Side Effects of Effexor (venlafaxine)

Effexor (venlafaxine) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant used to treat depression, depression with associated symptoms of anxiety, generalized anxiety disorder, social anxiety disorder, and adults with panic disorder. 

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. 

Effexor 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 Effexor increases the effect of serotonin and norepinephrine in the brain. Effexor is available in an extended release formulation (Effexor XR). 

Common side effects of Effexor include:

• nausea,
• headaches,
• anxiety,
• insomnia,
• drowsiness,
• loss of appetite,
• dizziness,
• ejaculation disorder,
• sweating,
• dry mouth, and
• weight loss

Serious side effects of Effexor include:

• increased blood pressure,
• seizures, and
• increased risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults with depression and other psychiatric disorders. 

If Effexor is discontinued abruptly, withdrawal symptoms may occur such as:

• dizziness,
• headache,
• nausea,
• changes in mood, or
• changes in the sense of smell, and taste. 

Drug interactions of Effexor include monoamine oxidase inhibitors (MAOIs) because it 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 Effexor 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. 

Combining Effexor with the following may increase the risk of bleeding:

• aspirin,
• nonsteroidal anti-inflammatory drugs (NSAIDs),
• warfarin or other drugs that are associated with bleeding . 

The effects of Effexor on the fetus during pregnancy are unknown. It is unknown if Effexor is secreted in breast milk, and therefore, if it may have an effect on nursing infants. Consult your doctor before breastfeeding. 

Venlafaxine, like most anti-depressants, can cause:

• nausea,
• headaches,
• anxiety,
• insomnia,
• drowsiness, and
• loss of appetite.

Other side effects that can occur are:

• dizziness,
• ejaculation disorder,
• sweating,
• dry mouth, and
• weight loss

Increased blood pressure can occur, and blood pressure should be monitored.

Seizures have been reported.

The FDA suggests if anti-depressants are discontinued abruptly, symptoms may occur such as dizziness, headache, nausea, changes in mood, or changes in the sense of smell, taste, etc. (Such symptoms even may occur when even a few doses of anti-depressant are missed.) Therefore, it is generally recommended that the dose of anti-depressant be reduced gradually when therapy is discontinued.

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with depression and other psychiatric disorders. Anyone considering the use of venlafaxine 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.

Associated With Discontinuation Of Treatment

Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies discontinued treatment due to an adverse event. The more common events ( ≥ 1%) associated with discontinuation and considered to be drug-related (i.e., those events associated with dropout at a rate approximately twice or greater for venlafaxine compared to placebo) included:

Incidence In Controlled Trials

Commonly Observed Adverse Events In Controlled Clinical Trials

The most commonly observed adverse events associated with the use of venlafaxine tablets, USP (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine tablets, USP at least twice that for placebo), derived from the 1% incidence table below, were:

• asthenia,
• sweating,
• nausea,
• constipation,
• anorexia,
• vomiting,
• somnolence,
• dry mouth,
• dizziness,
• nervousness,
• anxiety,
• tremor, and
• blurred vision 
• abnormal ejaculation/orgasm and impotence in men.

Adverse Events Occurring at an Incidence of 1% or More Among Venlafaxine tablets, USP-Treated Patients

The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among venlafaxine tablets, USP-treated patients who participated in short-term (4 to 8 week) placebo-controlled trials in which patients were administered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

TABLE 2: Treatment-Emergent Adverse Experience Incidence in 4 to 8 Week Placebo-Controlled Clinical Trials1

Dose Dependency Of Adverse Events

A comparison of adverse event rates in a fixed-dose study comparing venlafaxine tablets, USP 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine tablets, USP use, as shown in the table that follows. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine tablets, USP group.

Tests for potential dose relationships for these events (Cochran- Armitage Test, with a criterion of exact 2 sided p-value ≤ 0.05) suggested a dose-dependency for several adverse events in this list, including:

• chills,
• hypertension,
• anorexia,
• nausea,
• agitation,
• dizziness,
• somnolence,
• tremor,
• yawning,
• sweating, and
• abnormal ejaculation.

TABLE 3: Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial

Adaptation To Certain Adverse Events

Over a 6 week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., dizziness and nausea), but less to other effects (e.g., abnormal ejaculation and dry mouth).

Vital Sign Changes

Venlafaxine tablets, USP treatment (averaged over all dose groups) in clinical trials was associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared with a decrease of about 1 beat per minute for placebo.

In controlled clinical trials, venlafaxine tablets, USP was associated with mean increases in diastolic blood pressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase.

Laboratory Changes

Of the serum chemistry and hematology parameters monitored during clinical trials with venlafaxine tablets, USP, a statistically significant difference with placebo was seen only for serum cholesterol. In premarketing trials, treatment with venlafaxine tablets, USP was associated with a mean final on-therapy increase in total cholesterol of 3 mg/dL.

Patients treated with venlafaxine tablets, USP for at least 3 months in placebo-controlled 12 month extension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over the study period and tended to be greater with higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol = 50 mg/dL from baseline and to a value = 261 mg/dL or 2) an average on-therapy increase in serum cholesterol = 50 mg/dL from baseline and to a value = 261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients.

ECG Changes

In an analysis of ECGs obtained in 769 patients treated with venlafaxine tablets, USP and 450 patients treated with placebo in controlled clinical trials, the only statistically significant difference observed was for heart rate, i.e., a mean increase from baseline of 4 beats per minute for venlafaxine tablets, USP. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo.

Other Events Observed During The Premarketing Evaluation Of Venlafaxine

During its premarketing assessment, multiple doses of venlafaxine tablets, USP were administered to 2897 patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of venlafaxine hydrochloride extended-release capsules, multiple doses were administered to 705 patients in Phase 3 major depressive disorder studies and venlafaxine tablets, USP was administered to 96 patients. During its premarketing assessment, multiple doses of venlafaxine hydrochloride extended-release capsules were also administered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social Anxiety Disorder studies.

The conditions and duration of exposure to venlafaxine in both development programs varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (venlafaxine tablets, USP only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTARTbased Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an event of the type cited on at least one occasion while receiving venlafaxine. All reported events are included except those already listed in TABLE 2 and those events for which a drug cause was remote. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. It is important to emphasize that, although the events reported occurred during treatment with venlafaxine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a whole

Frequent

• accidental injury,
• chest pain substernal,
• neck pain

Infrequent

• face edema,
• intentional injury,
• malaise,
• moniliasis,
• neck rigidity,
• pelvic pain,
• photosensitivity reaction,
• suicide attempt,
• withdrawal syndrome

Rare

• appendicitis,
• bacteremia,
• carcinoma,
• cellulitis.

Cardiovascular system

Frequent

• migraine 

Infrequent

• angina pectoris,
• arrhythmia,
• extrasystoles,
• hypotension,
• peripheral vascular disorder (mainly cold feet and/or cold hands),
• syncope,
• thrombophlebitis

Rare

• aortic aneurysm,
• arteritis,
• first-degree atrioventricular block,
• bigeminy,
• bradycardia,
• bundle branch block,
• capillary fragility,
• cardiovascular disorder (mitral valve and circulatory disturbance),
• cerebral ischemia,
• coronary artery disease,
• congestive heart failure,
• heart arrest,
• mucocutaneous hemorrhage,
• myocardial infarct,
• pallor.

Digestive system

Frequent

• eructation

Infrequent

• bruxism,
• colitis,
• dysphagia,
• tongue edema,
• esophagitis,
• gastritis,
• gastroenteritis,
• gastrointestinal ulcer,
• gingivitis,
• glossitis,
• rectal hemorrhage,
• hemorrhoids,
• melena,
• oral moniliasis,
• stomatitis,
• mouth ulceration

Rare

• cheilitis,
• cholecystitis,
• cholelithiasis,
• duodenitis,
• esophageal spasm,
• hematemesis,
• gastrointestinal hemorrhage,
• gum hemorrhage,
• hepatitis,
• ileitis,
• jaundice,
• intestinal obstruction,
• parotitis,
• periodontitis,
• proctitis,
• increased salivation,
• soft stools,
• tongue discoloration.

Endocrine system

Rare

• goiter,
• hyperthyroidism,
• hypothyroidism,
• thyroid nodule,
• thyroiditis.

Hemic and lymphatic system

Frequent

• ecchymosis

Infrequent 

• anemia,
• leukocytosis,
• leukopenia,
• lymphadenopathy,
• thrombocythemia,
• thrombocytopenia;

Rare

• basophilia,
• bleeding time increased,
• cyanosis,
• eosinophilia,
• lymphocytosis,
• multiple myeloma,
• purpura.

Metabolic and nutritional

Frequent

• edema,
• weight gain

Infrequent

• alkaline phosphatase increased,
• dehydration,
• hypercholesteremia,
• hyperglycemia,
• hyperlipemia,
• hypokalemia,
• SGOT (AST) increased,
• SGPT (ALT) increased,
• thirst

Rare

• alcohol intolerance,
• bilirubinemia,
• BUN increased,
• creatinine increased,
• diabetes mellitus,
• glycosuria,
• gout,
• healing abnormal,
• hemochromatosis,
• hypercalcinuria,
• hyperkalemia,
• hyperphosphatemia,
• hyperuricemia,
• hypocholesteremia,
• hypoglycemia,
• hyponatremia,
• hypophosphatemia,
• hypoproteinemia,
• uremia.

Musculoskeletal system

Infrequent

• arthritis,
• arthrosis,
• bone pain,
• bone spurs,
• bursitis,
• leg cramps,
• myasthenia,
• tenosynovitis

Rare

• pathological fracture,
• myopathy,
• osteoporosis,
• osteosclerosis,
• plantar fasciitis,
• rheumatoid arthritis,
• tendon rupture.

Nervous system

Frequent

• trismus,
• vertigo

Infrequent

• akathisia,
• apathy,
• ataxia,
• circumoral paresthesia,
• CNS stimulation,
• emotional lability,
• euphoria,
• hallucinations,
• hostility,
• hyperesthesia,
• hyperkinesia,
• hypotonia,
• incoordination,
• libido increased,
• manic reaction,
• myoclonus,
• neuralgia,
• neuropathy,
• psychosis,
• seizure,
• abnormal speech,
• stupor;

Rare

• akinesia,
• alcohol abuse,
• aphasia,
• bradykinesia,
• buccoglossal syndrome,
• cerebrovascular accident,
• loss of consciousness,
• delusions,
• dementia,
• dystonia,
• facial paralysis,
• feeling drunk,
• abnormal gait,
• Guillain-Barre Syndrome,
• hyperchlorhydria,
• hypokinesia,
• impulse control difficulties,
• neuritis,
• nystagmus,
• paranoid reaction,
• paresis,
• psychotic depression,
• reflexes decreased,
• reflexes increased,
• suicidal ideation,
• torticollis.

Respiratory system

Frequent

• bronchitis,
• dyspnea

Infrequent

• asthma,
• chest congestion,
• epistaxis,
• hyperventilation,
• laryngismus,
• laryngitis,
• pneumonia,
• voice alteration

Rare

• atelectasis,
• hemoptysis,
• hypoventilation,
• hypoxia,
• larynx edema,
• pleurisy,
• pulmonary embolus,
• sleep apnea.

Skin and appendages

Infrequent

• acne,
• alopecia,
• brittle nails,
• contact dermatitis,
• dry skin,
• eczema,
• skin hypertrophy,
• maculopapular rash,
• psoriasis,
• urticaria

Rare

• erythema nodosum,
• exfoliative dermatitis,
• lichenoid dermatitis,
• hair discoloration,
• skin discoloration,
• furunculosis,
• hirsutism,
• leukoderma,
• petechial rash,
• pustular rash,
• vesiculobullous rash,
• seborrhea,
• skin atrophy,
• skin striae.

Special senses

Frequent

• abnormality of accommodation,
• abnormal vision

Infrequent

• cataract,
• conjunctivitis,
• corneal lesion,
• diplopia,
• dry eyes,
• eye pain,
• hyperacusis,
• otitis media,
• parosmia,
• photophobia,
• taste loss,
• visual field defect

Rare

• blepharitis,
• chromatopsia,
• conjunctival edema,
• deafness,
• exophthalmos,
• angle-closure glaucoma,
• retinal hemorrhage,
• subconjunctival hemorrhage,
• keratitis,
• labyrinthitis,
• miosis,
• papilledema,
• decreased pupillary reflex,
• otitis externa,
• scleritis,
• uveitis.

Urogenital system

Frequent

• metrorrhagia*,
• prostatic disorder (prostatitis and enlarged prostate)*,
• vaginitis*

Infrequent

• albuminuria,
• amenorrhea*,
• cystitis,
• dysuria,
• hematuria,
• leukorrhea*,
• menorrhagia*,
• nocturia,
• bladder pain,
• breast pain,
• polyuria,
• pyuria,
• urinary incontinence,
• urinary urgency,
• vaginal hemorrhage*

Rare

• abortion*,
• anuria,
• balanitis*,
• breast discharge,
• breast engorgement,
• breast enlargement,
• endometriosis*,
• fibrocystic breast,
• calcium crystalluria,
• cervicitis*,
• ovarian cyst*,
• prolonged erection*,
• gynecomastia (male)*,
• hypomenorrhea*,
• kidney calculus,
• kidney pain,
• kidney function abnormal,
• female lactation*,
• mastitis,
• menopause*,
• oliguria,
• orchitis*,
• pyelonephritis,
• salpingitis*,
• urolithiasis,
• uterine hemorrhage*,
• uterine spasm*,
• vaginal dryness*.

* Based on the number of men and women as appropriate.

Postmarketing Reports

Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have been received since market introduction and that may have no causal relationship with the use of venlafaxine include the following:

• agranulocytosis,
• anaphylaxis,
• angioedema,
• aplastic anemia,
• catatonia,
• congenital anomalies,
• impaired coordination and balance,
• CPK increased,
• deep vein thrombophlebitis,
• delirium,
• EKG abnormalities such as QT prolongation;
• cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillation and ventricular tachycardia, including torsade de pointes;
• toxic epidermal necrolysis/Stevens-Johnson syndrome,
• erythema multiforme,
• extrapyramidal symptoms (including dyskinesia and tardive dyskinesia),
• angle-closure glaucoma,
• hemorrhage (including eye and gastrointestinal bleeding),
• hepatic events (including GGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty liver),
• interstitial lung disease,
• involuntary movements,
• LDH increased,
• neutropenia,
• night sweats,
• pancreatitis,
• pancytopenia,
• panic,
• prolactin increased,
• renal failure,
• rhabdomyolysis,
• shock-like electrical sensations or tinnitus (in some cases, subsequent to the discontinuation of venlafaxine or tapering of dose), and
• syndrome of inappropriate antidiuretic hormone secretion (usually in the elderly).

There have been reports of elevated clozapine levels that were temporally associated with adverse events, including seizures, following the addition of venlafaxine. There have been reports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients receiving warfarin therapy.

Controlled Substance

Venlafaxine tablets, USP is not a controlled substance.

Physical And Psychological Dependence

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.

Discontinuation effects have been reported in patients receiving venlafaxine.

While venlafaxine tablets, USP has not been systematically studied in clinical trials 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 history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of venlafaxine tablets, USP (e.g., development of tolerance, incrementation of dose, drugseeking behavior).

As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Alcohol

A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and psychometric effects induced by ethanol in these same subjects when they were not receiving venlafaxine.

Cimetidine

Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than is venlafaxine.

The overall pharmacological activity of venlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with preexisting hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

Diazepam

Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam.

Haloperidol

Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects decreased total oral-dose clearance (CI/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t½) was unchanged. The mechanism explaining this finding is unknown.

Lithium

The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. Odesmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs, below).

Drugs Highly Bound To Plasma Protein

Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine tablets, USP to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.

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 and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when venlafaxine tablets, USP is initiated or discontinued.

Drugs That Inhibit Cytochrome P450 Isoenzymes

CYP2D6 Inhibitors

In vitro and in vivo studies indicate that venlafaxine is metabolized to its active metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine.

However, although imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical study involving CYP2D6-poor and €“extensive metabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.

Ketoconazole

A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desvenlafaxine (ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and PM subjects, respectively.

Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs - 2% to 206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs - 38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on average by approximately 23% in EMs and 53% in PMs, (range in PMs 4% to 134%).

Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV. Therefore, caution is advised if a patient €™s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.

CYP3A4 Inhibitors

In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, Ndesmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small.

The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution is advised should a patient's therapy include venlafaxine and any agent(s) that produce potent simultaneous inhibition of these two enzyme systems.

Drugs Metabolized By Cytochrome P450 Isoenzymes

CYP2D6

In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.

Imipramine

Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine. The 2-OHdesipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown.

Metoprolol

Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by approximately 30 to 40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, Odesmethylvenlafaxine.

Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised with coadministration of venlafaxine and metoprolol.

Venlafaxine treatment has been associated with dose-related increases in blood pressure in some patients. It is recommended that patients receiving venlafaxine tablets, USP have regular monitoring of blood pressure.

Risperidone

Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited the CYP2D6- mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9- hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).

CYP3A4

Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Indinavir

In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.