Approval date: December 11, 2007
Revision date: March 14, 2008
June 19, 2009
December 01, 2015
February 17, 2017
20 years
Month
Date
Venlafaxine Hydrochloride Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Suicidal Tendencies and Antidepressants
Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressants increase the risk of suicidal thoughts and committing suicidal acts (suicidal ideation) in children, adolescents, and young adults (<24 years of age) compared to placebo. Anyone considering the use of this or other antidepressants in children, adolescents, or young adults (<24 years of age) must weigh their risks against their clinical needs. Short-term clinical trials have not shown an increased risk of suicidal ideation with antidepressant use compared with placebo in adults older than 24 years of age; and in adults aged 65 years and older, the risk of suicidal ideation was reduced with antidepressant use. Depression and certain psychiatric disorders are themselves associated with an increased risk of suicide, and patients of all ages must be closely monitored for worsening clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of treatment with antidepressants. Families and caregivers should be advised that they must closely observe and communicate with their physicians. This product is not approved for use in pediatric patients (see [Precautions]-Warnings, Worsening of Clinical Symptoms and Risk of Suicide, [Precautions]-Information on Patient Use, and [Pediatric Use]).
Drug Name]
Generic Name: Venlafaxine Hydrochloride Extended Release Tablets
English name: Venlafaxine Hydrochloride Sustained-release Tablets
Hanyu Pinyin: Yansuan Wenlafaxin Huanshipian
Ingredients
Main ingredient: Venlafaxine Hydrochloride
Chemical name: (±)-1-[2-(N,N-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride.
Chemical structure formula.
Molecular formula: C17H27NO2-HCl
Molecular weight: 313.87
【Properties】.
This product is a film-coated tablet with a small hole on the surface, which appears white or off-white after removing the coating.
Indications
This product is used for the treatment of depression (including depression with anxiety) and generalized anxiety disorder.
Specification
75mg (based on C17H27NO2)
Dosage]
This product should be taken at a relatively regular time in the morning or evening along with food once a day. It should be taken as a whole avoiding breaking, crushing, chewing or soaking in water.
Initial treatment
Depression
For most patients, the recommended starting dose is 75 mg per day, taken once daily. For some first-time patients, it may be necessary to start treatment at a dose of 37.5 mg per day for 4 to 7 days. For patients who do not respond to treatment with 75 mg per day, dosing up to a maximum of 225 mg per day may be effective. It is recommended that dose increases be made at 75 mg with dosing intervals of 4 days or more. In clinical studies, titration of the drug was allowed over a period of more than 2 weeks at an average dose of approximately 140 to 180 mg per day (see [Clinical Trials]). Clinical safety and efficacy data are lacking for dosing above 225 mg per day (see [Precautions] – for patients with concomitant disorders).
Generalized anxiety disorder
For most patients, the recommended starting dose is 75 mg once daily. For some first-time patients, treatment may need to be initiated at a dose of 37.5 mg per day for 4 to 7 days. For patients who do not respond to treatment with 75 mg per day, dosing up to a maximum of 225 mg per day may be effective. Dose increases of 75 mg are recommended at dose intervals of 4 days or more.
Switching from venlafaxine hydrochloride immediate-release formulation to extended-release formulation
Patients with depression currently treated with venlafaxine hydrochloride immediate-release formulation may be switched to an extended-release formulation at an almost equivalent daily therapeutic dose, e.g., 37.5 mg immediate-release formulation twice daily may be switched to an extended-release formulation of 75 mg once daily. Adjustments need to be made as necessary to suit the individual patient.
Special Populations
Pregnant women in the second trimester of pregnancy
Neonates exposed to this product, other 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), and selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) after the 7th month of pregnancy have an increased incidence of complications requiring respiratory support, gastric tube feeding, and prolonged hospitalization (see [Medications for Pregnant and Lactating Women]). Physicians should carefully weigh the pros and cons of using this product in the second trimester of pregnancy and need to consider dose reduction.
Patients with hepatic insufficiency
Patients with cirrhosis and mild to moderate hepatic insufficiency have a prolonged clearance half-life and decreased clearance of venlafaxine and O-desmethylvenlafaxine (ODV) compared to healthy subjects (see [Pharmacokinetics]), and the total daily dose must be reduced by 50% in patients with mild to moderate hepatic insufficiency. For some patients, it is necessary to reduce the dose by more than 50%. There are large individual differences in drug clearance in patients with cirrhosis, and individualized dosing is recommended.
Patients with renal insufficiency
Patients with renal insufficiency (GFR=10-70 mL/min) have reduced clearance of venlafaxine and prolonged clearance half-life of venlafaxine and ODV compared to healthy subjects (see [Pharmacokinetics]), and the total daily dose must be reduced by 25% to 50%. In patients receiving dialysis, the total daily dose must be reduced by 50%. There are large individual differences in drug clearance in patients with renal insufficiency and individualized dosing is recommended.
Children
There are no data on the safety and efficacy of this product in pediatric and adolescent patients under 18 years of age.
Geriatric Patients
No dose adjustment for age is required in elderly patients. However, as with other medications used for depression and generalized anxiety disorder, geriatric patients should be administered with caution, doses should be individualized, and patients should be carefully monitored if dose increases are needed.
Maintenance therapy
There is no definitive clinical research evidence on how long treatment is required for depression and generalized anxiety disorder. It is generally accepted that after the acute phase of depression has been treated effectively for symptoms, the medication needs to be continued for several months or longer to consolidate treatment. In 1 study, patients who were effective for 8 weeks of treatment were randomized to either a placebo treatment group or a treatment group at the same dose as the previous treatment (75, 150, or 225 mg per day in the morning) for 26 weeks of maintenance treatment, and the results of the trial confirmed maintenance efficacy.
There is no definitive clinical study evidence as to whether the dose of this product for maintenance treatment should be equal to the effective dose of initial treatment.
It has been shown to be effective in patients with generalized anxiety disorder in a 6-month clinical study. Patients with generalized anxiety disorder who are effectively treated should be evaluated periodically during treatment for the need to continue medication.
Discontinuation
Symptoms associated with discontinuation of this product, other SNRIs, and SSRIs have been reported (see [Precautions]). Patients should be monitored for these symptoms when discontinuing the drug, and gradual dose reduction is recommended rather than abrupt discontinuation. If venlafaxine is used for more than 6 weeks, a taper period of at least 2 weeks is recommended. If intolerable reactions occur during tapering or discontinuation, a return to the previously prescribed dose may be considered, after which the dose may be tapered at a slower rate. In clinical studies, the daily dose is often tapered by 75 mg every 1 week. The timing of taper can be determined clinically based on dose, duration of therapy, and individual patient variability.
Switching with a monoamine oxidase inhibitor (MAOI)
Do not start this product until at least 14 days after discontinuation of the MAOI. Do not start treatment with MAOI until at least 7 days after discontinuation of this product (see [Contraindications] and [Precautions] – Warnings).
Adverse Reactions
Summary of adverse reactions
Adverse reactions reported as very common (>1/10) in clinical studies include: nausea, dry mouth, headache, and sweating (including night sweats).
Adverse Reaction Table
Adverse reactions are listed below by system organ category and frequency category and are ranked in descending order according to their medical severity within each frequency category.
The frequencies are defined as follows: very common (≥10%), common (1% to 10% inclusive), occasional (0.1% to 1% inclusive), rare (0.01% to 0.1% inclusive), very rare (<0.01%), and unknown (cannot be estimated from current data).
Body systems Very common Common Occasional Rare Very rare Unknown Blood and lymphatic system abnormalities Granulocyte deficiency*, aplastic anemia*, holocytopenia*, neutropenia* thrombocytopenia* Immune system abnormalities Allergic reactions* Endocrine disorders Inappropriate secretion of antidiuretic hormone* Elevated blood prolactin* Metabolic disorders and nutritional disorders Loss of appetite Hyponatremia* Mental abnormalities Insomnia blurred states of consciousness*, depersonalization*, abnormal dreams
neuroticism, hypersexuality, and
arousal*.
sexual pleasure deficit mania.
hypomania, hallucinations, loss of reality, abnormal orgasm, molarism*, affective apathy
Delirium* Suicidal ideation and suicidal behaviora.
Aggression b abnormal neurological headache* c.
Dizziness, the
sedation inability to sit still*, tremors, tactile disorders, taste disorders syncope, myoclonus
balance disorders*, coordination disorders*, movement disorders* nerve blocker malignant syndrome (NMS)*, 5-hydroxytryptamine syndrome*, convulsions, dystonia* tardive dyskinesia* ocular abnormalities visual impairment, disorders of eye regulation including blurred vision, astigmatism
Closed-angle glaucoma* Ear and vagus abnormalities Tinnitus* Vertigo Heart disease Tachycardia, palpitations* Ventricular tachycardia*, ventricular tachycardia*, ventricular fibrillation, prolonged ECG QT* Vascular symptoms Hypertension, hot flashes Postural hypotension, hypotension* Respiratory, thoracic and mediastinal abnormalities Dyspnea*, yawning Interstitial lung disease*, pulmonary eosinophilia* Gastrointestinal abnormalities Nausea, mouth dryness, constipation diarrhea*, vomiting
gastrointestinal bleeding* pancreatitis* hepatobiliary abnormalities abnormal liver function tests* hepatitis* skin and subcutaneous tissue abnormalities excessive sweating* (including night sweats)* rash, pruritus* rubella*,
hair loss*.
petechiae.
angioedema*, photosensitivity reactions
Stevens-Johnson syndrome*, toxic epidermolysis bullosa*, erythema multiforme* Musculoskeletal and connective tissue abnormalities Increased muscle tone Rhabdomyolysis* Renal and urinary system abnormalities Urinary urgency, urinary retention, urinary frequency* Urinary incontinence* Reproductive system and breast abnormalities Excessive menstruation*, irregular uterine bleeding*, erectile dysfunction, ejaculatory disorders
Systemic abnormalities and administration site reactions Fatigue, malaise, chills* Mucosal bleeding* Laboratory tests Weight loss, weight gain, elevated blood cholesterol Prolonged bleeding time* *Adverse reactions identified after marketing
a Cases of suicidal ideation and suicidal behavior have been reported early after treatment with venlafaxine or discontinuation of treatment (see [Precautions]).
b See [Precautions].
c
In the pooled clinical trials, the incidence of headache was similar with venlafaxine and with placebo.
The following symptoms were reported when venlafaxine was abruptly discontinued, dosed down, or tapered: light mania, anxiety, agitation, nervousness, confusion, insomnia or other sleep disturbances, fatigue, drowsiness, abnormal sensations, dizziness, convulsions, vertigo, headache, flu-like symptoms, tinnitus, coordination and balance disturbances, tremor, sweating, dry mouth, anorexia, diarrhea, nausea, or vomiting. In premarketing studies, the majority of discontinuation reactions were mild and recovered without treatment.
Adverse reactions identified in post-marketing applications: interstitial lung disease (see [PRECAUTIONS] – General Precautions), Takotsubo cardiomyopathy.
Pediatric patients
Overall, adverse reactions to venlafaxine in children/adolescents (6-17 years) are similar to those in adults. For example, decreased appetite, weight loss, increased blood pressure, and elevated cholesterol may occur.
In clinical trials in children, the occurrence of adverse reactions with suicidal ideation was observed. There have also been increased reports of hostility and self-injury, particularly in patients with depression.
In particular, the following adverse events have been observed: dyspepsia, abdominal pain, agitation, bruising, epistaxis, and myalgia.
Contraindications
Contraindicated in patients with hypersensitivity to venlafaxine hydrochloride or any excipients.
Contraindicated in patients taking concomitant MAOIs: do not start venlafaxine until at least 14 days after discontinuation of MAOIs, which may be shortened for reversible monoamine oxidase inhibitors (refer to the instructions for reversible monoamine oxidase inhibitors); do not start treatment with MAOIs until at least 7 days after discontinuation of venlafaxine.
Contraindicated in patients being treated with MAOI such as linezolid or intravenous methylene blue, as this increases the risk of 5-hydroxytryptamine syndrome.
[Caution].
Warning.
Worsening of clinical symptoms and risk of suicide
Adult and pediatric patients with depression, with or without antidepressants, are at risk for worsening of depression and for suicidal ideation and suicidal behavior and abnormal changes in behavior, which may persist until significant remission occurs. Depression and certain psychiatric disorders are known to be associated with suicide risk, and these psychiatric disorders are themselves the strongest predictors of suicide. However, there are long-standing concerns that antidepressants may play a role in inducing worsening depressive symptoms, as well as suicidal ideation and behavior, early in the treatment of some patients. A pooled analysis of short-term placebo-controlled studies of antidepressants (SSRIs and others) showed that in children, adolescents, and young adults (18-24 years of age) with depression and other psychiatric disorders, antidepressants increased the risk of having suicidal thoughts and committing suicidal behaviors (suicidal ideation, behaviors) compared with placebo. However, short-term clinical trials did not show an increased risk of suicidal ideation, behavior with antidepressants compared to placebo in adults aged >24 years; in adults aged 65 years and older, the risk of suicidal ideation, behavior was reduced with antidepressant use.
Placebo-controlled trials in children and adolescents with depression, obsessive-compulsive disorder, or other psychiatric disorders (total of 24 short-term clinical trials, 9 antidepressants, including more than 4400 patients) and placebo-controlled trials in adults with depression or other psychiatric disorders (total of 295 short-term clinical trials [median duration of 2 months], 11 antidepressants, more than 77000 patients). The risk of suicidal ideation and behavior varied considerably among medications, but most of the medication studies showed a trend toward increased risk of suicidal ideation and behavior in younger patients. The absolute risk of suicidal ideation and behavior varied across indications, with the highest absolute risk in depression. Although the absolute risk differed across indications (drug versus placebo), the risk was relatively stable across age groups for different indications. Table 1 provides the risk differences (number of cases per 1000 patients with differences in risk of suicidal ideation, behavior from drug and placebo treatment).
Table 1
Age Range Number of Cases per 1000 Patients with Differences in Risk of Suicidal Ideation, Behavior Produced by Drug and Placebo Treatment Number of Cases with Increase in Drug versus Placebo<18 14 cases with Increase 18-24 5 cases with Decrease in Drug versus Placebo 25-64 1 case with Decrease ≥65 6 cases
No suicidal events in pediatric clinical trials There were suicidal events in adult clinical trials, but the number of occurrences was not sufficient to draw conclusions about the effect of the drug in suicide.
It is unknown whether the risk of suicidal ideation and behavior is perpetuated over the course of long-term medication use (e.g., after several months). However, evidence from placebo-controlled maintenance treatment clinical trials conducted in adults with depression strongly suggests that the use of antidepressants delays the recurrence of depression.
Regardless of the indication treated, all patients receiving antidepressant medication should be appropriately monitored and closely observed for worsening clinical symptoms, suicidal ideation, and abnormal behavioral changes. This is especially true during the initial months of treatment and when doses are increased or decreased.
The following symptoms can occur in adult and pediatric patients with depression, other psychotic or non-psychotic disorders treated with antidepressants: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor agitation), and light mania and hypomania. Although a causal relationship between the presence of these symptoms and the worsening of depression and/or the development of suicidal impulses has not been established, it is noted that the presence of these symptoms may be a precursor to the development of suicidal ideation.
When a patient’s depressive symptoms continue to worsen, suicidal ideation develops, or symptoms that may be a precursor to worsening depressive symptoms or suicidal ideation occur, adjustments to the treatment regimen including possible discontinuation of medication should be carefully considered. This is especially true if these symptoms are severe, sudden, or inconsistent with the patient’s current symptoms.
If a decision is made to discontinue treatment, the dose should be tapered as soon as possible, but be aware that abrupt discontinuation may cause some symptoms (see [PRECAUTIONS] and [DOSAGE] for a description of the risks in discontinuing treatment with this product).
When treating pediatric patients with depression or other psychotic or non-psychotic disorders with antidepressants, families and caregivers should be reminded of the need to monitor the patient for agitation, irritability, abnormal changes in behavior, other symptoms mentioned above, and suicidal ideation, and to report these symptoms to a health care professional as soon as they occur. Family members and caregivers should monitor the patient daily for these symptoms. When using this product, the prescription should start with the smallest amount and be accompanied by good patient management to reduce the risk of overdose.
Screening of patients with bipolar disorder.
Depressive episodes may be the initial manifestation of bipolar disorder. It is generally believed (although not clarified by controlled trials) that treatment of such episodes with antidepressants alone may increase the likelihood of mixed/manic episodes in patients at risk for bipolar disorder. It is not clear whether the symptoms mentioned above imply that such a transition may occur. However, before initiating treatment with antidepressants, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; this screening should include a detailed psychiatric history including a family history of suicide, bipolar disorder and depression. It should be noted that this product is not approved for the treatment of depressive episodes in bipolar disorder.
All patients on venlafaxine should be appropriately monitored and closely observed for worsening clinical symptoms and suicidal behavior, and patients, family members, and caregivers should be alerted to the presence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor agitation), hypomania, mania, other abnormal changes in behavior, worsening depressive symptoms, and suicidal ideation. tendencies, especially during initiation of treatment or during dose changes or changes in dosing regimen. The risk of possible suicide attempts must be considered, especially in depressed patients, and the smallest packaged amount (i.e., box size) of medication should be given, along with effective patient management to reduce the risk of overdose (see [Pediatric Dosage] and [Adverse Reactions]).
Suicidal behavior is known to predispose to risk of depression and certain other psychiatric disorders, which in turn are themselves high risk factors for suicide. Pooled analyses of short-term, placebo-controlled trials have shown that antidepressants (SSRIs and others) increase the risk of suicide in children, adolescents, and young adults (18-24 years of age) when treating depression and other psychiatric disorders. Short-term, controlled trial studies have not shown an increased risk of suicide compared to placebo with antidepressants in adults aged 24 years and older. The use of antidepressants in adults aged 65 years and older was associated with a reduced risk of suicide compared with placebo.
Similar to other 5-hydroxytryptaminergic drugs, treatment with venlafaxine is particularly important in combination with other drugs that act on the 5-hydroxytryptamine transmitter system (including tretinoin, SSRIs, other SNRIs, amphetamines, lithium salts, sibutramine, fentanyl and its analogs, tramadol, methadone, pethidine, methadone, pentazocine, or St. John’s wort), or that may impair 5-hydroxytryptamine metabolism (e.g., MAOIs, including linezolid [an antibiotic that is a reversible, nonselective MAOI] and methylene blue) or antipsychotics or other dopamine antagonists when a potentially life-threatening 5-hydroxytryptamine syndrome or neuroblocker malignant syndrome (NMS)-like reaction may occur. 5-hydroxytryptamine syndrome may include altered mental status (e.g., agitation, hallucinations, and coma), The most severe manifestations of 5-hydroxytryptamine syndrome are similar to NMS and include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuations in vital signs, and altered mental status. . (See [Drug Interactions] – 5-hydroxytryptamine Syndrome).
If there is a reasonable clinical need to combine venlafaxine with other drugs that affect the 5-hydroxytryptaminergic and/or dopaminergic neurotransmitter systems, careful patient observation is recommended, particularly during the initial and dose-escalation phases of therapy.
Combined use of venlafaxine and 5-hydroxytryptamine precursors (e.g., tryptophan supplements) is not recommended.
Potential interactions with monoamine oxidase inhibitors (MAOIs)
Adverse and sometimes serious adverse reactions may occur if treatment with venlafaxine is started shortly after discontinuation of MAOIs or if treatment with MAOIs is started shortly after discontinuation of venlafaxine. These adverse reactions include tremor, myoclonus, excessive sweating, nausea, vomiting, flushing, dizziness, hypothermia with a malignant-like syndrome, seizures, and even death. Serious, even fatal, adverse reactions have been reported with other antidepressants similar in pharmacology to this product in combination with MAOIs. When MAOIs are combined with SSRIs, these reactions also include hypothermia, tonicity, myoclonus and instability of vital signs, and altered mental status (including extreme agitation that progresses to delirium and coma). Malignant syndromes (severe hypothermia, seizures), sometimes fatal, have been reported in some cases treated with tricyclic antidepressants (TCAs) in combination with MAOIs. Similar reports have been reported in patients treated with MAOIs soon after discontinuation of TCAs. There are no human and animal studies combining venlafaxine and MAOIs because venlafaxine inhibits both is norepinephrine and 5-HT reuptake, so this product should not be given concomitantly with MAOIs until at least 14 days after discontinuation of MAOIs or at least 7 days after discontinuation of MAOIs.
5-hydroxytryptamine syndrome
Similar to other 5-hydroxytryptaminergic drugs, 5-hydroxytryptamine syndrome (a potentially life-threatening condition) may occur with treatment with venlafaxine, especially when combined with other drugs that may act on the 5-hydroxytryptamine transmitter system (including tretinoin, SSRIs, SNRIs, amphetamines, lithium salts, sibutramine, St. John’s wort [Hypericum perforatum plant extract], fentanyl and its analogs, tramadol, methamphetamine, tapentadol, pethidine, methadone, pentazocine, tricyclic antidepressants, tryptophan, and buspirone), when combined with drugs that impair 5-hydroxytryptamine metabolism including MAOIs such as methylene blue, when combined with 5-hydroxytryptamine precursor substances (e.g., tryptophan supplements), when combined with antipsychotics or with other dopamine antagonists.
The 5-hydroxytryptamine syndrome may include altered mental status (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, blood pressure instability, hyperthermia, sweating, flushing, and dizziness), neuromuscular disorders (e.g., tremor, tonicity, myoclonus, hyperreflexia, movement disorders), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The most severe form of 5-hydroxytryptamine syndrome is similar to the manifestations of antipsychotic malignant syndrome and includes hyperthermia, muscle tonicity, autonomic instability possibly accompanied by rapid fluctuations in vital signs, and altered mental status. (See [Drug Interactions]
).
Combination of this product with MAOIs (for the treatment of psychiatric disorders) is prohibited. Venlafaxine should also not be initiated in patients receiving MAOI therapy such as linezolid or intravenous methylene blue. The route of administration of methylene blue in all reports was intravenous in the dose range of 1 mg/kg to 8 mg/kg. No other routes (e.g., oral tablet or local tissue injection) or lower doses of methylene blue were reported. In some cases, patients taking venlafaxine may have to receive MAOI therapy such as linezolid or intravenous methylene blue. Venlafaxine should be discontinued prior to initiating MAOI therapy (see [Contraindications] and [Precautions]-Warnings, Potential Interactions with Monoamine Oxidase Inhibitors (MAOIs)).
If there is a reasonable clinical need to combine venlafaxine with an SSRI, SNRI, or other serotonergic drug (e.g., traptans, tricyclic antidepressants, mirtazapine, fentanyl, lithium salts, tramadol, buspirone, tryptophan, and St. John’s wort), close patient monitoring is recommended, especially at the beginning of treatment and at increasing doses (see [Drug Interactions]).
The combined use of venlafaxine and 5-hydroxytryptamine precursor substances (e.g., tryptophan supplements) is not recommended (see [Drug Interactions]).
When these events occur, venlafaxine and any combined serotonergic drugs must be discontinued immediately and symptomatic supportive therapy initiated.
Closed-angle glaucoma
In patients with narrowed atrial angles in the anatomy who have not undergone definitive iridectomy, pupil dilation following the use of multiple antidepressants (including this product) may cause glaucomatous episodes due to atrial angle closure.
Persistent hypertension
Treatment with venlafaxine was associated with persistent elevated blood pressure (defined as a prone diastolic blood pressure (SDBP) ≥90 mmHg and 3 consecutive blood pressure monitoring 10 mmHg above baseline blood pressure, see Table 2) in some patients.
In an analysis of patients taking venlafaxine (immediate-release) who met criteria for persistent hypertension, the incidence of persistent hypertension with venlafaxine (immediate-release) was shown to be associated with increasing doses (see Table 3).
In order to adequately evaluate the incidence of persistent elevation of blood pressure at high doses, studies receiving a mean dose greater than 300 mg/day of venlafaxine hydrochloride extended-release formulations were conducted, but the number of cases was small.
Table 2 . Number (%) of occurrences of sustained elevations of supine diastolic blood pressure (SDBP) according to different indications before marketing
Depressive disorder (MDD)
(75-375 mg/day) Generalized anxiety disorder (generalized anxiety disorder)
(37.5-225mg/day) 19/705 (3) 5/1011 (0.5)
Table 3. incidence of sustained elevation of supine diastolic blood pressure (SDBP) with venlafaxine (immediate release)
Venlafaxine
(mg/day) Incidence<1003%>100- ≤2005%>200- ≤3007%>30013%
In pre-marketing studies of venlafaxine hydrochloride extended-release formulations for the treatment of patients with depression, 0.7% (5/705) of patients discontinued treatment due to elevated blood pressure, most of whom had moderately elevated blood pressure (12 to 16 mm Hg increase in SDBP). In the 2 studies of generalized anxiety disorder, 0.7% (10/1381) and 1.3% (7/535) of patients discontinued treatment due to elevated blood pressure at 8 weeks or 6 months of follow-up, respectively, and most of these patients had moderate elevations (SDBP of 12 to 25 mm Hg at 8 weeks and 8 to 28 mm Hg at 6 months).
Sustained SDBP elevations can have adverse consequences, and the occurrence of hypertension requiring immediate treatment has been reported in post-marketing studies, and pre-existing hypertension must be controlled before treatment with venlafaxine can be administered. It is recommended that blood pressure should be monitored regularly in patients treated with this product. In patients who develop persistent elevated blood pressure after treatment with venlafaxine, reduction or discontinuation of therapy should be considered.
Elevated systolic and diastolic blood pressure
In placebo-controlled premarketing studies, changes in mean blood pressure are shown in Table 4 Mean changes in systolic and diastolic blood pressure in the supine position. Between indications, supine systolic and diastolic blood pressures were confirmed to correlate with increasing doses in patients treated with venlafaxine hydrochloride extended-release formulations.
Table 4. Mean change from baseline in supine systolic and diastolic blood pressure across indications, trial duration, and dose groups in placebo-controlled clinical trials
Venlafaxine hydrochloride extended-release formulation mg/day placebo ≤75 >75 SSBP1SDBP2SSBPSDBPSSBPSDBP Depression 8-12 weeks -0.280.372.933.56-1.08-0.10 Generalized anxiety disorder 8 weeks -0.280.022.401.68-1.26-0.926 months 1.27 -0.692.061.28-1.29-0.741 Systolic blood pressure in the supine position
2 Supine diastolic blood pressure
Between all clinical trials in depression and generalized anxiety disorder, supine diastolic blood pressure was elevated ≥15 mmHg in 1.4% of patients treated with venlafaxine hydrochloride extended-release formulations (diastolic blood pressure ≥105 mmHg) compared to 0.9% for placebo. Similarly patients treated with venlafaxine hydrochloride extended-release formulation had a supine systolic blood pressure increase of ≥20 mmHg in 1% of patients (systolic blood pressure ≥180 mmHg) compared with 0.3% for placebo.
General Precautions.
Discontinuation of this product
Discontinuation symptoms should be systematically assessed in patients treated with venlafaxine at the time of discontinuation, including the results of a prospective analysis of clinical studies of venlafaxine for generalized anxiety disorder and a retrospective survey of treatment of depression. New symptoms can occur when patients are abruptly discontinued or when high doses of medication are reduced, with the frequency increasing with the dose of medication and duration of treatment. Reported symptoms include: agitation, anorexia, anxiety, confusion, coordination and balance disturbances, diarrhea, dizziness, dry mouth, irritability, muscle bundle tremor, fatigue, headache, hypomania, insomnia, nausea, nervousness, nightmares, abnormal sensations (electric shock-like sensations), drowsiness, sweating, tremor, vertigo, and vomiting.
Some spontaneous post-discontinuation adverse events have been reported after the introduction of this product, other SNRIs and SSRIs, especially during abrupt discontinuation: irritability, irritability, agitation, dizziness, sensory abnormalities (e.g., electric shock sensation), anxiety, confusion, headache, drowsiness, emotional instability, insomnia, mild mania, tinnitus and seizures. The above manifestations are generally self-limiting, but severe discontinuation reactions have been reported.
Care should be taken to monitor these possible discontinuation symptoms when patients discontinue this product. It is recommended that venlafaxine in either dosage form be tapered to avoid abrupt discontinuation and that the patient be monitored. If intolerable symptoms occur during taper and discontinuation, consider returning to the previous therapeutic dose, followed by a slower taper by the physician (see [DOSAGE AND ADMINISTRATION]).
Excretion in its original form
Venlafaxine hydrochloride extended-release tablets use the principle of osmotic pressure to release venlafaxine hydrochloride at a controlled rate over a period of approximately 24 hours. The delivery system is similar in appearance to a conventional tablet and consists of an osmotically active tablet core and a semi-permeable film coating. The single tablet core consists of the drug and excipients (including the permeable active ingredient). The semi-permeable film on one side of the tablet has a small hole punched by a precision laser. In an aqueous environment, such as the gastrointestinal environment, water enters the tablet core through the film, dissolving the drug and allowing diffusion of the permeable ingredients, which in turn allows the drug to be released through the small hole. The semi-permeable film controls the rate of drug release by controlling the rate of water penetration into the core of the tablet. The controlled rate of drug dispersion into the gastrointestinal lumen is not dependent on pH or gastrointestinal motility. The function of venlafaxine hydrochloride extended release tablets is dependent on the presence of an osmotic pressure difference between the tablet core composition and the gastrointestinal fluid. Since the osmotic gradient remains constant, drug release remains essentially constant.
During gastrointestinal transit, the biologically inert component of the tablet remains intact and is excreted as an insoluble shell through the feces.
Insomnia and neuroticism
In the short-term treatment of depression and generalized anxiety disorder with venlafaxine hydrochloride extended-release formulations, insomnia and neuroticism were frequently induced compared with placebo. See Table 5.
Table 5. Incidence of insomnia and neuroticism in placebo-controlled studies for the treatment of depression and generalized anxiety disorder
Depression Generalized anxiety disorder Venlafaxine hydrochloride extended-release formulation placebo Venlafaxine hydrochloride extended-release formulation placebo symptoms n=357n=285n=1381n=555 insomnia 17%11%15%10% neuroticism 10%5%6%4%
In the treatment of depression with venlafaxine hydrochloride extended-release formulation, the incidence of patients discontinuing the drug due to insomnia and neuroticism, respectively, was both 0.9%.
In the study of venlafaxine hydrochloride extended-release formulation for generalized anxiety disorder, the incidence of discontinuation due to insomnia and neuroticism was 3% and 2%, respectively, in patients treated for more than 8 weeks, and 2% and 0.7%, respectively, in patients treated for more than 6 months.
Changes in body weight
Adult patients: Clinical studies have shown that 7% of depressed patients receiving venlafaxine hydrochloride extended-release and 2% receiving placebo lost more than 5% of their body weight. The percentage of patients who discontinued the drug because of weight loss was 0.1%. In the placebo-controlled study of generalized anxiety disorder, 3% and 1% of patients in the venlafaxine hydrochloride extended-release group and placebo group, respectively, lost more than 7% of their body weight at 6 months. At 8 weeks of follow-up, 0.3% of patients with generalized anxiety disorder taking venlafaxine hydrochloride extended release discontinued the drug due to weight loss.
The efficacy and safety of venlafaxine in combination with weight loss medications (e.g., phentermine) is not known, and it is recommended that venlafaxine and weight loss medications not be combined. Venlafaxine is also not approved for use alone or in combination for weight reduction therapy.
Pediatric patients: Weight loss has been reported in pediatric patients treated with venlafaxine hydrochloride extended-release formulations. A pooled analysis of four double-blind, placebo-controlled variable-dose clinical studies of venlafaxine hydrochloride extended-release formulations for the treatment of depression over an 8-week period showed a mean weight loss of 0.45 kg (n=333) in patients treated with venlafaxine hydrochloride extended-release formulations and 0.77 kg (n=333) in patients in the placebo group. In the treatment of patients with depression and generalized anxiety disorder, more patients with venlafaxine hydrochloride extended-release formulation lost at least 3.5% of their body weight compared with placebo (18% in the venlafaxine hydrochloride extended-release formulation group versus 3.6% in the placebo group, p <0.001). The effect of treatment-induced anorexia symptoms on patient weight loss may be more extensive and difficult to evaluate (see [Caution] – Changes in appetite).
In an open study of children and adolescents receiving venlafaxine hydrochloride extended-release formulation for 6 months for the treatment of depression, the risks of long-term treatment with the drug were evaluated. The results showed that weight gain in children and adolescents with venlafaxine hydrochloride extended-release formulation was less than the expected weight gain in those age- and sex-matched children and adolescents. This difference was more pronounced in children (<12 years) than in adolescents (>12 years).
Changes in height
Pediatric patients: In the 8-week placebo-controlled study of treatment for generalized anxiety disorder, patients (aged 6 to 17 years) treated with venlafaxine hydrochloride extended-release formulation had a mean height gain of 0.3 cm (n=132) and the placebo group had a mean gain of 1.0 cm (n=132), p=0.041. This difference in height gain was more pronounced in patients younger than 12 years of age. In an 8-week placebo-controlled study of depression, patients treated with venlafaxine hydrochloride extended-release formulation had a mean height increase of 0.8 cm (n=146) compared with 0.7 cm (n=147) in the placebo group. In 1 6-month open study of depression, treated children and adolescents increased in height, but less than their age- and sex-matched expectations based on age, and this difference between actual and expected height was greater in children aged <12 years.
Changes in appetite
Adult patients: By pooled analysis of short-course, double-blind and placebo-controlled studies of depression, more patients in the treatment group with venlafaxine hydrochloride extended-release formulation experienced anorexia than in the placebo group, up to 8% and 4%, respectively. One percent of patients in the treatment of depression discontinued venlafaxine hydrochloride extended-release formulation because of anorexia. In a pooled analysis of short-course, double-blind and placebo-controlled studies of generalized anxiety disorder, more patients in the venlafaxine hydrochloride extended-release group experienced anorexia than in the placebo group, 8% and 2%, respectively, and 0.9% of patients with generalized anxiety disorder discontinued venlafaxine hydrochloride extended-release because of anorexia during the 8-week treatment period.
Pediatric patients: Anorexia was also seen in pediatric patients with generalized anxiety disorder depression treated with venlafaxine hydrochloride extended-release and placebo controls, with 10% of patients aged 6 to 17 years taking venlafaxine hydrochloride extended-release over the course of anorexia, compared with 3% in the placebo group. No patients discontinued venlafaxine hydrochloride extended-release formulation because of anorexia and weight loss.
Induction of mania/light mania
Pre-marketing clinical studies showed that 0.3% of patients taking venlafaxine hydrochloride extended-release for depression developed mania or hypomania, compared to 0% in the placebo group, and none of the patients taking venlafaxine hydrochloride extended-release for generalized anxiety disorder developed mania or hypomania, compared to 0.2% in the placebo group. In all studies of venlafaxine (immediate-release) for depression, mania or hypomania occurred in 0.5% of patients taking venlafaxine, but not in the placebo group. Mania or hypomania has also been reported in a minority of patients on marketed antidepressants (including venlafaxine) for depression. As with all antidepressants, this product should be used with caution in patients with a history or family history of bipolar disorder.
Aggressive behavior
Aggressive behavior may occur in a smaller percentage of patients previously treated with antidepressants, including treatment with venlafaxine, dose reductions, and treatment interruptions. Similar to the use of other antidepressants, venlafaxine needs to be used with caution in patients with a history of aggressive tendencies.
Hyponatremia
Hyponatremia and/or abnormal antidiuretic hormone secretion syndrome may occur with the use of SSRIs and SNRIs, including venlafaxine, usually in hypovolemic or dehydrated patients. Elderly patients, patients taking diuretics, and those with hypovolemia due to other causes are at greater risk of developing hyponatremia. In most cases, hyponatremia is due to the syndrome of abnormal secretion of antidiuretic hormone (SIADH). Cases have been reported with serum sodium below 110 mmol/L. Discontinuation of this product and appropriate medical intervention should be considered for patients who develop symptoms of hyponatremia.
Symptoms of hyponatremia include headache, difficulty concentrating the mind, memory impairment, confusion, weakness, and wavering that may lead to falls. Severe or acute symptoms include hallucinations, syncope, seizures, coma, respiratory arrest, and death.
Convulsions
As with other antidepressants, venlafaxine has been known to cause convulsions. It should be used with caution in patients with a history of convulsions.
Seizures In pre-marketing clinical studies, there were no seizures in all 705 patients with depression and 1381 patients with generalized anxiety disorder treated with venlafaxine hydrochloride extended-release formulations. In all premarketing studies of venlafaxine (immediate-release), seizures occurred in 0.3% (8/3082) of patients treated with different doses of venlafaxine. As with other antidepressants, this product should be used with caution in patients with a history of seizures and should be discontinued when the patient has a seizure.
Abnormal bleeding
SSRIs and SNRIs, including this product, may increase the risk of bleeding events, including petechiae, hematomas, epistaxis, petechiae, gastrointestinal bleeding, and life-threatening bleeding. Combining with aspirin, nonsteroidal anti-inflammatory drugs, warfarin and other anticoagulants or other drugs known to affect platelet function may increase this risk. Case reports and epidemiological studies (case-control and cohort designs) have demonstrated the association of drugs that interfere with 5-hydroxytryptamine reuptake with gastrointestinal bleeding. Bleeding events associated with the use of SSRIs and SNRIs drugs include petechiae, hematomas, epistaxis, petechiae, and life-threatening bleeding. The risk of bleeding may be increased in patients on griseofulvin. When this product is combined with NSAIDs, aspirin, or any other drug that affects coagulation, patients should be warned that this carries an abnormal risk of bleeding.
Drugs that inhibit 5-hydroxytryptamine reuptake can cause abnormal platelet aggregation. Abnormal bleeding has been reported with venlafaxine, including skin and mucosal bleeding, gastrointestinal bleeding, and life-threatening bleeding. Therefore, as with other 5-hydroxytryptamine reuptake inhibitors, venlafaxine should be used with caution in patients with bleeding tendencies, including those on anticoagulants and platelet inhibitors.
Elevation of serum cholesterol
In placebo-controlled studies over 3 months, clinically significant elevations in serum cholesterol were observed in 5.3% of patients treated with venlafaxine compared with 0% in the placebo group. Serum cholesterol levels should be monitored in patients on long-term therapy.
Interstitial lung disease and eosinophilic pneumonia
Interstitial lung disease and eosinophilic pneumonia associated with treatment with venlafaxine have been reported rarely. The possibility of these adverse events should be considered in patients on venlafaxine with progressive dyspnea, cough or chest discomfort and these patients should be medically evaluated immediately and discontinuation of treatment with venlafaxine should be considered.
For use in patients with concomitant disease
Prior to marketing, there was limited experience with venlafaxine in patients with concomitant somatic disorders. The use of this product in patients with concomitant physical illness may affect hemodynamics and metabolism and should be prescribed with caution.
Dose-related increases in blood pressure have been reported in some patients using venlafaxine. In post-marketing clinical experience, cases of elevated blood pressure requiring immediate treatment have been reported. Therefore, blood pressure monitoring is recommended in patients using venlafaxine. Pre-existing hypertension should be controlled prior to treatment with venlafaxine. Caution should be exercised in those patients with pre-existing underlying disease that can be exacerbated by elevated blood pressure.
There is a lack of experience with venlafaxine in patients with a recent history of myocardial infarction or unstable heart disease, so evaluation is difficult. Therefore, the drug should be used with caution in these patients. Patients with these disorders at the time of the premarketing study were excluded. In a double-blind, placebo-controlled study of 8 to 12 weeks for the treatment of depression, 275 patients taking venlafaxine hydrochloride extended-release formulation and 220 patients taking placebo, and in an 8-week double-blind, placebo-controlled study of generalized anxiety disorder in 610 patients taking venlafaxine hydrochloride extended-release formulation and 298 patients taking placebo, analysis of the above patients’ The QT interval (QTc) was prolonged compared to baseline in depressed patients treated with venlafaxine hydrochloride extended-release and placebo groups (4.7 msec longer in those taking venlafaxine hydrochloride extended-release and 1.9 msec shorter in placebo group), while QT interval (QTc) was not significantly changed compared to baseline in patients with generalized anxiety disorder treated with venlafaxine hydrochloride extended-release and placebo groups. There was no significant change compared to baseline.
In these studies, for the treatment of depression, the change in heart rate relative to baseline was significantly higher in patients treated with venlafaxine hydrochloride extended-release than in the placebo group (mean increase of 4 beats/min in the venlafaxine hydrochloride extended-release group compared to 1 beat/min in the placebo group). In studies treating generalized anxiety disorder, patients treated with venlafaxine hydrochloride extended-release formulations had significantly higher changes in heart rate relative to baseline than the placebo group (mean increase of 3 beats/min in the venlafaxine hydrochloride extended-release formulation group and no change in the placebo group).
In 1 variable-dose study, when venlafaxine (immediate-release) was administered at doses of 200 to 375 mg/day, with a mean dose higher than 300 mg/day, patients taking venlafaxine had a mean increase in heart rate of 8.5 beats/min compared with a mean increase of 1.7 beats/min in the placebo group.
Because venlafaxine has the potential to increase the heart rate, care should be taken that patients with underlying medical conditions (e.g., hyperthyroidism, heart failure, or recent myocardial infarction) may be at risk due to increased heart rate, especially at high doses of venlafaxine. Therefore, the drug should be used with caution in patients whose health status may be compromised by an increased heart rate.
In a 4-6 week double-blind, placebo-controlled clinical trial, electrocardiographic evaluation of 769 of these patients taking venlafaxine (immediate-release) showed no abnormal incidence of trial-induced conduction abnormalities compared to placebo.
Cases of QTc prolongation, tip-twisting ventricular tachycardia (TdP), ventricular tachycardia and sudden death have been reported during post-marketing use of venlafaxine. Most of these reports were related to overdose or occurred in patients with other risk factors for QTc prolongation/TdP. The risk-benefit ratio should be considered when prescribing venlafaxine to patients with high risk factors for severe arrhythmias or QTc prolongation (see [Pharmacologic Toxicology]).
In patients with renal insufficiency (GFR = 10 to 70 mL/min) and cirrhosis, smaller doses should be used because of the reduced clearance and prolonged elimination half-life of venlafaxine and its metabolites (see [DOSAGE AND ADMINISTRATION]), and this product, like other antidepressants, should be used with caution in these patients.
Restlessness/psychomotor agitation
Sedentary restlessness can occur with venlafaxine and is characterized by subjective, unpleasant, or distressing fidgeting, the need to move back and forth, and often an inability to sit still or stand quietly. It may occur within the first few weeks of treatment. If the patient experiences these symptoms, increasing the dose may be harmful.
Dry mouth
10% of patients on venlafaxine report dry mouth. This may increase the risk of dental caries and patients should be advised to focus on oral hygiene.
Diabetes
The application of SSRI or venlafaxine in diabetic patients may affect the current blood glucose level. Therefore, dose adjustment of insulin and/or other anti-diabetic oral medications may be required.
Patient Medication Information
Physicians or other health care professionals should inform patients, their families and their caregivers about the benefits and risks of treatment with this product and advise them of the proper way to administer it.
Patients should be advised to be concerned about the following and asked to notify their physician promptly if they develop these conditions while taking this product
Worsening of clinical symptoms and risk of suicide: Patients, their families and their caregivers should be encouraged to be alert for the onset of the following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (psychomotor agitation), hypomania, mania, other abnormal changes in behavior, worsening of depressive symptoms, suicidal ideation, especially early in treatment with antidepressants and when the dose is increased or decreased. Because these changes may be sudden, the patient’s family and caregivers should be advised to look for these symptoms daily and should report them to the patient’s physician or health care professional, especially if they are severe, sudden, or different from the patient’s complaints. Because these symptoms may increase the incidence of suicidal ideation and behavior, there is a need for close monitoring and changes in medication.
Impairment of cognitive and motor function
Although venlafaxine does not affect the ability to perform psychomotor, cognitive, or complex behaviors in healthy volunteers, any psychoactive drug may impair the ability to perform judgment, thinking, and movement. Therefore, patients should exercise caution when driving vehicles and operating dangerous machines until it is clear that venlafaxine does not negatively affect them in these capacities.
Concomitant Medication
Because of the potential for drug-drug interactions, patients are advised to notify their physician if they are taking or are about to take any prescription or over-the-counter medications, including herbs and nutritional supplements.
Patients should remain cautious about the risk of 5-hydroxytryptamine syndrome from the combination of this product with the following drugs: tritane, tramadol, amphetamines, tryptophan supplements, and other 5-hydroxytryptaminergic drugs (see [Drug Interactions]).
Patients should be advised that this product may cause mild pupillary dilation and, in sensitive individuals, may cause closed-angle glaucoma attacks. The majority of existing glaucoma is open-angle glaucoma, as closed-angle glaucoma can be treated with iridotomy after diagnosis. Open-angle glaucoma is not a risk factor for closed-angle glaucoma. Patients may want to be tested to determine if they are at high risk for closed-angle glaucoma and, if so, to use preventive measures (e.g., iridotomy).
Patients should be cautious about combining this product with NSAIDs, aspirin, warfarin, or other drugs that affect platelet agglutination, as these drugs and psychotherapeutic drugs that affect 5-hydroxytryptamine reuptake are associated with an increased risk of bleeding (see [Precautions]-General Precautions, Abnormal Bleeding).
Alcohol
Although venlafaxine does not increase alcohol-induced impairment of mental and motor skills, patients are advised to abstain from alcohol while taking venlafaxine.
Allergic reactions
Patients are advised to notify their physician when they develop rashes, urticaria, and manifestations related to allergies.
Pregnancy
Patients are advised to notify their physician if they become pregnant or are planning to become pregnant during the treatment period.
Breastfeeding
Patients should notify their physician if they are breastfeeding their infant.
Physical and Mental Dependence
In vitro studies have shown venlafaxine to have no affinity for opioid receptors, benzodiazepine receptors, phencyclidine (PCP) receptors, and NMDA receptors. Venlafaxine has no excitatory effect on the central nervous system in rodents. In studies with primates, venlafaxine showed no significant excitatory or sedative abuse tendencies.
Discontinuation reactions have been reported with venlafaxine (see [DOSAGE]).
There are no systematic clinical studies of the potential abuse of venlafaxine, and no foraging behavior has been observed in other clinical studies. However, for a central nervous system (CNS) active drug, experience from premarketing clinical studies is not predictive of postmarketing misuse and/or abuse. Therefore, physicians should carefully evaluate and closely follow patients with a history of drug abuse to detect misuse or abuse of venlafaxine (e.g., increased tolerance, dosing, and foraging behavior) in a timely manner.
Pregnant and lactating women
Pregnancy
The safety of venlafaxine extended-release formulation for use in pregnant women has not been established. If pregnancy occurs or is planned during treatment, inform your physician. Use this product only if the benefits of venlafaxine use truly outweigh the possible risks. If venlafaxine is used until delivery or before delivery, discontinuation reactions in the newborn should be taken into account. Some newborns exposed to venlafaxine after the 7th to 9th trimester have had complications requiring nasal feeding, respiratory support, or extended hospitalization. These complications can occur immediately after the birth of the newborn.
Epidemiological data suggest that the use of SSRIs during pregnancy, especially in the second trimester, can increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have explored the relevance of PPHN to SNRI treatment, this potential risk of griseofulvin cannot be ruled out, given the mechanism of action associated with griseofulvin (inhibition of 5-hydroxytryptamine reabsorption).
If the mother used an SSRI/SNRI during the second trimester, the following symptoms may occur in the newborn: irritability, tremor, hypotonia, persistent crying and difficulty sucking and sleeping. These symptoms may be due to 5-hydroxytryptaminergic effects or exposure symptoms. In most cases, these complications appear immediately after delivery or within 24 hours after delivery.
Teratogenic effects
There are no appropriate and well-controlled studies in pregnant women. This is because the results of reproductive studies in animals do not necessarily predict the response in humans (see [Pharmacology and Toxicology]). Therefore, venlafaxine should not be used in pregnant women unless necessary.
Non-teratogenic effects
Prolonged hospitalization after delivery and increased complications with respiratory support and gastrostomy tube feeding have been reported in fetuses exposed to treatment with this product, other SNRIs (5-HT and norepinephrine reuptake inhibitors), or SSRIs in the second trimester of pregnancy. Reported clinical manifestations also included respiratory distress, cyanosis, increased/decreased muscle tone, temperature instability, feeding difficulties, vomiting, hypoglycemia, hyperreflexia, tremor, irritability, and incessant crying. These manifestations are similar to the direct toxic effects of SSRIs and SNRIs and may also be a discontinuation syndrome. It is important to note that some patients have clinical manifestations similar to the 5-HT syndrome (see [Drug Interactions] – CNS Active Drugs). When administering this product to a pregnant woman in the second trimester, the physician should carefully weigh the advantages and disadvantages of treatment (see [DOSAGE]).
Labor and Delivery
The effects of venlafaxine on the human labor and delivery process are unknown.
Nursing women
Venlafaxine and ODV have been reported to be secreted by breast milk. There have been post-marketing reports of crying, irritability and abnormal sleep rhythms in breastfed infants. Symptoms consistent with venlafaxine withdrawal have also been reported after cessation of breastfeeding. Because of the potential for serious adverse reactions in the feeding fetus, the need for maternal administration must be considered and a choice must be made between discontinuation of breastfeeding and discontinuation of the drug.
[For Children].
This product should not be used in children and adolescents under 18 years of age. The efficacy and safety of this product for use in children (under 18 years of age) has not been demonstrated (see [PRECAUTIONS] – Warning, worsening of clinical signs and risk of suicide). Although 766 children with depression in 2 placebo-controlled studies and 793 pediatric patients with generalized anxiety disorder in 2 placebo-controlled studies were treated with venlafaxine hydrochloride extended-release formulations, the above data are not yet sufficient to support the indication of the drug for pediatric patients.
The occurrence of adverse reactions with suicidal ideation has been observed in clinical trials in children. There have also been increased reports of hostility and self-injury, with self-injury seen particularly in patients with depression.
Although no studies have directly evaluated the effects of this product on growth, development, and maturation in children and adolescents, previous studies suggest that venlafaxine hydrochloride extended-release formulations may have negative effects on height and weight (see [PRECAUTIONS] – Changes in Height and Weight). When deciding to administer this product to pediatric patients, especially for long-term use, regular monitoring of height and weight is recommended. The safety of continuous treatment with this product for more than 6 months in pediatric patients has not been systematically evaluated.
Similar to adult patients, decreased appetite, weight loss, increased blood pressure and increased cholesterol levels have been observed in pediatric and adolescent patients (6 to 17 years of age). If venlafaxine is used in children/adolescents, periodic weight and blood pressure checks are recommended. If there is persistent elevated blood pressure, venlafaxine should be discontinued, and serum cholesterol should be measured in children/adolescents on long-term venlafaxine use. Therefore, the warnings for adult patients also apply to pediatric patients. (See [PRECAUTIONS] – Persistent Hypertension and [PRECAUTIONS] – Elevated Serum Cholesterol).
The safety of children under 6 years of age has not been evaluated.
Geriatric Use]
Approximately 4% (14/357) and 6% (77/1381) of patients enrolled in premarketing venlafaxine hydrochloride extended-release formulation versus placebo control for the treatment of depression and generalized anxiety disorder were older than 65 years of age, respectively. Of the 2897 patients enrolled in the premarketing study of venlafaxine (immediate-release) for depression, 12% (357) were older than 65 years of age. No fundamental differences in efficacy or safety were found between older and younger patients, and in other reports, no differences in clinical efficacy were found. The use of SSRIs, SNRIs including venlafaxine extended-release capsules in elderly patients was associated with the development of clinical hyponatremia and a higher risk of this adverse effect (see [Precautions]-
General Precautions, Hyponatremia).
There are no essential changes in the pharmacokinetics of venlafaxine and ODV in elderly patients (see [Pharmacokinetics]). There is no need to adjust the dose of the drug according to the age of the patient, although appropriate dose reductions should be made in the presence of other clinical conditions common to the elderly such as renal or hepatic insufficiency (see [Dosage]).
Drug Interactions]
Through a complex mechanism of action, venlafaxine may have potential interactions with other drugs.
Alcohol
Single ingestion of alcohol (0.5 g/kg) after 150 mg/day of venlafaxine in 15 healthy male volunteers did not affect the pharmacokinetics of venlafaxine and ODV. In addition, regular administration of venlafaxine did not exacerbate alcohol-induced psychomotor and psychometric changes in the above population. However, patients should be advised to avoid alcohol while taking venlafaxine.
Cimetidine
The combined use of venlafaxine and cimetidine inhibited the first-pass metabolism of venlafaxine in 18 healthy volunteers. The clearance of oral venlafaxine was reduced by approximately 43% and the AUC and Cmax of the drug increased by approximately 60%, but the combined use of cimetidine had no effect on the metabolism of ODV because the amount of ODV in the circulation was much greater than that of venlafaxine, so the pharmacologic effect of venlafaxine and ODV combined was only mildly enhanced and no dose adjustment of the drug was necessary for most adults. However, the interaction between venlafaxine and cimetidine may be more pronounced in patients with prior hypertension, the elderly, and hepatic insufficiency, and should be used with caution.
Diazepam
A single dose of 10 mg of diazepam had no effect on the pharmacokinetics of both venlafaxine and ODV in 18 healthy volunteers taking 150 mg/day of venlafaxine orally to achieve steady-state conditions. Venlafaxine also had no effect on the metabolism of diazepam and its active metabolites, nor on diazepam-induced alterations in psychomotor and psychometric measures.
Haloperidol
Pharmacokinetic studies with haloperidol found a 42% decrease in total oral clearance, a 70% increase in AUC, and an 88% increase in maximum blood concentration, but no change in the elimination half-life of haloperidol, and the mechanism for this change remains unknown.
Ketoconazole
In a pharmacokinetic study, administration of ketoconazole 100 mg (twice a day) followed by a single dose of venlafaxine 50 mg resulted in increased blood concentrations of both venlafaxine and ODV in subjects (accelerated metabolic response [EM; n=14] type for CYP2D6 or slowed metabolic response [PM; n=6] type for 25 mg). For subjects with accelerated metabolic response (EM), venlafaxine Cmax was elevated by 26%, while for subjects with slowed metabolic response (PM), venlafaxine Cmax was elevated by 48%. For subjects with accelerated metabolic response (EM) and slowed metabolic response (PM), the Cmax of ODV was increased by 14% and 29%, respectively.
For subjects with accelerated metabolic response (EM), venlafaxine AUC was increased by 21%, while for subjects with slowed metabolic response (PM), venlafaxine AUC was increased by 70% (range -2%-206% for PM). For subjects with accelerated metabolic response (EM) and slowed metabolic response (PM), the AUC of ODV was elevated by 23% and 33%, respectively (range for PM -38%-105%). The combined AUC of venlafaxine and ODV increased EM and PM by an average of approximately 23% and 53%, respectively (range of -4%-134% for PM)
Metoprolol.
A pharmacokinetic study in which venlafaxine (50 mg given every 8 hours for 5 days) and metoprolol (100 mg given every 24 hours for 5 days) were given concurrently to healthy volunteers showed an increase in blood concentrations of metoprolol of approximately 30-40%, while blood concentrations of its active metabolite, α-hydroxymetoprolol, were not affected. In this study, venlafaxine appeared to attenuate the effect of metoprolol in healthy volunteers while lowering blood pressure. The relevant clinical significance for patients with hypertension is unclear. Metoprolol does not alter the pharmacokinetic properties of venlafaxine or its active metabolite ODV. Caution should be exercised when using metoprolol and venlafaxine in combination.
In some patients, venlafaxine treatment is dose-related to increased blood pressure. Patients are advised to monitor their blood pressure regularly while taking this product (see [Precautions]-Warnings).
Lithium Salt
The pharmacokinetics of a single dose of 600 mg of lithium salt administered orally to 12 healthy volunteers taking venlafaxine 150 mg/day and reaching steady state were not affected, nor was the metabolism of ODV by lithium salt. Venlafaxine also has no effect on the metabolism of lithium salts (see also CNS-active drugs).
Drugs with high plasma protein binding
Venlafaxine is a low protein-binding drug; therefore, it is unlikely to increase the free concentration of other drugs with high protein binding.
Drugs that interfere with coagulation (e.g., NSAIDs, aspirin, and warfarin)
Platelet 5-hydroxytryptamine release plays an important role in the coagulation process. Epidemiological studies in case-control and cohort designs have demonstrated that the combination of these drugs with psychotherapeutic agents can interfere with 5-hydroxytryptamine reuptake, and the occurrence of upper gastrointestinal bleeding suggests that the combination of NSAIDs or aspirin with psychotropic drugs may produce a risk of bleeding. Altered anticoagulant effects, including an increase in bleeding, have been reported when SSRIs and SNRIs are combined with warfarin. Patients on warfarin should be carefully monitored when starting or interrupting treatment with this product.
Other Drugs That May Affect Venlafaxine
The metabolic pathways of venlafaxine include CYP2D6 and CYP3A4. venlafaxine is primarily metabolized by the cytochrome P450 CYP2D6 enzyme to the active metabolite, ODV. in contrast to CYP2D6, CYP3A4 is a minor pathway in the metabolism of venlafaxine.
CYP2D6 inhibitors.
In vitro and in vivo studies confirm that venlafaxine is metabolized primarily by the CYP2D6 enzyme to the active metabolite, ODV, and that the metabolic activity of the CYP2D6 enzyme for a variety of antidepressants is determined by genetic polymorphisms. When venlafaxine and CYP2D6 inhibitors are combined, the metabolism of venlafaxine into ODV may be reduced, resulting in higher venlafaxine blood levels and lower ODV concentrations. This effect is similar to the metabolic profile of people with low CYP2D6 enzyme activity (see [Pharmacokinetics] – Metabolism and Excretion). Because both venlafaxine and ODV are pharmacologically active, no dose adjustment is required when venlafaxine is combined with drugs that inhibit CYP2D6.
CYP3A4 inhibitors.
The combined use of CYP3A4 inhibitors and venlafaxine may elevate venlafaxine and ODV levels (see [Drug Interactions] – Ketoconazole). Therefore, caution should be exercised when combining CYP3A4 inhibitors and venlafaxine.
CYP2D6 and CYP3A4 dual inhibitors.
The major metabolizing enzymes of venlafaxine are CYP2D6 and CYP3A4. No studies have been performed combining venlafaxine with drugs that inhibit both CYP2D6 and CYP3A4 enzymes. However, it can be expected that the combination will increase the blood concentration of venlafaxine. Therefore, caution should be exercised when combining venlafaxine with these dual inhibitors of CYP2D6 and CYP3A4.
Drugs metabolized by cytochrome P450 enzymes
CYP2D6: In vitro studies have shown weak inhibition of CYP2D6 by venlafaxine, which was also confirmed in a controlled study of the metabolic effects of venlafaxine and fluoxetine on methamphetamine, a drug metabolized by the CYP2D6 enzyme.
Promethazine: Venlafaxine had no effect on the pharmacokinetics of promethazine and 2-hydroxypromethazine. However, venlafaxine increased the AUC, Cmax, and Cmin of desipramine by approximately 35%. the AUC of 2-hydroxydesipramine could be increased 2.5-fold to 4.5-fold. Promethazine does not affect the metabolism of venlafaxine and ODV. The clinical significance of the increased concentration of 2-hydroxydexipramine is unknown.
Risperidone: Oral venlafaxine 150 mg/day at steady state mildly inhibited the metabolism of risperidone by the CYP2D6 enzyme (single oral dose of 1 mg) to the active metabolite 9-hydroxyrisperidone, resulting in an approximately 32% increase in the AUC of risperidone. However, coadministration of venlafaxine had no significant effect on the pharmacokinetic profile of the overall active fraction (risperidone and 9-hydroxyrisperidone).
CYP3A4: In vitro venlafaxine did not inhibit CYP3A4 activity. This was confirmed in drug interaction studies in humans, where venlafaxine did not inhibit the metabolism of CYP3A4 enzyme substrates such as alprazolam, diazepam and terfenadine.
Indinavir: In a study of nine healthy volunteers, venlafaxine decreased the AUC of a single oral dose of 800 mg of indinavir by 28% and reduced the Cmax by 36% when 150 mg/day of oral venlafaxine was administered to achieve steady state. Indinavir did not affect the metabolism of venlafaxine and ODV. Clinical significance is unknown.
CYP1A2: In vitro venlafaxine does not inhibit CYP1A2. This was confirmed in human drug interaction studies, and venlafaxine does not inhibit the metabolism of caffeine (a CYP1A2 substrate).
CYP2C9: In vitro venlafaxine does not inhibit CYP2C9. In vivo, oral venlafaxine (75 mg q12h for 1 month) does not affect the metabolism of a single 500 mg dose of toluenosulfonylurea or 4-hydroxytoluenosulfonylurea.
CYP2C19: Venlafaxine does not affect the metabolism of diazepam, which is primarily metabolized by CYP2C19 (see Diazepam).
MAOIs
Adverse and sometimes serious reactions can occur if treatment with venlafaxine is started shortly after discontinuation of MAOIs or if treatment with MAOIs is started shortly after discontinuation of venlafaxine. These adverse reactions include tremor, myoclonus, hyperhidrosis, nausea, vomiting, flushing, dizziness, hyperthermia with features similar to the malignant syndrome of nerve blockers, seizures, to death (see [CONTRAINDICATIONS] and [PRECAUTIONS] – WARNINGS).
Central nervous system active drugs
The risks of combining venlafaxine with CNS-active drugs other than those mentioned above have not been systematically evaluated. Therefore, caution should be exercised when combining venlafaxine with other CNS-active drugs. Based on its mechanism of action, venlafaxine has the potential to cause 5-HT syndrome, and attention should be paid to the risk of combining venlafaxine with other drugs that act on the 5-HT system (e.g., amitriptyline, SSRIs, and lithium salts).
Drugs that may prolong the QT interval
Concomitant use of other medications that prolong the QTc interval increases the risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP). Combination of such drugs should be avoided (see [Precautions]).
Relevant classifications include
Class Ia and III antiarrhythmic agents (e.g., quinidine, amiodarone, sotalol, dofetilide)
Partial antipsychotics (e.g., methiodiazine)
Some macrolides (e.g., erythromycin)
Some antihistamines
Some quinolone antibiotics (e.g., moxifloxacin)
The above list is not exhaustive and other medications known to significantly prolong the QT interval should also be avoided.
5-hydroxytryptamine syndrome
Similar to other 5-hydroxytryptaminergic drugs, 5-hydroxytryptamine syndrome (a potentially life-threatening condition) may occur with treatment with venlafaxine, especially when combined with: other drugs that act on the 5-hydroxytryptamine transmitter system (including tretinoin, SSRIs, other SNRIs, amphetamines, lithium salts, sibutramine, tramadol, or St. John’s wort [Hypericum spp. extracts]), drugs that impair 5-hydroxytryptamine metabolism (e.g., MAOIs, including linezolid [an antibiotic that is a reversible, non-selective MAOI] and methylene blue) or 5-hydroxytryptamine precursors (e.g., tryptophan supplements) (see [Contraindications] and [Precautions]).
If there is a reasonable clinical need to combine venlafaxine with an SSRI, SNRI, or 5-hydroxytryptamine receptor agonist (tretinoin), close patient monitoring is recommended, especially at the beginning of treatment and at increasing doses. The combination of venlafaxine and a 5-hydroxytryptamine precursor substance (e.g., tryptophan supplementation) is not recommended (see [Precautions]).
Tretinoin: Post-marketing reports of 5-hydroxytryptamine syndrome due to combined use of SSRI and tretinoin are rare. If concomitant use of this product and tretinoin is clinically indicated, careful patient observation is recommended, particularly at the beginning of treatment and at increasing doses (see [Precautions]).
Electroconvulsive therapy
There are no clinical data suggesting benefit of the combination of venlafaxine hydrochloride extended-release formulation with electroconvulsive therapy.
Drug Laboratory Tests
False-positive results for phencyclidine (PCP) and amphetamine have been reported with urine immunoassay screening tests in patients taking venlafaxine. This is due to the lack of specificity of this screening test. False-positive results may also occur in screening tests within a few days of stopping venlafaxine. Confirmatory tests such as gas chromatography/mass spectrometry can distinguish venlafaxine from phencyclidine (PCP) and amphetamines.
Post-marketing spontaneous drug interactions have been reported
See [Adverse Reactions].
Oral contraceptives
In post-marketing experience, unintended pregnancies have been reported in subjects taking oral contraceptives while using venlafaxine.
There is no clear evidence that these pregnancies were the result of interactions with venlafaxine. No interaction studies with hormonal contraceptives have been conducted.
[Drug Overdose].
Human experience
Acute overdose (either with venlafaxine hydrochloride extended-release formulation alone or in combination with other drugs) was reported in 2 cases in pre-marketing studies of venlafaxine hydrochloride extended-release formulation for the treatment of depression. One patient took 6 g of venlafaxine hydrochloride extended-release formulation and 2.5 mg of lorazepam, was admitted to the hospital, treated symptomatically and recovered without further effects. Another patient who took 2.85g of venlafaxine hydrochloride extended-release preparation developed abnormal sensation in the extremities and recovered with no sequelae.
Acute overdose (either with venlafaxine hydrochloride extended-release formulation alone or in combination with other medications) was reported in 2 cases in premarketing studies of venlafaxine hydrochloride extended-release formulation for the treatment of generalized anxiety disorder. In one patient taking 0.75 g of venlafaxine hydrochloride extended-release formulation, 200 mg of paroxetine, and 50 mg of zolpidem, the patient was conscious, could talk, was mildly drowsy, was admitted to the hospital, and recovered from treatment with activated carbon with no further effects. Another patient on 1.2 g of venlafaxine hydrochloride extended-release formulation exhibited moderate dizziness, nausea, numbness in the hands and feet and occasional coldness for 5 days, with recovery of symptoms after 1 week and no other special conditions.
A total of 14 cases of acute venlafaxine (alone or with other drugs or alcohol) overdose were reported, including the pre-marketing study of venlafaxine (immediate release). The majority of the cases took no more than several times the usual dose of venlafaxine, with the three largest doses of venlafaxine being approximately 6.75 g, 2.75 g, and 2.5 g orally, with the latter two patients achieving peak venlafaxine blood concentrations of 6.24 and 2.35 µg/mL, respectively. drug concentrations were not available for patients taking 6.75 g of drug. All 14 patients recovered without sequelae. Most patients were asymptomatic, with drowsiness being the most common symptom in the remaining patients. Two generalized twitches and prolongation of QTc to 500 ms from baseline were observed in patients taking 2.75 g of venlafaxine. 2 cases of sinus tachycardia were reported in other patients.
In post-marketing use of venlafaxine, venlafaxine overdose was mostly combined with other drugs/alcohol. The most commonly reported events of overdose included tachycardia, altered level of consciousness (from drowsiness to coma), pupil dilation, seizures, and vomiting. Other reported events include electrocardiographic changes (e.g., QT interval prolongation, bundle branch block, and QRS prolongation; see [Pharmacologic Toxicology]), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, hepatic necrosis, 5-hydroxytryptamine syndrome, and death.
Published retrospective studies have reported that venlafaxine overdose may be associated with an increased risk of death compared with that observed in the 5-hydroxytryptamine reuptake inhibitor (SSRI) class of antidepressants, but that its overdose causes a lower risk of death than tricyclic antidepressants. Epidemiological studies have shown that patients using venlafaxine have higher risk factors for suicide compared to those using SSRIs. The increased risk of death from venlafaxine overdose has been attributed to toxicity from venlafaxine overdose and certain idiosyncrasies of the patient population using venlafaxine, but the extent of this is not known. Physicians prescribing venlafaxine should give the smallest pack size (i.e., box size) of the drug along with effective patient management to reduce the risk of venlafaxine overdose.
Management of overdose
General management measures are similar to other antidepressant overdoses, ensuring airway patency and appropriate oxygenation and ventilation, monitoring heart rate and vital signs, and using general supportive and symptomatic treatment. If there is a risk of aspiration, emetics are not recommended. Gastric lavage may be performed in patients who become symptomatic or who have been on medication for a short time, and the airway may be kept open during lavage. The use of activated carbon (which can limit the absorption of the drug) may be considered. Because the drug has a large volume of distribution, strong diuresis, dialysis, hemoperfusion, and blood exchange therapy may be less effective. There are no specific antidotes available. When dealing with an overdose, the possibility of taking multiple drugs at the same time should be considered and the physician should contact a poison control center for further information.
[Pharmacology and Toxicology].
Pharmacological effects
The exact mechanism of antidepressant action of venlafaxine in humans is not clear, but it is thought to be related to the enhancement of 5-HT and NE effects in the central nervous system by inhibiting the reuptake of 5-hydroxytryptamine (5-HT) and norepinephrine (NE)
. Non-clinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are strong inhibitors of selective 5-HT, NE reuptake and weak inhibitors of dopamine.
Venlafaxine and O-desmethylvenlafaxine have no significant affinity for M-cholinergic receptors, H1-histamine receptors, and α1-adrenergic receptors in vitro. Venlafaxine and O-desmethylvenlafaxine have no monoamine oxidase (MAO) inhibitory activity.
Toxicological studies
Genotoxicity
Venlafaxine and the major human metabolite, O-desmethylvenlafaxine, were negative in the Ames test and the CHO/HGPRT mammalian cell forward mutation test. The results of the BALB/c-3T3 mouse cell transformation test, the CHO cell sister chromatid exchange test, and the in vivo bone marrow chromosome aberration test in rats were negative for venlafaxine.
Reproductive toxicity
No effects on male and female fertility were observed when venlafaxine was administered orally to rats at doses up to twice the maximum recommended human dose (MRHD) of 225 mg/day (converted to mg/m2, hereinafter). However, in male and female rats given O-desmethylvenlafaxine orally before mating, during mating and during pregnancy, reduced fertility was seen at an O-desmethylvenlafaxine exposure (AUC) of approximately 2 to 3 times the human dose of 225 mg/day of venlafaxine.
No offspring malformations were seen in rats and rabbits given venlafaxine orally during pregnancy and lactation at doses 2.5 and 4 times the MRHD, respectively; however, reduced pup weight, increased stillbirth rate, and increased number of pups dying in the first 5 days of lactation were seen in rats, and the cause of animal death was unknown, with no effect on pup mortality at a dose 0.25 times the MRHD.
In reproductive toxicity tests in rats and rabbits given O-desmethylvenlafar orally, no teratogenic effects were seen at 13 times (rats) and 0.3 times (rabbits) the exposure level, respectively.
Carcinogenicity
In mice given venlafaxine at doses up to 120 mg/kg/day by gavage for 18 months (equivalent to 1.7 times MRHD) and in rats given venlafaxine at doses up to 120 mg/kg/day by gavage for 24 months (venlafaxine blood concentrations in male and female rats were 1 and 6 times higher than human blood concentrations at MRHD, respectively, but O-desmethylvenlafaxine blood concentrations were lower than (human blood concentrations), no increase in tumor incidence was observed.
O-desmethylvenlafaxine was administered by gavage for 2 years to mice and rats at doses up to 500/300 mg/kg/day (reduced after 45 weeks), with exposure at 300 mg/kg/day equivalent to 9 times the human dose of 225 mg/day, and to rats at doses up to 300 mg/kg/day (males) or 500 mg/kg/day (females), respectively. No increase in tumor incidence was observed at doses equivalent to approximately 8 (males) and 11 (females) times the human dose, respectively.
[Pharmacokinetics]
Steady-state blood concentrations of venlafaxine and ODV were achieved within 3 days by multiple oral doses. The mean steady-state plasma clearance was 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, with apparent clearance half-lives of 5 ± 2 and 11 ± 2 h and apparent (steady-state) volumes of distribution of 7.5 ± 3.7 and 5.7 ± 1.8 L/kg for venlafaxine and ODV, respectively, in the dose range of 75 to 450 mg/day. therapeutic blood concentrations were less bound to plasma proteins, 27% and 30%, respectively.
Absorption
Venlafaxine is readily absorbed and metabolized mainly in the liver, with ODV being the main active metabolite. After a single oral dose of venlafaxine, at least 92% is absorbed. The absolute bioavailability of venlafaxine is approximately 45%.
Administration of an extended-release formulation of venlafaxine hydrochloride (150 mg, q24h) typically has a lower peak concentration (150 ng/mL and 260 ng/mL for venlafaxine and ODV, respectively) and a later time to peak (5.5 h and 9 h for venlafaxine and ODV, respectively). Fluctuations in blood concentrations were significantly lower in patients taking the extended-release formulation of venlafaxine hydrochloride when the same daily dose of venlafaxine was administered. Thus, the extended-release formulation of venlafaxine hydrochloride was absorbed more slowly compared to the immediate-release tablets, but the total amount of drug absorbed was the same.
No effect of food on the bioavailability of venlafaxine and its active metabolite ODV was found with the 75 mg extended-release formulation of venlafaxine hydrochloride, and the difference in the time of administration (morning or afternoon) did not affect the drug metabolism of venlafaxine and ODV.
Metabolism and excretion
Venlafaxine is absorbed and first-pass metabolized in the liver, with ODV as the major metabolite, along with N-desmethylvenlafaxine, N,O-desmethylvenlafaxine, and other minor metabolites. In vitro studies have shown that ODV is produced through the metabolism of the CYP2D6 enzyme, and clinical studies have confirmed that patients with low CYP2D6 activity (slow metabolism) have higher venlafaxine and lower ODV concentrations compared to those with normal CYP2D6 activity. Because the total amount of venlafaxine and ODV were close in the 2 groups of patients with different CYP2D6 activity, and because ODV and venlafaxine have similar pharmacological effects and strength of action, this difference in metabolic capacity is not clinically important.
Approximately 87% of the drug is excreted in the urine 48 hours after venlafaxine administration, including 5% of the prototype, 29% of the unbound ODV, 26% of the bound ODV, and 27% of the inactive metabolites. Thus, venlafaxine and its metabolites are excreted primarily through the kidneys.
Application to special populations
Age and gender: 2 pharmacokinetic studies with 404 patients showed that blood concentrations of venlafaxine and ODV were not affected by age or gender in patients taking the drug twice and three times daily. Therefore, it is generally not necessary to adjust the dose of the drug according to the age and gender of the patient (see [Dosage]).
Fast/slow metabolizers: Patients with lower CYP2D6 activity have higher venlafaxine blood concentrations compared to fast metabolizers because the total AUCs of venlafaxine and ODV are close and therefore there is no need to use different doses in these 2 groups of patients.
Liver disease: After oral administration of venlafaxine in 9 patients with cirrhosis, drug metabolism of venlafaxine and ODV was significantly affected. The elimination half-life of venlafaxine was prolonged by about 30% and drug clearance was decreased by 50% in patients with cirrhosis compared with healthy subjects, and the elimination half-life of ODV was prolonged by about 60% and drug clearance was decreased by 30%. Greater variability in drug clearance was also noted, with a more pronounced decrease in venlafaxine clearance (approximately 90%) in three patients with more severe cirrhosis.
In another study, venlafaxine was administered orally and intravenously in normal subjects (n=21), graded by Child-Pugh, Child-Pugh class A (n=8) and Child-Pugh class B (n=11) (mild and moderate impairment). Oral bioavailability of venlafaxine was increased 2-3 fold, oral elimination half-life was prolonged to approximately 2-fold compared to normal subjects, and oral clearance was reduced by more than half. In subjects with hepatic insufficiency, the oral elimination half-life of ODV was prolonged by approximately 40%, while oral clearance was similar to that of normal subjects. Significant differences between individual subjects were noted.
Dosing must be adjusted for patients with concomitant hepatic insufficiency (see [DOSAGE]).
Renal disease: Patients with renal insufficiency (GFR of 10 to 70 mL/min) have an approximately 50% longer elimination half-life and an approximately 24% lower clearance of venlafaxine compared to normal subjects. In patients on dialysis, the elimination half-life of venlafaxine is prolonged by approximately 180% and the clearance is decreased by approximately 57%. Similarly, in patients with renal insufficiency (GFR of 10-70 mL/min), the elimination half-life of ODV was prolonged by approximately 40%, but clearance was unchanged. In patients treated with dialysis, the clearance half-life of ODV was prolonged by approximately 142% and clearance decreased by approximately 56% compared to normal subjects. It should also be noted that there are large individual differences in these populations and the dose of venlafaxine must be adjusted when used in these patients (see [Dosage]).
Storage
Seal and store in a dry place.
Packaging
Polyvinyl chloride/polyvinylidene chloride solid pharmaceutical laminate/aluminum foil for pharmaceutical packaging, 7 tablets/box, 14 tablets/box.
Expiration date
18 months.
Execution Standard
Approval number】
State Drug Certificate H20070269
【Marketing license holder】
Company name: Chengdu Kanghong Pharmaceutical Group Co.
Registered address: No. 36, Shu Xi Road, Jinniu District, Chengdu
Postal Code: 610036
Telephone number: 028-87509966
Fax number: 028-87505658
Free consultation phone number: 800-8861866
Website: www.cnkh.com
Manufacturer
Company name: Chengdu Kanghong Pharmaceutical Group Co.
Address: No. 36, Shu Xi Road, Jinniu District, Chengdu
Postal Code: 610036
Telephone number: 028-87509966
Fax number: 028-87505658
Free consultation phone number: 800-8861866
Website: www.cnkh.com