
  • decreased appetite, and
  • hyperhidrosis.

Diabetic Peripheral Neuropathic Pain

• The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were
  • nausea,
  • somnolence,
  • decreased appetite,
  • constipation,
  • hyperhidrosis, and
  • dry mouth.

Fibromyalgia

The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation.

Chronic Pain Due To Osteoarthritis

The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.

Chronic Low Back Pain

The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

Adverse Reactions Occurring At An Incidence Of 5% Or More Among Cymbalta-Treated Patients In Adult Placebo-Controlled Trials

Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with Cymbalta and with an incidence greater than placebo.

Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Indications^a

Adverse Reactions Occurring At An Incidence Of 2% Or More Among Cymbalta-Treated Patients In Adult Placebo-Controlled Trials

Pooled MDD And GAD Trials

Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with Cymbalta and with an incidence greater than placebo.

Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials^a,b

DPNP, FM, OA, And CLBP

Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo.

Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials^a

Effects On Male And Female Sexual Function In Adults

• Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment.
• Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with Cymbalta experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo.
• Gender analysis showed that this difference occurred only in males.
• Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo.
• Females did not experience more sexual dysfunction on Cymbalta than on placebo as measured by ASEX total score.
• Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients.
• Physicians should routinely inquire about possible sexual side effects.

Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials

Vital Sign Changes In Adults

• In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, Cymbalta treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic in placebo-treated patients.
• There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure.
• Cymbalta treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in Cymbalta -treated patients, decrease of 0.17 beats per minute in placebo-treated patients).

Laboratory Changes In Adults

• Cymbalta treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Cymbalta-treated patients when compared with placebo-treated patients.
• High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in Cymbalta treated patients compared to placebo.

Electrocardiogram Changes In Adults

• The effect of Cymbalta 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects.
• No QT interval prolongation was detected.
• Cymbalta appears to be associated with concentration-dependent but not clinically meaningful QT shortening.

Other Adverse Reactions Observed During The Premarketing And Postmarketing Clinical Trial Evaluation Of Cymbalta In Adults

• Following is a list of treatment-emergent adverse reactions reported by patients treated with Cymbalta in clinical trials. In clinical trials of all indications, 34,756 patients were treated with Cymbalta.
• Of these, 26.9% (9337) took Cymbalta for at least 6 months, and 12.4% (4317) for at least one year.
• The following listing is not intended to include reactions
  • (1) already listed in previous tables or elsewhere in labeling,
  • (2) for which a drug cause was remote,
  • (3) which were so general as to be uninformative,
  • (4) which were not considered to have significant clinical implications, or
  • (5) which occurred at a rate equal to or less than placebo.
• Reactions are categorized by body system according to the following definitions:
  • frequent adverse reactions are those occurring in at least 1/100 patients;
  • infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients;
  • rare reactions are those occurring in fewer than 1/1000 patients.

Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.

Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus.

Endocrine Disorders — Infrequent: hypothyroidism.

Eye Disorders — Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment.

Gastrointestinal Disorders — Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.

General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.

Infections and Infestations — Infrequent: gastroenteritis and laryngitis.

Investigations — Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.

Metabolism and Nutrition Disorders — Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.

Musculoskeletal and Connective Tissue Disorders — Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.

Nervous System Disorders — Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.

Psychiatric Disorders — Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.

Renal and Urinary Disorders — Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.

Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.

Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness.

Skin and Subcutaneous Tissue Disorders — Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.

Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.

Adverse Reactions Observed In Children And Adolescent Placebo-Controlled Clinical Trials

• The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug reaction profile observed in adult clinical trials.
• The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients (children and adolescents) [see Adverse Reactions Occurring At An Incidence Of 2% Or More Among Cymbalta-Treated Patients In Adult Placebo-Controlled Trials].
• The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness.
• Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with Cymbalta and with an incidence greater than placebo.

Table 6: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10week Pediatric Placebo-Controlled Trials^a

• Other adverse reactions that occurred at an incidence of less than 2% but were reported by more Cymbalta treated patients than placebo treated patients and are associated Cymbalta treatment:
  • abnormal dreams (including nightmare),
  • anxiety,
  • flushing (including hot flush),
  • hyperhidrosis,
  • palpitations,
  • pulse increased, and
  • tremor.
• Discontinuation-emergent symptoms have been reported when stopping Cymbalta.
• The most commonly reported symptoms following discontinuation of Cymbalta in pediatric clinical trials have included
  • headache,
  • dizziness,
  • insomnia, and
  • abdominal pain.

Growth (Height And Weight)

• Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs.
• Pediatric patients treated with Cymbalta in clinical trials experienced a 0.1kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated patients.
• The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the Cymbalta group than in the placebo group (14% and 6%, respectively).
• Subsequently, over the 4-to 6-month uncontrolled extension periods, Cymbalta-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age-and sex-matched peers. In studies up to 9 months, Cymbalta-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in children [7 to 11 years of age] and 1.3 cm increase in adolescents [12 to 17 years of age]).
• While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in children [7 to 11 years of age] and increase of 0.3% in adolescents [12 to 17 years of age]).
• Weight and height should be monitored regularly in children and adolescents treated with Cymbalta.

Postmarketing Spontaneous Reports

• The following adverse reactions have been identified during post-approval use of Cymbalta.
• Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• Adverse reactions reported since market introduction that were temporally related to Cymbalta therapy and not mentioned elsewhere in labeling include:
  • acute pancreatitis,
  • anaphylactic reaction,
  • aggression and anger (particularly early in treatment or after treatment discontinuation),
  • angioneurotic edema,
  • angle-closure glaucoma,
  • colitis (microscopic or unspecified),
  • cutaneous vasculitis (sometimes associated with systemic involvement),
  • extrapyramidal disorder,
  • galactorrhea,
  • gynecological bleeding,
  • hallucinations,
  • hyperglycemia,
  • hyperprolactinemia,
  • hypersensitivity,
  • hypertensive crisis,
  • muscle spasm,
  • rash,
  • restless legs syndrome,
  • seizures upon treatment discontinuation,
  • supraventricular arrhythmia,
  • tinnitus (upon treatment discontinuation),
  • trismus, and
  • urticaria.

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Inhibitors Of CYP1A2

• When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t_1/2 was increased approximately 3-fold.
• Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin.

Inhibitors Of CYP2D6

• Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine.
• Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).

Dual Inhibition Of CYP1A2 And CYP2D6

• Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, And Warfarin)

• Serotonin release by platelets plays an important role in hemostasis.
• Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.
• Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin.
• Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07).
• The total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R-and S-warfarin were not altered by duloxetine.
• Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued.

Lorazepam

• Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.

Temazepam

• Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.

Drugs That Affect Gastric Acidity

• Cymbalta has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol.
• Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics).
• Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine.
• However, co-administration of Cymbalta with aluminum-and magnesium-containing antacids (51 mEq) or Cymbalta with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose.
• It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption.

Drugs Metabolized By CYP1A2

• In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity.
• Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed.
• Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).

Drugs Metabolized By CYP2D6

• Duloxetine is a moderate inhibitor of CYP2D6.
• When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold.

Drugs Metabolized By CYP2C9

• Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine.

Drugs Metabolized By CYP3A

• Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity.
• Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.

Drugs Metabolized By CYP2C19

• Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations.
• Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.

Monoamine Oxidase Inhibitors (MAOIs)

• See prescribing information. 

Serotonergic Drugs

• See prescribing information. 

Alcohol

• When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol.
• In the Cymbalta clinical trials database, three Cymbalta-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction.
• Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen.

CNS Drugs

• See prescribing information. 

Drugs Highly Bound To Plasma Protein

• Because duloxetine is highly bound to plasma protein, administration of Cymbalta to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions.
• However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug).

Drug Abuse And Dependence

Abuse

• In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.
• While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials.
• However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed.
• Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

Dependence

• In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.