VENLAFAXINE
DESCRIPTION
Venlafaxine hydrochloride is a structurally novel antidepressant for oral administration. It is chemically unrelated to tricyclic, tetracyclic, or other available antidepressant agents. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[(alpha)-[(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C 17 H 27 NO 2 HCl. Its molecular weight is 313.87.
venlafaxine hydrochloride
Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol: water (0.2 M sodium chloride) partition coefficient is 0.43.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active 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 (alpha)-1 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 and extensively metabolized in the liver. O-desmethylvenlafaxine (ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% of a single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100% when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or on the formation of ODV.
The degree of binding of venlafaxine to human plasma is 27%±2% at concentrations ranging from 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30%±12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not expected.
Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 days of multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, elimination half-life and steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-dosing. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2 L/h/kg, respectively; elimination half-life is 5±2 and 11±2 hours, respectively; and steady-state volume of distribution is 7.5±3.7 L/kg and 5.7±1.8 L/kg, respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens.
Age and Gender
A pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered due to age or gender differences. Dosage adjustment based upon the age or gender of a patient is generally not necessary (see " DOSAGE AND ADMINISTRATION " ).
Liver Disease
In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A large degree of inter subject variability was noted. Three patients with more severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects.
Dosage adjustment is necessary in these patients (see " DOSAGE AND ADMINISTRATION " ).
Renal Disease
In a renal impairment study, venlafaxine elimination half-life after oral administration was prolonged by about 50% and clearance was reduced by about 24% in renally impaired patients (GFR =10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced by about 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40% although clearance was unchanged in patients with renal impairment (GFR =10-70 mL/min) compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged by about 142% and clearance was reduced by about 56%, compared to normal subjects. A large degree of inter subject variability was noted.
Dosage adjustment is necessary in these patients (see " DOSAGE AND ADMINISTRATION " ).
CLINICAL TRIALS
The efficacy of SENTOSA (venlafaxine hydrochloride) as a treatment for depression was established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration with SENTOSA in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed SENTOSA doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of 25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of inpatients meeting DSM-III-R criteria for major depression with melancholia whose SENTOSA doses were titrated in a range of 150 to 375 mg/day (t.i.d schedule). In these 5 studies, SENTOSA was shown to be significantly superior to placebo on at least 2 of the following 3 measures: Hamilton Depression Rating Scale (total score), Hamilton depressed mood item, and Clinical Global Impression--Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo in outpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data from the 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the range of 75 to 225 mg/day. There was no suggestion of increased response with doses greater than 225 mg/day.
While there were no efficacy studies focusing specifically on an elderly population, elderly patients were included among the patients studied. Overall, approximately 2 / 3 of all patients in these trials were women. Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
INDICATIONS AND USAGE
SENTOSA (venlafaxine hydrochloride) is indicated for the treatment of depression.
The efficacy of SENTOSA in the treatment of depression was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III or DSM-III-R category of major depressive disorder and in a 4-week controlled trial of inpatients meeting diagnostic criteria for major depressive disorder with melancholia (see " CLINICAL PHARMACOLOGY ").
A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
The effectiveness of SENTOSA in long-term use, that is, for more than 4 to 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use SENTOSA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
CONTRAINDICATIONS
SENTOSA (venlafaxine hydrochloride) is contraindicated in patients known to be hypersensitive to it.
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see " WARNINGS ").
WARNINGS
Potential for Interaction with Monoamine Oxidase Inhibitors
Adverse reactions, some of which were serious, have been reported in patients who have recently been discontinued from a monoamine oxidase inhibitor (MAOI) and started on SENTOSA, or who have recently had SENTOSA therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death. In patients receiving antidepressants with pharmacological properties similar to venlafaxine in combination with a monoamine oxidase inhibitor, there have also been reports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. Some cases presented with features resembling neuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported in association with the combined use of tricyclic antidepressants and MAOIs. These reactions have also been reported in patients who have recently discontinued these drugs and have been started on an MAOI. Therefore, it is recommended that SENTOSA not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of SENTOSA, at least 7 days should be allowed after stopping SENTOSA before starting an MAOI.
Sustained Hypertension
Venlafaxine treatment is associated with sustained increases in blood pressure. (1) In a premarketing study comparing three fixed doses of venlafaxine (75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure (SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially no changes in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo group. (2) An analysis for patients meeting criteria for sustained hypertension (defined as treatment-emergent SDBP >/= 90 mm Hg and >/= 10 mm Hg above baseline for 3 consecutive visits) revealed a dose-dependent increase in the incidence of sustained hypertension for venlafaxine:
Probability of Sustained Elevation in SDBP
(Pool of Premarketing Venlafaxine Studies)
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 patients with sustained hypertension and the 19 venlafaxine patients who were discontinued from treatment because of hypertension (<1% of total venlafaxine-treated group) revealed that most of the blood pressure increases were in a modest range (10-15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could have adverse consequences. Therefore, it is recommended that patients receiving venlafaxine have regular monitoring of blood pressure. For patients who experience a sustained increase in blood pressure while receiving venlafaxine, either dose reduction or discontinuation should be considered.
PRECAUTIONS
General
Anxiety and Insomnia
Treatment-emergent anxiety, nervousness, and insomnia were more commonly reported for venlafaxine-treated patients compared to placebo-treated patients in a pooled analysis of short-term, double-blind, placebo-controlled depression studies:
Symptom
Venlafaxine Placebo
n = 1033 n = 609
Anxiety 6% 3%
Nervousness 13% 6%
Insomnia 18% 10%
Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%, respectively, of the patients treated with venlafaxine in the phase 2-3 depression studies.
Changes in Appetite and Weight
Treatment-emergent anorexia was more commonly reported for venlafaxine-treated (11%) than placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled depression studies. A dose-dependent weight loss was often noted in patients treated with venlafaxine for several weeks. Significant weight loss, especially in underweight depressed patients, may be an undesirable result of venlafaxine treatment. A loss of 5% or more of body weight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treated with placebo and 3% of patients treated with another antidepressant. However, discontinuation for weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patients in the phase 2-3 depression trials).
Activation of Mania/Hypomania
During phase 2-3 trials, hypomania or mania occurred in 0.5% of patients treated with venlafaxine. 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, SENTOSA (venlafaxine hydrochloride) should be used cautiously in patients with a history of mania.
Hyponatremia
Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur with venlafaxine. This should be taken into consideration in patients who are, for example, volume-depleted, elderly, or taking diuretics.
Mydriasis
Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at risk of acute narrow angle glaucoma should be monitored.
Seizures
During premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less. SENTOSA should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
Skin and Mucous Membrane Bleeding
The risk of skin and mucous membrane bleeding may be increased in patients taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously in patients predisposed to bleeding at these sites.
Suicide
The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Close supervision of high-risk patients should accompany initial drug therapy. Prescriptions for SENTOSA should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness
Clinical experience with SENTOSA in patients with concomitant systemic illness is limited. Caution is advised in administering SENTOSA to patients with diseases or conditions that could affect hemodynamic responses or metabolism.
SENTOSA 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 sytematically excluded from many clinical studies during the product' premarketing testing. Evaluation of the electrocardiograms for 769 patients who received SENTOSA in 4- to 6-week double-blind placebo-controlled trials, however, showed that the incidence of trial-emergent conduction abnormalities did not differ from that with placebo. The mean heart rate in SENTOSA-treated patients was increased relative to baseline by about 4 beats per minute.
The electrocardiograms for 357 patients who received SENTOSA XR (the extended-release form of venlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval (QTc) for SENTOSA XR-treated patients was increased relative to that for placebo-treated patients (increase of 4.7 msec for SENTOSA XR and decrease of 1.9 msec for placebo). In these same trials, the mean change from baseline in heart rate for SENTOSA XR-treated patients was significantly higher than that for placebo (a mean increase of 4 beats per minute for SENTOSA XR and 1 beat per minute for placebo). The clinical significance of these changes is unknown.
In patients with renal impairment (GFR=10-70 mL/min) or cirrhosis of the liver, the clearances of venlafaxine and its active metabolite were decreased, thus prolonging the elimination half-lives of these substances. A lower dose may be necessary (see " DOSAGE AND ADMINISTRATION "). SENTOSA (venlafaxine hydrochloride), like all antidepressants, should be used with caution in such patients.
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe SENTOSA:
Interference with Cognitive and Motor Performance
Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of healthy individuals. The results revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that SENTOSA therapy does not adversely affect their ability to engage in such activities.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Nursing
Patients should be advised to notify their physician if they are breast-feeding an infant.
Concomitant Medication
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol
Although SENTOSA has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking SENTOSA.
Allergic Reactions
Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic phenomenon.
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
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 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 (C max ) of the drug were increased by about 60%. However, co-administration 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 pre-existing 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 pyschomotor 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 (Cl/F) of a single 2 mg dose of haloperidol by 42%, which resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol C max increased 88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t 1/2 ) 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. O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium.
Drugs Highly Bound to Plasma Protein
Venlafaxine is not highly bound to plasma proteins; therefore, administration of SENTOSA to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug.
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.
CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, 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' 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, C max , and C min increased by about 35% in the presence of venlafaxine. The 2-OH-desipramine AUC's 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.
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 health 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 C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown.
CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2 substrate.
CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. The clinical significance of this finding is unknown.
CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by CYP2C19 (see Diazepam above).
Monoamine Oxidase Inhibitors
See " CONTRAINDICATIONS " and " WARNINGS ."
CNS-Active Drugs
The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is advised if the concomitant administration of venlafaxine and such drugs is required.
Electroconvulsive Therapy
There are no clinical data establishing the benefit of electroconvulsive therapy combined with SENTOSA treatment.
Postmarketing Spontaneous Drug Interaction Reports
See " ADVERSE REACTIONS , Postmarketing Reports ."
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m 2 basis, the maximum recommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels of venlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patients receiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.
Mutagenicity
Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured CHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was not mutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving 200 times, on a mg/kg basis, or 50 times, on a mg/m 2 basis, the maximum human daily dose. The no effect dose was 67 times (mg/kg) or 17 times (mg/m 2 ) the human dose.
Impairment of Fertility
Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m 2 basis
Pregnancy
Teratogenic Effects--Pregnancy Category C
Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m 2 basis. However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. These effects occurred at 10 times (mg/kg) or 2.5 times (mg/m 2 ) the maximum human daily dose. The no effect dose for rat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human dose on a mg/m 2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery
The effect of SENTOSA® (venlafaxine hydrochloride) on labor and delivery in humans is unknown.
Nursing Mothers
Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from SENTOSA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Usage in Children
Safety and effectiveness in individuals below 18 years of age have not been established.
Geriatric Use
Of the 2,897 patients in phase 2-3 depression studies with SENTOSA, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience generally has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usually in the elderly.
The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (see " CLINICAL PHARMACOLOGY "). No dose adjustment is recommended for the elderly on the basis of age alone, although other clinical circumstances, some of which may be more common in the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see " DOSAGE AND ADMINISTRATION ").
ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Nineteen percent (537/2897) of venlafaxine patients in phase 2-3 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: CNS
-------------------------------------------------------------------------------------------------------------------------------
Venlafaxine Placebo
-------------------------------------------------------------------------------------------------------------------------------
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
Commonly Observed Adverse Events in Controlled Clinical Trials
The most commonly observed adverse events associated with the use of SENTOSA® (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., incidence for SENTOSA 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 as well as abnormal ejaculation/orgasm and impotence in men.
Adverse Events Occurring at an Incidence of 1% or More Among SENTOSA-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 SENTOSA-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 1
Treatment-Emergent Adverse Experience Incidence in
4- to 8-Week Placebo-Controlled Clinical Trials 1 Body System Preferred Term
------------------------------------------------------------------------------------------------------------------------------------------------------------
SENTOSA Placebo
(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%
CardiovascularVasodilatation 4% 3%
Increased blood pressure/hypertension 2% --
Tachycardia 2% --
Postural hypotension 1% --
Dermatological Sweating 12% 3%
Rash 3% 2%
Pruritus 1% --
GastrointestinalNausea 37% 11%
Constipation 15% 7%
Anorexia 11% 2%
Diarrhea 8% 7%
Vomiting 6% 2%
Dyspepsia 5% 4%
Flatulence 3% 2%
MetabolicWeight loss 1% --
Nervous System 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%
Paresthesia 3% 2%
Libido decreased 2% --
Agitation 2% --
Confusion 2% 1%
Thinking abnormal 2% 1%
Depersonalization 1% --
Depression 1% --
Urinary retention 1% --
Twitching 1% --
RespirationYawn 3% --
Special Senses Blurred vision 6% 2%
Taste perversion 2% --
Tinnitus 2% --
Mydriasis 2% --
Urogenital System 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 SENTOSA (venlafaxine hydrochloride) are included, and are rounded to the nearest %. Events for which the SENTOSA 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, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, urinary tract infection, and dysmenorrhea 3
--Incidence less than 1%.
2 Incidence based on number of male patients.
3 Incidence based on number of female patients.
Dose Dependency of Adverse Events
A comparison of adverse event rates in a fixed-dose study comparing SENTOSA (venlafaxine hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with SENTOSA 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 SENTOSA 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.