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Physician’s Resource The physician’s psychoactive medication resource guide 25% of your patients taking an antidepressant will have weight gain and the weight gain is directly caused by the antidepressant.
Venlafaxine Brand name (Effexor) Effexor withdrawal. Effexor withdrawal side effects, Effexor withdrawal warnings, Effexor  withdrawal precautions, Effexor withdrawal adverse effects, overdose, withdrawal symptoms  and Effexor natural alternatives. Before you begin the spiral down with Effexor, try giving  your body what it really wants.  Your patients will be experiencing head symptoms when attempting to discontinue Effexor. Fatigue, nausea and flu like symptoms are also common. At times anxiety and insomnia will be an issue during withdrawal or normal usage of Effexor. Whether you want your patient to remain on Effexor or discontinue Effexor, they do not have to suffer the ADR's. How to Get Off Effexor, is written for the patient, physician and pharmacists. The book provides the patient a step-by-step process to eliminate the side effects. The AMA acknowledges up to 20% of patients attempting to taper off an antidepressant will not complete the process due to withdrawal side effects. Let's handle the 20% that need to additional help. Click here to read free copy on The Road Back site. Effexor Withdrawal Effexor Side Effects Effexor - Alert from the F.D.A. FDA ALERT [07/2005]: Suicidal Thoughts or Actions in Children and Adults Patients with depression or other mental illnesses often think about or attempt suicide. Closely watch anyone taking antidepressants, especially early in treatment or when the dose is changed. Patients who become irritable or anxious, or have new or increased thoughts of suicide or other changes in mood or behavior (or their care givers) should contact their healthcare professional right away. Children Taking antidepressants may increase suicidal thoughts and actions in about 1 out of 50 people 18 years or younger. FDA has approved Zoloft for use in children only if they have obsessive- compulsive disorder. Adults Several recent scientific publications report the possibility of an increased risk for suicidal behavior in adults who are being treated with antidepressant medications. Even before these reports became available, FDA began a complete review of all available data to determine whether there is an increased risk of suicidal thinking or behavior in adults being treated with antidepressant medications. It is expected that this review will take a year or longer to complete. In the meantime, FDA is highlighting that adults being treated with antidepressant medication, particularly those being treated for depression, should be watched closely for worsening of depression and for increased suicidal thinking or behavior. This information reflects FDA’s preliminary analysis of data concerning this drug. FDA is considering, but has not reached a final conclusion about, this information. FDA intends to update this sheet when additional information or analyses become available. Fatal venlafaxine overdose with acinar zone 3 liver cell necrosis. Shaw MW, Sheard JD. Department of Cellular Pathology, University Hospital Aintree, Liverpool, UK. We present a case of fatal venlafaxine overdose in a 34-year-old male with a history of depression and previous suicide attempts. He presented unwell, and his condition deteriorated with the development of rhabdomyocytolysis and renal failure. Although treatment was provided, this was unsuccessful, and he died within a day of his admission. A postmortem examination was
performed, and the findings included an acinar zone 3 pattern of liver cell necrosis and a very high level of serum venlafaxine in the deceased. No other elevated drug levels were detected. From this case, it is clear that venlafaxine overdose was the primary cause of a fatal acinar zone 3 pattern of liver cell necrosis. As far as we are aware, this is the first reported case of fatal acinar zone 3 liver necrosis caused by venlafaxine overdose alone. Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning: a case report. Hanekamp BB, Zijlstra JG, Tulleken JE, Ligtenberg JJ, van der Werf TS, Hofstra LS. Intensive and Respiratory Care, Groningen University Medical Centre, Groningen, the Netherlands. b.b.hanekamp@int.umcg.nl Newer, more selective, antidepressant agents are increasingly being used as first-line treatment. However, clinical experience in patients after a deliberate overdose is limited. We present a case of venlafaxine intoxication complicated by a late rise in creatine kinase, seizures and serotonin syndrome. Rhabdomyolysis prolonged the hospital stay in our patient but had no other serious consequences. Physicians should be aware of this late phenomenon in patients with venlafaxine poisoning. Severe rhabdomyolysis following venlafaxine overdose. Pascale P, Oddo M, Pacher P, Augsburger M, Liaudet L. Division of Critical Care, Department of Internal Medicine, University Hospital, Lausanne 1011, Switzerland. Venlafaxine is a recently developed serotoninergic antidepressant whose reported toxicity at overdose levels includes central nervous system depression, seizures, and cardiovascular toxicity. The authors now present a case of venlafaxine overdose in a young woman complicated by a rise in plasma creatine kinase activity up to 52,600 U/L. Immediate therapy with intravenous fluids, bicarbonate, and furosemide was administered, and there were no further complications, notably no renal failure. This case supports the notion that venlafaxine can induce direct skeletal muscle toxicity leading to severe rhabdomyolysis. Therefore, clinicians should monitor muscle enzymes in patients with venlafaxine overdose to detect the development of rhabdomyolysis at an early stage and to initiate appropriate therapy rapidly. Effects of paroxetine and venlafaxine XR on heart rate variability in depression. Davidson J, Watkins L, Owens M, Krulewicz S, Connor K, Carpenter D, Krishnan R, Nemeroff C. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. Depressed patients may exhibit reduced heart rate variability (HRV), and antidepressants which block norepinephrine uptake may also lower HRV. This study compared paroxetine (PAR) and venlafaxine XR (VEN-XR) on HRV. Outpatients were randomly assigned to double-blind treatment with PAR up to 40 mg or VEN-XR up to 225 mg daily. HRV measures of parasympathetic control consisted of change in R-R interval during forced 10-second breaths and respiratory sinus arrhythmia (RSA) during paced breathing. Ex vivo estimates of serotonin and norepinephrine transporter occupancy were obtained before and after treatment, as were measures of depression, anxiety, and resilience. Plasma drug concentrations were measured at end point. Forty-nine patients entered treatment; 44 of whom were evaluable (n = 22 per group). Significant within-group reductions were noted in R-R interval variation and in RSA after VEN-XR only. Between-group analyses showed significant group-by-time interaction, with greater reduction in R-R interval variation and in RSA for VEN-XR compared with PAR. Improvement in resiliency correlated significantly with norepinephrine transporter occupancy for VEN-XR. Further comparisons of selective serotonin reuptake inhibitor and serotonin and norepinephrine reuptake inhibitor drugs on HRV are warranted. Example of how an Effexor taper can go: Question: I had been taking Effexor XR for close to 9 years before tapering off. I used the plan from The Road to Recovery to withdraw from 225 mg per day over a 10 week period. The withdrawal went quite well with few side effects. I have been off Effexor completely for 3 weeks now and the withdrawal symptoms are awful: brain zaps, irritability, headaches, body aches, and I am so emotional I begin to weep at the drop of a hat. I am continuing to take the supplements as directed in the plan, but things seem to be getting worse instead of better. Suggestions? I need help. Answer: How much Omega 3 are you taking each day? Give me a breakdown of what you are doing. Somewhere at the time you were doing good and you began to not feel well we will find the item to address. Response: Thank you for your prompt reply. I have been taking 6 omega 3 caps/day; two in the morning, two around 11:00 am, and two around 4:00 pm. I am also taking the barley grass powder-1tbs- at the same times. I am taking 4 tsp of cherry extract around 8:00 pm. I am sleeping quite well. In fact since I have been off Effexor and taking the cherry extract I have stopped having the bizarre dreams that have been a part of my life for so long. I usually feel best early in the day. Depending on my activity, level the side effects tend to get worse as the day goes on. The more active I am, the more intense the brain zaps. I usually have a headache by late afternoon-early evening. Once I take the cherry extract and go to bed, the headache is gone. I certainly will appreciate any feedback you can give me. Answer: You might try taking 1 teaspoon of cherry starting around noon, 4 pm, 8 pm and at bedtime as normal. If the cherry at night gets rid of the headache, odds are it will during the day as well. Cherry should not make you tired during the day. If it does, cut the amount back a little. Response: I have been taking the cherry concentrate 3x / day as you suggested for five days now. I have definitely seen a reduction in side effects. I am feeling much better, thank you! I have been completely off Effexor for four weeks. I would like you to know how much I appreciate your book and the help you have given me. It is so wonderful to feel alive again. I have so much more energy and interest in the activities going on around me. I have accomplished more in the past few months than I have in the past few years. Thanks again for the work you are doing. You are truly making a difference in people's lives. Peace, W.D. Pharmacology Antidepressant Venlafaxine is a phenethylamine bicyclic derivative, chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents. The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its major metabolite, O-desmethylvenlafaxine (ODV), are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or alpha1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitory activity. Pharmacokinetics: Venlafaxine is well absorbed, with peak plasma concentrations occurring approximately 2 hours after dosing. Venlafaxine is extensively metabolized, with O-desmethylvenlafaxine, (ODV, the only major active metabolite) peak plasma levels occurring approximately 4 hours after dosing. Following single doses of 25 to 75 mg, mean (+/- SD) peak plasma concentrations of venlafaxine range from 34+/-14 to 96+/-43 ng/mL, respectively, and are reached in 2+/-1 hours, and mean peak ODV plasma concentrations range from 58+/-18 to 178+/- 40 ng/mL and are reached in 4+/-2 hours. Approximately 87% of a single dose of venlafaxine is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (30%), conjugated ODV (26%), or other minor metabolites (27%). Multiple-Dose Pharmacokinetic Profile: Steady-state concentrations of both venlafaxine and ODV in plasma were attained after approximately 3 days of multiple dose therapy. The clearance of venlafaxine is slightly (15%) lower following multiple doses than following a single dose. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total daily dose administered t.i.d. The mean +/- SD steady-state plasma clearances of venlafaxine and ODV are 1.3+/-0.6 and 0.4+/-0.2 L/h/kg, respectively; elimination half-life is 5+/-2 and 11+/-2 hours, respectively. Venlafaxine and ODV renal clearances are 49+/-27 and 94+/-56 mL/h/kg, respectively, which correspond to 5+/-3.0% and 25+/-13% of an administered venlafaxine dose recovered in urine as venlafaxine and ODV, respectively. Similar steady-state volumes of distribution are exhibited for venlafaxine (7+/-4 L/kg) and ODV (6+/-2 L/kg). Venlafaxine and ODV are less than 35% bound to plasma proteins. Therefore, protein-binding-induced drug interactions with venlafaxine are not expected. Food has no significant effect on the absorption of venlafaxine. When equal daily doses of venlafaxine were administered either b.i.d. or t.i.d., drug exposure (AUC) and fluctuation in plasma levels were comparable. Age and Gender: Age and sex do not significantly affect the pharmacokinetics of venlafaxine. A 20% reduction in clearance was noted for ODV in subjects over 60 years old; this was possibly caused by the decrease in renal function that typically occurs with aging. Dosage adjustment based upon age or gender is generally not necessary (See Dosage). Hepatic Disease: In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV were significantly altered. Venlafaxine elimination half-life was prolonged by about 30%, and clearance was decreased by about 50%. ODV elimination half-life was also prolonged (by about 60%) and its clearance decreased by about 30%. Three patients with more severe cirrhosis had a 90% decrease in venlafaxine clearance. Dosage adjustment is necessary in patients with liver disease (See Dosage). Renal Disease: In patients with moderate to severe impairment of renal function (GFR=10-70 mL/min), venlafaxine elimination half-life was prolonged by 50%, and clearance was deceased by about 24%. ODV elimination half-life was prolonged by about 40%, but clearance was unchanged. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was decreased by about 56%. Dosage adjustment is necessary in patients with renal disease (See Dosage). Indications For the symptomatic relief of depressive illness. The effectiveness of venlafaxine in long-term use (i.e., for more than 4 to 6 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use venlafaxine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Contraindications Patients with known hypersensitivity to venlafaxine or to any of the components of the formulation. MAO Inhibitors: There have been reports of serious, sometimes fatal reactions in patients receiving antidepressants with pharmacological properties similar to those of venlafaxine in combination with a MAO inhibitor. Therefore, venlafaxine should not be used in combination with MAO inhibitors or within two weeks of terminating treatment with MAO inhibitor's. Treatment with MAO inhibitors should not be started until two weeks after discontinuation of venlafaxine therapy. Warnings Sustained Hypertension: Treatment with venlafaxine was associated with modest but sustained increases in blood pressure during premarketing studies. Sustained hypertension, defined as treatment-emergent supine diastolic blood pressure (SDBP) >= 90 mm Hg and 10 mm Hg above baseline for 3 consecutive visits, showed the following incidence and dose-relationship in Table I. ----------------------------------------------- Table I Probability of Sustained Elevation in SDBP (Pool of Premarketing Studies with venlafaxine) ----------------------------------------------- Treatment Group Incidence of Sustained Elevation in SDBP ----------------------------------------------- Venlafaxine <100 mg/day 3% 101-200 mg/day 5% 201-300 mg/day 7% >300 mg/day 13% Placebo 2% ----------------------------------------------- An analysis of the blood pressure increases in patients with sustained hypertension and in the 19 patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) showed that most of the blood pressure increases were in the range of 10 to 15 mm Hg, SDBP. Since in individual patients sustained increases of this magnitude could have adverse consequences, it is recommended that patients receiving venlafaxine have their blood pressure monitored regularly. For patients who experience a sustained increase in blood pressure during treatment with venlafaxine, either a dose reduction or discontinuation of venlafaxine should be considered. Precautions Suicide: The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization. In order to reduce the risk of overdose, prescriptions for venlafaxine should be written for the smallest quantity of tablets consistent with good patient management. Seizures: During premarketing testing, seizures were reported in 8 out of 3082 venlafaxine-treated patients (0.26%). In 5 of the 8 cases, patents were receiving doses of 150 mg/day or less. However, patients with a history of convulsive disorders were excluded from most of these studies. venlafaxine should be used cautiously in patents with a history of seizures, and should be promptly discontinued in any patient who develops seizures. Activation of Mania/Hypomania: During Phase II and III trials, mania or hypomania occurred in 0.5% of venlafaxine-treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, venlafaxine should be used cautiously in patients with a history of mania. Patients with Concomitant Illness: Clinical experience with venlafaxine in patients with concomitant systemic illness is limited. Caution is advised in administering venlafaxine to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Patients should be questioned about any prescripton or "over the counter drugs" that they are taking, or planning to take, since there is a potential for interactions. Cardiac Disease: Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's clinical trials. Evaluation of the electrocardiograms for 769 patients who received venlafaxine in 4- to 6 week double-blind trials showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate was increased by about 4 beats per minute during treatment. Venlafaxine treatment has been associated with sustained hypertension (see Warnings). Hepatic and Renal Disease: In patients with hepatic or renal disease the pharmacokinetic disposition of both venlafaxine and ODV are significantly altered. Dosage adjustment is necessary in these patients (See Dosage). Occupational Hazards: Any psychoactive drug may impair judgement, thinking or motor skills. Therefore, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. Pregnancy, Labor and Delivery: There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed. Lactation: It is not known whether venlafaxine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, lactating women should not nurse their infants while receiving venlafaxine. Children: Safety and efficacy in children below the age of 18 have not been established. Geriatrics: Of the 2,897 patients in Phase II and III trials, 357 (12%) were 65 years of age or older. No overall differences in effectiveness and safety were observed between these patients and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. Discontinuation Symptoms: While the discontinuation effects of venlafaxine have not been systematically evaluated in controlled clinical trials, a retrospective survey of new events occurring during taper or following discontinuation revealed the following six events that occurred at an incidence of at least 5%, and for which the incidence for venlafaxine was at least twice the placebo incidence: asthenia, dizziness, headache, insomnia, nausea and nervousness. Therefore, it is recommended that the dosage be tapered gradually and the patient monitored (See Dosage). Drug Interactions: As with all drugs, the potential for interaction by a variety of mechanisms is a possibility. Lithium: The steady-state pharmacokinetics of venlafaxine administered as 50 mg every 8 hours was not affected when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. Venlafaxine had no effect on the pharmacokinetics of lithium. It should be noted that the venlafaxine dose was in the low end of the therapeutic dosage, as was the single lithium dose. The potential interaction of venlafaxine and lithium in clinical practice is unknown. Diazepam: The steady-state pharmacokinetics of venlafaxine administered as 50 mg every 8 hours was not affected when a single 10 mg oral dose of diazepam was administered to 18 healthy male subjects. Venlafaxine had no effect on the pharmacokinetics of diazepam or its active metabolite, desmethyidiazepam. It should be noted that the venlafaxine dose was in the low end of the therapeutic dosage, as was the single diazepam dose. The potential interaction of venlafaxine and diazepam in clinical practice is unknown. Cimetidine: Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs in 18 healthy male subjects resulted in inhibition of first-pass metabolism of venlafaxine. 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, there was no effect on the pharmacokinetics of ODV. The overall pharmacological activity of venlafaxine plus ODV is expected to rise only slightly, and no dosage adjustment should be necessary for most subjects. However, for patients with pre-existing hypertension, for elderly patients and for patients with hepatic or renal dysfunction, the interaction associated with the concomitant use of cimetidine and venlafaxine is not known and potentially could be more pronounced. Therefore, caution is advised in these patients. Other CNS-Active Drugs: The risk of using venlafaxine in combination with other CNS-active drugs (including alcohol) has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required. Electroconvulsive Therapy: There are no clinical data on the use of electroconvulsive therapy combined with venlafaxine treatment. Cytochrome P450 IID6: Venlafaxine is metabolized to its active metabolite, ODV, by cytochrome P450 IID6 Therefore, the potential exists for a drug interaction between venlafaxine and drugs that inhibit cytochrome P450-IID6 metabolism. Venlafaxine is a relatively weak inhibitor of cytochrome P450 IID6, however, the clinical significance of this finding is unknown. Drug Abuse and Dependence: 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. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability. While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behaviour 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 (e.g., development of tolerance incrementation of dose, drug-seeking behaviour). Adverse Effects Commonly Observed Adverse Reactions: The most commonly observed adverse events associated with the use of venlafaxine (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for venlafaxine at least twice that for placebo), derived from the 1% incidence Table III, were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness nervousness, anxiety, tremor, blurred vision, and abnormal ejaculation/orgasm and impotence in men. Adverse Reactions Associated with Discontinuation of Treatment: Nineteen percent (537/2897) of venlafaxine-treated patients in Phase II and III depression studies discontinued treatment due to an adverse reaction (see Table II). The more common events (>=1%) associated with discontinuation of treatment 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 Table II. --------------------------------------------------------------- Table II Adverse Reactions Associated with Discontinuation of Treatment --------------------------------------------------------------- Venlafaxine Placebo --------------------------------------------------------------- CNS Somnolence 3% 1% Insomnia 3% 1% Dizziness 3% -- Nervousness 2% -- Dry Mouth 2% -- Anxiety 2% 1% Gastrointestinal Nausea 6% 1% Urogenital Abnormal Ejaculation* 3% -- Other Headache 3% 1% Asthenia 2% -- Sweating 2% -- * percentages based on the number of males. -- Less than 1% --------------------------------------------------------------- Incidence in Controlled Trials: Table III 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-treated patients who participated in 4- to 8-week placebo-controlled trials in which patients were administered doses in the range of 75 to 375 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose study comparing Effexor 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with Effexor use, as shown in Table IV. 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 Effexor 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 III  Treatment-Emergent Adverse Experience Incidence in 4-to 8-Week Placebo-Controlled Clinical Trials (Percentage) ------------------------------------------------------------------------- Effexor Placebo Body System Preferred Term (n=1033) (n=609) ------------------------------------------------------------------------- Body as a whole Headache 25 24 Asthenia 12 6 Infection 6 5 Chills 3 -- Chest Pain 2 1 Trauma 2 1 Cardiovascular Vasodilatation 4 3 Increased blood/pressure hypertension 2 -- Tachycardia 2 -- Postural hypotension 1 -- Dermatological Sweating 12 3 Rash 3 2 Pruritus 1 -- Gastrointestinal Nausea 37 11 Constipation 15 7 Anorexia 11 2 Diarrhoea 8 7 Vomiting 6 2 Dyspepsia 5 4 Flatulence 3 2 Metabolic Weight loss 1 -- Nervous Somnolence 23 9 Dry mouth 22 11 Dizziness 19 7 Insomnia 18 10 Nervousness 13 6 Anxiety 6 3 Tremor 5 1 Abnormal Dreams 4 3 Hypertonia 3 2 Paraesthesia 3 2 Libido decreased 2 -- Agitation 2 -- Confusion 2 1 Thinking abnormal 2 1 Depersonalization 1 -- Depression 1 -- Urinary retention 1 -- Twitching 1 -- Respiration Yawn 3 -- Special Senses Blurred vision 6 2 Taste perversion 2 -- Tinnitus 2 -- Mydriasis 2 -- Urogenital Abnormal ejaculation/ orgasm 12 [2] 2 Impotence 6 [2] 2 Urinary frequency 3 2 Urination impaired 2 -- Orgasm disturbance 2 [3] -- [3] Menstrual disorder 1 [3] -- [3] ------------------------------------------------------------------------- [1] Events reported by at least 1% of patients treated with Effexor are included, and are rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite, myalgia, arthralgia, amnesia, hypaesthesia, rhinitis pharyngitis, sinusitis cough increased urinary tract infection and dysmenorrhoea [3] -- Incidence less than 1% [2] Incidence based on number of male patients. [3] Incidence based on number of female patients. ------------------------------------------------------------------------- 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 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. It 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 O.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase (see Warnings). Laboratory Changes: Of the serum chemistry and hematology parameters monitored during clinical trials with venlafaxine, a statistically significant difference with placebo was seen only for serum cholesterol, i.e., patients treated with venlafaxine had mean increases from baseline of 3 mg/dL, a change of unknown clinical significance. ----------------------------------------------------------------- Table IV Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial ----------------------------------------------------------------- Effexor (mg/day) Body System/ Placebo 75 225 375 Preferred Term (n=92) (n=89) (n=89) (n=88) ----------------------------------------------------------------- Body as Whole Abdominal pain 3.3% 3.4% 2.2% 8.0% Asthenia 3.3% 16.9% 14.6% 14.8% Chills 1.1% 2.2% 5.6% 6.8% Infection 2.2% 2.2% 5.6% 2.3% Cardiovascular Hypertension 1.1% 1.1% 2.2% 4.5% Vasodilatation 0.0% 4.5% 5.6% 2.3% Digestive System Anorexia 2.2% 14.6% 13.5% 17.0% Dyspepsia 2.2% 6.7% 6.7% 4.5% Nausea 14.1% 32.6% 38.2% 58.0% Vomiting 1.1% 7.9% 3.4% 6.8% Nervous Agitation 0.0% 1.1% 2.2% 4.5% Anxiety 4.3% 11.2% 4.5% 2.3% Dizziness 4.3% 19.1% 22.5% 23.9% Insomnia 9.8% 22.5% 20.2% 13.6% Libido decreased 1.1% 2.2% 1.1% 5.7% Nervousness 4.3% 21.3% 13.5% 12.5% Somnolence 4.3% 16.9% 18.0% 26.1% Tremor 0.0% 1.1% 2.2% 10.2% Respiratory Yawn 0.0% 4.5% 5.6% 8.0% Skin and Appendages Sweating 5.4% 6.7% 12.4% 19.3% Special Senses Abnormality of accommodation 0.0% 9.1% 7.9% 5.6% Urogenital System Abnormal ejaculation/ orgasm 0.0% 4.5% 2.2% 12.5% Impotence 0.0% 5.8% 2.1% 3.6% (number of men) (n=63) (n=52) (n=48) (n=56) ----------------------------------------------------------------- ECG Changes: In an analysis of ECGs obtained in 769 patients treated with venlafaxine 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. Other Events Observed During the Premarketing Evaluation of Venlafaxine: During its premarketing assessment, multiple doses of venlafaxine were administered to 2,181 patients in phase II and III studies. The conditions and duration of exposure of venlafaxine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient 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 COSTART-based dictionary terminology . The frequencies presented, therefore, represent the proportion of the 2,181 patients exposed to multiple doses 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 III 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 classified by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. The frequent adverse events have been provided below. Body as a whole: accidental injury, malaise, neck pain. Cardiovascular: migraine. Digestive: dysphagia, eructation. Hemic and lymphatic: ecchymosis. Metabolic and nutritional: peripheral edema, weight gain. Nervous: emotional lability, trismus, vertigo. Respiratory: bronchitis, dyspnea. Special senses: abnormal vision, ear pain. Urogenital: anorgasmia, dysuria, hematuria, metrorrhagia*, urination impaired, vaginitis*. * Based on the number of male or female patients as appropriate. Overdose Symptoms and Treatment: Human Experience: There were 14 reports of acute overdose with venlafaxine, either alone or in combination with other drugs and/or alcohol, among the patients included in the premarketing evaluation. The majority of the reports involved ingestions in which the total dose of venlafaxine taken was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 mcg/mL, respectively and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 mcg/mL, respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among the remaining patients, somnolence was the most commonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of the other patients. Overdosage Management: Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitoring of cardiac rhythm and vital signs is recommended. General supportive and symptomatic measures are also recommended. Use of activated charcoal, induction of emesis, or gastric lavage should be considered. Due to the large volume of distribution of venlafaxine hydrochloride, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control centre on the treatment of any overdose. Dosage Adults: The recommended treatment dose is 75 mg per day, administered in two or three divided doses, taken with food. If the expected clinical improvement does not occur after a few weeks, a gradual dose increase to 150 mg/day may be considered. If needed, the dose may be further increased up to 225 mg/day. Increments of up to 75 mg/day should be made at intervals of no less than 4 days. In outpatient settings there was no evidence of the usefulness of doses greater than 225 mg/day for moderately depressed patients. More severely depressed inpatients have responded to higher doses, between 350 and 375 mg/day, given in 3 divided doses. Maximum: The maximum dose recommended is 375 mg per day (in an inpatient setting). Patients With Hepatic Impairment: Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with hepatic cirrhosis compared to normal subjects (see Pharmacology), it is recommended that the total daily dose be reduced by about 50% in patients with moderate hepatic impairment. Since there was much individual variability in clearance between patients with cirrhosis, it may be necessary to reduce the dose even more than 50%, and individualization of dosing may be desirable in some patients. Patients with Renal Impairment: Given the decrease in clearance for venlafaxine and increase in elimination half-life for both venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min) compared to normals (see Pharmacology), it is recommended that the total daily dose be decreased by 25% in patients with mild to moderate renal impairment. It is recommended that the total daily dose be reduced by 50% and the dose be withheld until the dialysis treatment is completed (4 hrs) in patients undergoing hemodialysis. Since there was so much individual variability in clearance between patients with renal impairment, individualization of dosing may be desirable in some patients. Geriatrics: No dose adjustment is recommended for elderly patients on the basis of their age. As with any antidepressant, however, caution should be exercised in treating the elderly. When individualizing the dosage, extra care should be taken when increasing the dose. Discontinuing Venlafaxine: When venlafaxine therapy that has been administered for more than 1 week is stopped, it is generally recommended that the dose be tapered gradually to minimize the risk of discontinuation symptoms. Patients who have received venlafaxine for 6 weeks or more should have their dose tapered gradually over a 2-week period.