Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3541
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Effexor (Tablet)
|
| dailymed-instance:dosage |
Initial Treatment: The recommended
starting dose for Effexor is 75 mg/day, administered in two or
three divided doses, taken with food. Depending on tolerability and
the need for further clinical effect, the dose may be increased to
150 mg/day. If needed, the dose should be further increased up
to 225 mg/day. When increasing the dose, 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 usefulness of doses
greater than 225 mg/day for moderately depressed patients, but
more severely depressed inpatients responded to a mean dose of 350 mg/day.
Certain patients, including more severely depressed patients, may
therefore respond more to higher doses, up to a maximum of 375 mg/day,
generally in three divided doses (see PRECAUTIONS, General, Use in Patients with Concomitant
Illness).<br/>Special Populations:<br/>Treatment of Pregnant Women During the Third Trimester: Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third
trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding . When treating
pregnant women with Effexor during the third trimester, the physician
should carefully consider the potential risks and benefits of treatment.
The physician may consider tapering Effexor in the third trimester.<br/>Dosage for 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 and mild and moderate hepatic impairment compared to normal
subjects (see CLINICAL
PHARMACOLOGY), it is recommended that the total
daily dose be reduced by 50% in patients with mild to moderate hepatic
impairment. Since there was much individual variability in clearance
between subjects with cirrhosis, it may be necessary to reduce the
dose even more than 50%, and individualization of dosing may be desirable
in some patients.<br/>Dosage for Patients with Renal Impairment: Given the decrease in clearance for venlafaxine
and the 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 , it is recommended that
the total daily dose be reduced by 25% in patients with
mild to moderate renal impairment. It is recommended that the total
daily dose be reduced by 50% in patients undergoing hemodialysis.
Since there was much individual variability in clearance between patients
with renal impairment, individualization of dosing may be desirable
in some patients.<br/>Dosage for Elderly Patients: No dose adjustment is recommended for elderly patients on the basis
of 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.<br/>Maintenance Treatment: It is generally
agreed that acute episodes of major depressive disorder require several
months or longer of sustained pharmacological therapy beyond response
to the acute episode. In one study, in which patients responding during
8 weeks of acute treatment with Effexor XR were assigned randomly
to placebo or to the same dose of Effexor XR (75,150, or 225 mg/day, qAM)
during 26 weeks of maintenance treatment as they had received during
the acute stabilization phase, longer-term efficacy was demonstrated.
A second longer-term study has demonstrated the efficacy of Effexor
in maintaining an antidepressant response in patients with recurrent
depression who had responded and continued to be improved during an
initial 26 weeks of treatment and were then randomly assigned to placebo
or Effexor for periods of up to 52 weeks on the same dose (100 to 200mg/day, on a
b.i.d. schedule) . Based on these
limited data, it is not known whether or not the dose of Effexor/Effexor
XR needed for maintenance treatment is identical to the dose needed
to achieve an initial response. Patients should be periodically reassessed
to determine the need for maintenance treatment and the appropriate
dose for such treatment.<br/>Discontinuing Effexor (venlafaxine hydrochloride): Symptoms associated
with discontinuation of Effexor, other SNRIs, and SSRIs, have been
reported . Patients should be monitored for these symptoms when
discontinuing treatment. A gradual reduction in the dose rather than
abrupt cessation is recommended whenever possible. If intolerable
symptoms occur following a decrease in the dose or upon discontinuation
oftreatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the
dose but at a more gradual rate.<br/>SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR: At least 14 days
should elapse between discontinuation of an MAOI and initiation of
therapy with Effexor. In addition, at least 7 days should be allowed
after stopping Effexor before starting an MAOI .
|
| dailymed-instance:descripti... |
Effexor (venlafaxine hydrochloride)
is a structurally novel antidepressant for oral administration. It
is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]
cyclohexanol hydrochloride or (��)-1-[��-[(dimethyl-amino)methyl]-p-methoxybenzyl]
cyclohexanol hydrochloride and has the empirical formula of CHNOHCl. Its molecular weight is
313.87. The structural formula is shown below. 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. Compressed tablets contain venlafaxine hydrochloride equivalent to
25 mg, 37.5 mg, 50 mg, 75 mg, or 100 mg venlafaxine.
Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium
stearate, and sodium starch glycolate.
|
| dailymed-instance:clinicalP... |
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��-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.<br/>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 oralsolution. 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.<br/>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 .<br/>Liver Disease: In 9 subjects
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 subjects compared to
normal subjects. ODV eliminationhalf-life was prolonged by about
60% and clearance decreased by about 30% in cirrhotic subjects compared
to normal subjects. A large degree of intersubject variability was
noted. Three patients with more severe cirrhosis had a more substantial
decrease in venlafaxine clearance (about 90%) compared to normal subjects. In a second study,
venlafaxine was administered orally and intravenously in normal (n
= 21) subjects, and in Child-Pugh A (n = 8) and Child-Pugh B (n =
11) subjects (mildly and moderately impaired, respectively). Venlafaxine
oral bioavailability was increased 2-3 fold, oral elimination half-life
was approximately twice as long and oral clearance was reduced by
more than half, compared to normal subjects. In hepatically impaired
subjects, ODV oral elimination half-life was prolonged by about 40%,
while oral clearance for ODV was similar to that for normal subjects.
A large degree of intersubject variability was noted. Dosage adjustment is necessary in these hepatically impaired patients
.<br/>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. Alarge degree of intersubject
variability was noted. Dosage adjustment is necessary in these patients .
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
Hypersensitivity to venlafaxine
hydrochloride or to any excipients in the formulation. Concomitant use in patients taking
monoamine oxidase inhibitors (MAOIs) is contraindicated .
|
| dailymed-instance:supply |
Effexor (venlafaxine hydrochloride) Tablets are available as follows: 25 mg, peach, shield-shaped
tablet with���25���and a������on one side and���701���on scored reverse side. 37.5 mg, peach, shield-shaped
tablet with���37.5���and a������on one side and���781���on scored reverse side. 50 mg, peach, shield-shaped
tablet with���50���and a������on one side and���703���on scored reverse side. 75 mg, peach, shield-shaped
tablet with���75���and a������on one side and���704���on scored reverse side. 100 mg, peach, shield-shaped
tablet with���100���and a������on one side and���705���on scored reverse side. The appearance of these
tablets is a trademark of Wyeth Pharmaceuticals. Store at controlled room temperature 20��to 25��C (68��to 77��F) in a dry place. Dispense in a well-closed container as defined in
the USP. The unit of use package is intended to be dispensed as a unit. U.S. Patent Nos. 4,535,186, 5,916,923,
and 6,444,708
|
| dailymed-instance:boxedWarn... |
Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal
thinking and behavior (suicidality) in children, adolescents, and
young adults in short-term studies of Major Depressive Disorder (MDD)
and other psychiatric disorders. Anyone considering the use of Effexor
or any other antidepressant in a child, adolescent, or young adult
must balance this risk with the clinical need. Short-term studies
did not show an increase in the risk of suicidality with antidepressants
compared to placebo in adults beyond age 24; there was a reduction
in risk with antidepressants compared to placebo in adults aged 65
and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients
of all ages who are started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality,
or unusual changes in behavior. Families and caregivers should be
advised of the need for close observation and communication with the
prescriber. Effexor is not approved for use in pediatric patients.
(See WARNINGS: Clinical Worsening and Suicide
Risk,PRECAUTIONS: Information for
Patients, and PRECAUTIONS: Pediatric
Use)
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:precautio... |
General:<br/>Discontinuation of Treatment with Effexor: Discontinuation symptoms have been systematically evaluated in patients
taking venlafaxine, to include prospective analyses of clinical trials
in Generalized Anxiety Disorder and retrospective surveys of trials
in major depressive disorder. Abrupt discontinuation or dose reduction
of venlafaxine at various doses has been found to be associated with
the appearance of new symptoms, the frequency of which increased with
increased dose level and with longer duration of treatment. Reported
symptoms include agitation, anorexia, anxiety, confusion, impaired
coordination and balance, diarrhea, dizziness, dry mouth, dysphoric
mood, fasciculation, fatigue, flu-like symptoms, headaches, hypomania,
insomnia, nausea, nervousness, nightmares, sensory disturbances (including
shock-like electrical sensations), somnolence, sweating, tremor, vertigo,
and vomiting. During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine
Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors),
there have been spontaneous reports of adverse events occurring upon
discontinuation of these drugs, particularly when abrupt, including
the following: dysphoric mood, irritability, agitation, dizziness,
sensory disturbances (e.g. paresthesias such as electric shock sensations),
anxiety, confusion, headache, lethargy, emotional lability, insomnia,
hypomania, tinnitus, and seizures. While these events are generally
self-limiting, there have been reports of serious discontinuation
symptoms. Patients should be monitored for these symptoms when discontinuing
treatment with Effexor. A gradual reduction in the dose rather than
abrupt cessation is recommended whenever possible. If intolerable
symptoms occur following a decrease in the dose or upon discontinuation
of treatment, then resuming the previously prescribed dose may be
considered. Subsequently, the physician may continue decreasing the
dose but at a more gradual rate .<br/>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: Anxiety,
nervousness, and insomnia led to drug discontinuation in 2%, 2%, and
3%, respectively, of the patients treated with venlafaxine in the
Phase 2 and Phase 3 depression studies.<br/>Changes in Weight:<br/>Changes in Height:<br/>Changes in Appetite:<br/>Activation of Mania/Hypomania: During Phase 2 and Phase 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, Effexor (venlafaxine hydrochloride) should
be used cautiously in patients with a history of mania.<br/>Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs,
including Effexor. In many cases, this hyponatremia appears to be
the result of the syndrome of inappropriate antidiuretic hormone secretion
(SIADH). Cases with serum sodium lower than 110 mmol/L have been reported.
Elderly patients may be at greater risk of developing hyponatremia
with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise
volume depleted may be at greater risk . Discontinuation of Effexor
should be considered in patients with symptomatic hyponatremia and
appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty
concentrating, memory impairment, confusion, weakness, and unsteadiness,
which may lead to falls. Signs and symptoms associated with more severe
and/or acute cases have included hallucination, syncope, seizure,
coma, respiratory arrest, and death.<br/>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. Effexor
should be used cautiously in patients with a history of seizures.
It should be discontinued in any patient who develops seizures.<br/>Abnormal Bleeding: SSRIs and SNRIs, including Effexor, may increase
the risk of bleeding events. Concomitant use of aspirin, nonsteroidal
anti-inflammatory drugs, warfarin, and other anti-coagulants may add
to this risk. Case reports and epidemiological studies (case-control
and cohort design) have demonstrated an association between use of
drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs
use have ranged from ecchymoses, hematomas, epistaxis, and petechiae
to life-threatening hemorrhages. Patients should
be cautioned about the risk of bleeding associated with the concomitant
use of Effexor and NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Serum Cholesterol Elevation: Clinically relevant increases in serum cholesterol were recorded
in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated
patients treated for at least 3 months in placebo-controlled trials
(see ADVERSE REACTIONS���Laboratory
Changes). Measurement of serum cholesterol levels
should be considered during long-term treatment.<br/>Interstitial Lung Disease and Eosinophilic Pneumonia: Interstitial lung disease and eosinophilic pneumonia
associated with venlafaxine therapy have been rarely reported. The
possibility of these adverse events should be considered in venlafaxine-treated
patients who present with progressive dyspnea, cough or chest discomfort.
Such patients should undergo a prompt medical evaluation, and discontinuation
of venlafaxine therapy should be considered.<br/>Use in Patients with Concomitant Illness: Clinical experience with Effexor in patients
with concomitant systemic illness is limited. Caution is advised in
administering Effexor to patients with diseases or conditions that
could affect hemodynamic responses or metabolism. Effexor 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 premarketing
testing. Evaluation of the electrocardiograms for 769 patients who
received Effexor 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 Effexor-treated patients was increased relative to baseline
by about 4 beats per minute. The electrocardiograms for 357 patients who received Effexor 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 Effexor XR-treated patients was increased relative
to that for placebo-treated patients (increase of 4.7 msec for
Effexor XR and decrease of 1.9 msec for placebo). In these same
trials, the mean change from baseline in heart rate for Effexor XR-treated
patientswas significantly higher than that for placebo (a mean increase
of 4 beats per minute for Effexor XR and 1 beat per minute
for placebo). In a flexible-dose study, with Effexor doses in the
range of 200 to 375 mg/day and mean dose greater than
300 mg/day, Effexor-treated patients had a mean increase in heart
rate of 8.5 beats per minute compared with 1.7 beats per
minute in the placebo group. As increases in heart rate were observed, caution should be exercised
in patients whose underlying medical conditions might be compromised
by increases in heart rate (eg, patients with hyperthyroidism, heart
failure, or recent myocardial infarction), particularly when using
doses of Effexor above 200 mg/day. In patients with renal impairment (GFR=10 to 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 . Effexor (venlafaxine hydrochloride), like all antidepressants,
should be used with caution in such patients.<br/>Information for Patients: Prescribers or other
health professionals should inform patients, their families, and their
caregivers about the benefits and risks associated with treatment
with Effexor and should counsel them in its appropriate use. A patient
Medication Guide about���Antidepressant Medicines, Depression
and Other Serious Mental Illness, and Suicidal Thoughts or Actions���is available for Effexor. The prescriber or health professional should
instruct patients, their families, and their caregivers to read the
Medication Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of
the Medication Guide and to obtain answers to any questions they may
have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert
their prescriber if these occur while taking Effexor. Clinical Worsening and Suicide Risk: Patients,
their families, and their caregivers should be encouraged to be alert
to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, mania, other unusual changes in behavior, worsening of
depression, and suicidal ideation, especially early during antidepressant
treatment and when the dose is adjusted up or down. Families and caregivers
of patients should be advised to look for the emergence of such symptoms
on a day-to-day basis, since changes may be abrupt. Such symptoms
should be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of
the patient's presenting symptoms. Symptoms such as these may
be associated with an increased risk for suicidal thinking and behavior
and indicate a need for very close monitoring and possibly changes
in the medication.<br/>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 Effexor therapy does not adversely
affect their ability to engage in such activities.<br/>Pregnancy: Patients should be advised to notify their physician if they become
pregnant or intend to become pregnant during therapy.<br/>Nursing: Patients should be advised to notify their physician if they are
breast-feeding an infant.<br/>Mydriasis: Mydriasis (prolonged dilation of the pupils of the
eye) has been reported with venlafaxine. Patients should be advised
to notify their physician if they have a history of glaucoma or a
history of increased intraocular pressure .<br/>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, including herbal preparations and nutritional
supplements, since there is a potential for interactions. Patients should be cautioned about the risk of serotonin
syndrome with the concomitant use of Effexor and triptans, tramadol,
tryptophan supplements or other serotonergic agents (see WARNINGS, Serotonin Syndrome and PRECAUTIONS,
Drug Interactions, CNS-Active Drugs). Patients should be cautioned about the concomitant use
of Effexor and NSAIDs, aspirin, warfarin, or other drugs that affect
coagulation since combined use of psychotropic drugs that interfere
with serotonin reuptake and these agents has been associated with
an increased risk of bleeding .<br/>Alcohol: Although Effexor 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 Effexor.<br/>Allergic Reactions: Patients should be advised to notify their
physician if they develop a rash, hives, or a related allergic phenomenon.<br/>Laboratory Tests: There are no specific
laboratory tests recommended.<br/>Drug Interactions: As with all drugs,
the potential for interaction by a variety of mechanisms is a possibility.<br/>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.<br/>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
(C) 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.<br/>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.<br/>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 Cincreased 88% when coadministered with venlafaxine, but
the haloperidol elimination half-life (t) was unchanged.
The mechanism explaining this finding is unknown.<br/>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 (see also CNS-Active Drugs, below).<br/>Drugs Highly Bound to Plasma Protein: Venlafaxine is not highly bound to plasma proteins; therefore, administration
of Effexor to a patient taking another drug that is highly protein
bound should not cause increased free concentrations of the other
drug.<br/>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 Effexor is initiated or discontinued.<br/>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
Cincreased by 26% in EM subjects and 48% in PM subjects.
Cvalues 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 141% 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, 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's therapy include venlafaxine and
any agent(s) that produce potent simultaneous inhibition of these
two enzyme systems.<br/>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, and Cincreased by about 35% in the presence
of venlafaxine. The 2-OH-desipramine 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 30-40% without altering the plasma
concentrations of its active metabolite,�����hydroxymetoprolol.
Metoprolol did not alter the pharmacokinetic profile of venlafaxine
or its active metabolite, O-desmethylvenlafaxine. 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 co-administration 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 Effexor 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 C. 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. In vivo, venlafaxine
75 mg by mouth every 12 hours did not alter the pharmacokinetics of
a single 500 mg dose of tolbutamide or the CYP2C9 mediated formation
of 4-hydroxy-tolbutamide. CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which
is partially metabolized by CYP2C19 (see Diazepam above).<br/>Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.<br/>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. Serotonergic Drugs: Based on the
mechanism of action of Effexor and the potential for serotonin syndrome,
caution is advised when Effexor is co-administered with other drugs
that may affect the serotonergic neurotransmitter systems, such as
triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a
reversible non-selective MAOI), lithium, tramadol, or St. John's Wort
(see WARNINGS, Serotonin
Syndrome). If concomitant treatment of Effexor
with these drugs is clinically warranted, careful observation of the
patient is advised, particularly during treatment initiation and dose
increases (see WARNINGS,
Serotonin Syndrome). The concomitant use of Effexor
with tryptophan supplements is not recommended . Triptans: There have been rare
postmarketing reports of serotonin syndrome with use of an SSRI and
a triptan. If concomitant treatment of Effexor with a triptan is clinically
warranted, careful observation of the patient is advised, particularly
during treatment initiation and dose increases .<br/>Electroconvulsive Therapy: There are no clinical data establishing the benefit
of electroconvulsive therapy combined with Effexor treatment.<br/>Postmarketing Spontaneous Drug Interaction Reports: See ADVERSE REACTIONS,
Postmarketing Reports.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>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/mbasis, 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.<br/>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/mbasis, the maximum human daily dose. The no effect dose was
67 times (mg/kg) or 17 times (mg/m) the human
dose.<br/>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/mbasis.<br/>Pregnancy:<br/>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/mbasis. 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) 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/mbasis. 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.<br/>Non-teratogenic Effects: Neonates exposed to Effexor, other SNRIs (Serotonin
and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin
Reuptake Inhibitors), late in the third trimester have developed complications
requiring prolonged hospitalization, respiratory support, and tube
feeding. Such complications can arise immediately upon delivery. Reported
clinical findings have included respiratory distress, cyanosis, apnea,
seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia,
hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability,
and constant crying. These features are consistent with either a direct
toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation
syndrome. It should be noted that, in some cases, the clinical picture
is consistent with serotonin syndrome . When treating a pregnant woman with Effexor during the
third trimester, the physician should carefully consider the potential
risks and benefits of treatment .<br/>Labor and Delivery: The effect of Effexor (venlafaxine hydrochloride) on labor and delivery in
humans is unknown.<br/>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 Effexor,
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.<br/>Pediatric Use: Safety and effectiveness
in the pediatric population have not been established (see BOX WARNING and WARNINGS, Clinical
Worsening and Suicide Risk). Two placebo-controlled
trials in 766 pediatric patients with MDD and two placebo-controlled
trials in 793 pediatric patients with GAD have been conducted with
Effexor XR, and the data were not sufficient to support a claim
for use in pediatric patients. Anyone considering the use of Effexor in a child or adolescent must
balance the potential risks with the clinical need. Although no studies have been designed to
primarily assess Effexor XR's impact on the growth, development,
and maturation of children and adolescents, the studies that have
been done suggest that Effexor XR may adversely affect weight
and height (see PRECAUTIONS,
General, Changes in Height and Changes in Weight). Should the decision be made to treat
a pediatric patient with Effexor, regular monitoring of weight and
height is recommended during treatment, particularly if it is to be
continued long term. The safety of Effexor XR treatment for pediatric
patients has not been systematically assessed for chronic treatment
longer than six months in duration. In the studies conducted in pediatric patients (ages 6-17), the occurrence
of blood pressure and cholesterol increases considered to be clinically
relevant in pediatric patients was similar to that observed in adult
patients. Consequently, the precautions for adults apply to pediatric
patients (see WARNINGS,
Sustained Hypertension, and PRECAUTIONS, General, Serum
Cholesterol Elevation).<br/>Geriatric Use: Of the 2,897 patients
in Phase 2 and Phase 3 depression studies with Effexor, 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. SSRIs and SNRIs, including Effexor, have been associated with
cases of clinically significant hyponatremia in elderly patients,
who may beat greater risk for this adverse event . The pharmacokinetics of venlafaxine and ODV are not substantially
altered in the elderly . 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).
|
| dailymed-instance:overdosag... |
Human Experience: There were 14 reports
of acute overdose with Effexor (venlafaxine hydrochloride), 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 Effexor
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��g/mL,
respectively, and the peak plasma levels of O-desmethylvenlafaxine
were 3.37 and 1.30��g/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. In postmarketing experience, overdose with venlafaxine has occurred
predominantly in combination with alcohol and/or other drugs. The
most commonly reported events in overdosage include tachycardia, changes
in level of consciousness (ranging from somnolence to coma), mydriasis,
seizures, and vomiting. Electrocardiogram changes (eg, prolongation
of QT interval, bundle branch block, QRS prolongation), ventricular
tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver
necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine
overdosage may be associated with an increased risk of fatal outcomes
compared to that observed with SSRI antidepressant products, but lower
than that for tricyclic antidepressants. Epidemiological studies have
shown that venlafaxine-treated patients have a higher pre-existing
burden of suicide risk factors than SSRI-treated patients. The extent
to which the finding of an increased risk of fataloutcomes can be
attributed to the toxicity of venlafaxine in overdosage as opposed
to some characteristic(s) of venlafaxine-treated patients is not clear.
Prescriptions for Effexor should be written for the smallest quantity
of tablets consistent with good patient management, in order to reduce
the risk of overdose.<br/>Management of Overdosage: Treatment should
consist of those general measures employed in the management of overdosage
with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor
cardiac rhythm and vital signs. General supportive and symptomatic
measures are also recommended. Induction of emesis is not recommended.
Gastric lavage with a large-bore orogastric tube with appropriate
airway protection, if needed, may be indicated if performed soon after
ingestion or in symptomatic patients. Activated charcoal should be
administered. Due to the large volume of distribution of this drug,
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 center for
additional information on the treatment of any overdose. Telephone
numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).
|
| dailymed-instance:genericMe... |
venlafaxine hydrochloride
|
| dailymed-instance:fullName |
Effexor (Tablet)
|
| dailymed-instance:adverseRe... |
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 (ie, those events associated with dropout at a
rate approximately twice or greater for venlafaxine compared to placebo)
included:<br/>Incidence in Controlled Trials:<br/>Commonly Observed Adverse Events in Controlled Clinical Trials: The most commonly observed adverse events associated with the use
of Effexor (incidence of 5% or greater) and not seen
at an equivalent incidence among placebo-treated patients (ie, incidence
for Effexor 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.<br/>Adverse Events Occurring at an Incidence of 1% or More Among
Effexor-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 Effexor-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.<br/>Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose study comparing
Effexor (venlafaxine hydrochloride) 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 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 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.<br/>Adaptation to Certain Adverse Events: Over a 6-week period, there was evidence of adaptation to some adverse
events with continued therapy (eg, dizziness and nausea), but less
to other effects (eg, abnormal ejaculation and dry mouth).<br/>Vital Sign Changes: Effexor (venlafaxine hydrochloride) 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, Effexor 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 .<br/>Laboratory Changes: Of the serum chemistry and hematology parameters monitored
during clinical trials with Effexor, a statistically significant difference
with placebo was seen only for serum cholesterol. In premarketing
trials, treatment with Effexor tablets was associated with a mean
final on-therapy increase in total cholesterol of 3 mg/dL. Patients treated
with Effexor tablets 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 (see PRECAUTIONS-General-Serum Cholesterol
Elevation).<br/>ECG Changes: In an analysis of ECGs obtained in 769 patients
treated with Effexor and 450 patients treated with placebo in controlled
clinical trials, the only statistically significant difference observed
was for heart rate, ie, a mean increase from baseline of 4 beats per
minute for Effexor. 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 (see PRECAUTIONS, General, Use in
Patients with Concomitant Illness).<br/>Other Events Observed During the Premarketing Evaluation of
Venlafaxine: During its premarketing
assessment, multiple doses of Effexor were administered to 2897 patients
in Phase 2 and Phase 3 studies. In addition, in premarketing assessment
of Effexor XR (the extended release form of venlafaxine), multiple
doses were administered to 705 patients in Phase 3 major depressive
disorder studies and Effexor was administered to 96 patients. During
its premarketing assessment, multiple doses of Effexor XR 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 (Effexor 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 COSTART-based
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, increasedsalivation, 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, reflexesdecreased, 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, 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.<br/>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, 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, neuroleptic malignant syndrome-like events (including
a case of a 10-year-old who may have been taking methylphenidate,
was treated and recovered), neutropenia, night sweats, pancreatitis,
pancytopenia, panic, prolactin increased, renal failure, rhabdomyolysis,
serotonin syndrome, shock-like electrical sensations or tinnitus (in
some cases, subsequent to the discontinuation of venlafaxine or taperingof 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.
|
| dailymed-instance:warning |
Clinical Worsening and Suicide Risk: Patients with major
depressive disorder (MDD), both adult and pediatric, may experience
worsening of their depression and/or the emergence of suicidal ideation
and behavior (suicidality) or unusual changes in behavior, whether
or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk
of depression and certain other psychiatric disorders, and these disorders
themselves are the strongest predictors of suicide. There has been
a long standing concern, however, that antidepressants may have a
role in inducing worsening of depression and the emergence of suicidality
in certain patients during the early phases of treatment. Pooled analyses
of short-term placebo-controlled trials of antidepressant drugs (SSRIs
and others) showed that these drugs increase the risk of suicidal
thinking and behavior (suicidality) in children, adolescents, and
young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase
in the risk of suicidality with antidepressants compared to placebo
in adults beyond age 24; there was a reduction with antidepressants
compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and
adolescents with MDD, obsessive compulsive disorder (OCD), or other
psychiatric disorders included a total of 24 short���term trials
of 9 antidepressant drugs in over 4400 patients. The pooled analyses
of placebo-controlled trials in adults with MDD or other psychiatric
disorders included a total of 295 short���term trials (median
duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.
There was considerable variation in risk of suicidality among drugs,
but a tendency toward an increase in the younger patients for almost
all drugs studied. There were differences in absolute risk of suicidality
across the different indications, with the highest incidence in MDD.
The risk differences (drug vs placebo), however, were relatively stable
within age strata and across indications. These risk differences (drug-placebo
difference in the number of cases of suicidality per 1000 patients
treated) are provided in Table 1. No suicides occurred
in any of the pediatric trials. There were suicides in the adult trials,
but the number was not sufficient to reach any conclusion about drug
effect on suicide. It is unknown whether the
suicidality risk extends to longer-term use, i.e., beyond several
months. However, there is substantial evidence from placebo-controlled
maintenance trials in adults with depression that the use of antidepressants
can delay the recurrence of depression. All patients being treated with antidepressants
for any indication should be monitored appropriately and observed
closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of
drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety,
agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,
impulsivity, akathisia (psychomotor restlessness), hypomania, and
mania, have been reported in adult and pediatric patients being treated
with antidepressants for major depressive disorder as well as for
other indications, both psychiatric and nonpsychiatric. Although a
causal link between the emergence of such symptoms and either the
worsening of depression and/or the emergence of suicidal impulses
has not been established, there is concern that such symptoms may
represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen,
including possibly discontinuing the medication, in patients whose
depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient's presenting symptoms. If the decision has been
made to discontinue treatment, medication should be tapered, as rapidly
as is feasible, but with recognition that abrupt discontinuation can
be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION,
Discontinuation of Treatment with Effexor, for
a description of the risks of discontinuation of Effexor). Families and caregivers of patients
being treated with antidepressants for major depressive disorder or
other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation,
irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report
such symptoms immediately to health care providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for Effexor should be written for the smallest quantity
of tablets consistent with good patient management, in order to reduce
the risk of overdose.<br/>Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established
in controlled trials) that treating such an episode with an antidepressant
alone may increase the likelihood of precipitation of a mixed/manic
episode in patients at risk for bipolar disorder. Whetherany of the
symptoms described above represent such a conversion is unknown. However,
prior to initiating treatment with an antidepressant, patients with
depressive symptoms should be adequately screened to determine if
they are at risk for bipolar disorder; such screening should include
a detailed psychiatric history, including a family history of suicide,
bipolar disorder, and depression. It should be noted that Effexor
is not approved for use in treating bipolar depression.<br/>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 Effexor, or who
have recently had Effexor 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 Effexor 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 Effexor, at least 7 days should
be allowed after stopping Effexor before starting an MAOI.<br/>Serotonin Syndrome: The development of a potentially life-threatening
serotonin syndrome may occur with Effexor treatment, particularly
with concomitant use of serotonergic drugs (including SSRIs, SNRIs
and triptans) and with drugs that impair metabolism of serotonin (including
MAOIs). Serotonin syndrome symptoms may include mental status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g.,tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations
(e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms
(e.g., nausea, vomiting diarrhea) . The concomitant use of
Effexor with MAOIs intended to treat depression is contraindicated
(see CONTRAINDICATIONS and WARNINGS,
Potential for Interaction with Monoamine Oxidase Inhibitors). If concomitant
treatment of Effexor with an SSRI, an SNRI or a 5-hydroxytryptamine
receptor agonist (triptan) is clinically warranted, careful observation
of the patient is advised, particularly during treatment initiation
and dose increases . The concomitant use of Effexor with serotonin
precursors (such as tryptophan supplements) is not recommended .<br/>Sustained Hypertension: Venlafaxine treatment
is associated with sustained increases in blood pressure in some patients.
(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 mmHg 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: 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 to 15 mm Hg, SDBP).
Nevertheless, sustained increases of this magnitude could have adverse
consequences. Cases of elevated blood pressure requiring immediate
treatment have been reported in post marketing experience. Pre-existing
hypertension should be controlled before treatment with venlafaxine.
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.<br/>Mydriasis: Mydriasis has been reported in association with venlafaxine;
therefore patients with raised intraocular pressure or at risk of
acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored
(see PRECAUTIONS,
Information for Patients).
|
| dailymed-instance:indicatio... |
Effexor (venlafaxine hydrochloride)
is indicated for the treatment of major depressive disorder. The efficacy of Effexor in the
treatment of major depressive disorder was established in 6-week controlled
trials of adult outpatients whose diagnoses corresponded most closely
to the DSM-III or DSM-III-R category of major depression and in a
4-week controlled trial of inpatients meeting diagnostic criteria
for major depression with melancholia . 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
efficacy of Effexor XR in maintaining an antidepressant response for
up to 26 weeks following 8 weeks of acute treatment was demonstrated
in a placebo-controlled trial. The efficacy of Effexor in maintaining
an antidepressant response in patients with recurrent depression who
had responded and continued to be improved during an initial 26 weeks
of treatment and were then followed for a period of up to 52 weeks
was demonstrated in a second placebo-controlled trial . Nevertheless, the physician who elects to use Effexor/Effexor
XR for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Effexor
|