Instructions for Elifor prolonged-release tablets 50 mg blister No. 28
Composition
active ingredient: desvenlafaxine succinate;
1 prolonged-release tablet contains desvenlafaxine succinate in an amount equivalent to 50 mg or 100 mg of desvenlafaxine;
excipients: microcrystalline cellulose (Avicel PH102), microcrystalline cellulose (Avicel PH105), talc, magnesium stearate, hypromellose 2208, 100000 CR; for 100 mg tablets: Opadry® II, 85F94527 (polyvinyl alcohol, macrogol, titanium dioxide (E 171), talc, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake (E 110), red iron oxide (E 172)); for 50 mg tablets: Opadry® II, 85F94487 (polyvinyl alcohol, macrogol, titanium dioxide (E 171), talc, yellow iron oxide (E 172), red iron oxide (E 172)).
Dosage form
Extended-release tablets.
Main physicochemical properties:
50 mg tablets: light pink, square, film-coated tablets, debossed with “W” over “50” on the flat side and in the shape of a pyramid on the other side;
100 mg tablets: reddish-orange square film-coated tablets, debossed with “W” over “100” on the flat side and in the shape of a pyramid on the other side.
Pharmacotherapeutic group
Antidepressants. ATX code N06A X23.
Pharmacological properties
Pharmacodynamics.
The exact mechanism of antidepressant action of desvenlafaxine is unknown, but it is suggested that it is associated with potentiation of serotonin and norepinephrine in the central nervous system through inhibition of their reuptake. Preclinical studies have demonstrated that desvenlafaxine is a potent and selective inhibitor of serotonin and norepinephrine reuptake.
Desvenlafaxine did not show significant affinity for many receptors, including muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Desvenlafaxine also did not show significant activity as a monoamine oxidase (MAO) inhibitor.
Pharmacokinetics.
The pharmacokinetics of a single dose of desvenlafaxine are linear and dose-dependent over the dose range of 50 to 600 mg/day. With once-daily administration, steady-state plasma concentrations are reached within approximately 4-5 days. At steady-state, accumulation of multiple doses of desvenlafaxine is linear and predictable based on the single-dose pharmacokinetic profile.
Absorption and distribution
The absolute bioavailability of Elifor after oral administration is about 80%.
Studies of the effect of food intake on the administration of Elifor in healthy subjects in the fasted and fed state (high-fat meal, 800 to 1000 calories) demonstrated that Cmax of desvenlafaxine increased by approximately 16% after food intake, while AUC was similar. This difference is not clinically significant, so Elifor can be administered regardless of food intake (see “Method of administration and dosage”).
Desvenlafaxine plasma protein binding is low (30%) and is independent of drug concentration. The volume of distribution of desvenlafaxine at steady state after intravenous administration is 3.4 L/kg, indicating distribution to nonvascular parts of the body.
Metabolism and excretion
Desvenlafaxine is primarily metabolized by conjugation (mediated by uridine-5-diphosphate (UDP) isoforms) and to a lesser extent by oxidative metabolism. CYP3A4 is the cytochrome P450 isoenzyme involved in the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved, and after a 100 mg dose, the pharmacokinetics of desvenlafaxine were similar in patients with poor and extensive CYP2D6 metabolism. Approximately 45% of desvenlafaxine is excreted unchanged in the urine within 72 hours of oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and < 5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in the urine.
Age
In a study in healthy subjects receiving doses up to 300 mg, there was an approximately 32% increase in Cmax and a 55% increase in AUC in subjects over 75 years of age (n=17) compared to subjects 18 to 45 years of age (n=16). Patients 65 to 75 years of age (n=15) showed no change in Cmax, but AUC in this age group increased by approximately 32% compared to AUC in subjects 18 to 45 years of age (see Dosage and Administration).
Sex
No dose adjustment is necessary based on gender.
Race
No dose adjustment is necessary based on race.
Kidney failure
In patients with impaired renal function, the clearance of Elifor was reduced. In patients with severe renal insufficiency (24-hour creatinine clearance < 30 ml/min, Cockcroft-Gault formula) and end-stage renal disease, the half-life is significantly prolonged, which increases the exposure to Elifor, therefore, dose adjustment is recommended in these patients.
Liver failure
The mean elimination half-life (t1/2) varied from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in subjects with moderate and severe hepatic impairment, respectively. The recommended dose for subjects with hepatic impairment is 50 mg/day. Increasing the dose above 100 mg/day is not recommended (see section 4.2, section 4.4, section 4.4, section 4.4).
Indication
Contraindication
- Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any of the excipients of Elifor.
- Concomitant use of MAO inhibitors or their use within 7 days after discontinuation of Elifor treatment. Use of Elifor within 14 days after discontinuation of MAO inhibitors.
- Concomitant treatment with MAO inhibitors such as linezolid or intravenous methylene blue therapy.
Interaction with other medicinal products and other types of interactions
MAO inhibitors
MAO inhibitors for the treatment of psychiatric disorders should not be used concomitantly with desvenlafaxine or within 7 days of discontinuing desvenlafaxine. Desvenlafaxine should not be used within 14 days of discontinuing MAO inhibitors for the treatment of psychiatric disorders. In addition, desvenlafaxine therapy should not be initiated in patients receiving linezolid or intravenous methylene blue (see Dosage and Administration, Contraindications, Precautions).
Serotonergic agents
Given the mechanism of action of desvenlafaxine and the potential for serotonin syndrome, caution should be exercised when desvenlafaxine is used in combination with other drugs that may affect serotonergic neurotransmitter systems (see “Method of administration and dosage”, “Contraindications”, “Special warnings and precautions for use”).
Drugs that affect hemostasis (e.g., NSAIDs, aspirin, and warfarin)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological case-control and cohort studies have shown an association between the use of psychotropic drugs that affect serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concomitant use of NSAIDs or aspirin may increase the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs) were used concomitantly with warfarin. Patients receiving warfarin therapy should be closely monitored during initiation of treatment and when Elifor is discontinued (see “Special warnings and precautions for use”).
The ability of other drugs to affect desvenlafaxine
Based on in vitro data, no dose adjustment of Elifor is required when co-administered with inhibitors of CYP3A4 and CYP1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, 2E1 and the P-glycoprotein transporter. Clinical studies have not demonstrated a clinically significant pharmacokinetic interaction between Elifor and strong CYP3A4 inhibitors.
The ability of desvenlafaxine to affect other drugs
Desvenlafaxine at a dose of 100 mg per day has no clinically significant effect on CYP2D6 metabolism. Substrates that are primarily metabolized by CYP2D6 (e.g., desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine) should be administered at starting doses of 100 mg or less when co-administering Elifor or when Elifor is discontinued. The dose of these substrates should be halved when co-administered with 400 mg Elifor.
No additional dose adjustment is necessary when co-administering substrates of CYP3A4, 1A2, 2A6, 2C8, 2C9 and 2C19 isoenzymes and the P-glycoprotein transporter. Clinical studies have demonstrated the absence of clinically significant pharmacokinetic interactions between Elifor and CYP3A4 substrates.
Desvenlafaxine (100 mg/day) has no clinically significant effect on tamoxifen and aripiprazole, compounds that are metabolized by a combination of both CYP2D6 and CYP3A4 enzymes.
In vitro studies have demonstrated a minimal inhibitory effect of desvenlafaxine on the CYP2D6 isoenzyme.
Desvenlafaxine does not inhibit or induce CYP3A4 in vitro.
Desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19 isoenzymes and the P-glycoprotein transporter and does not affect the pharmacokinetics of drugs that are substrates of these CYP isoenzymes and transporters in vitro.
Other medicines containing desvenlafaxine or venlafaxine
The use of Elifor with other drugs containing desvenlafaxine or venlafaxine should be avoided. The simultaneous use of Elifor with other drugs containing desvenlafaxine or venlafaxine increases the level of desvenlafaxine in the blood and increases dose-dependent adverse reactions (see “Adverse reactions”).
Ethanol
Elifor does not increase the mental and motor impairments caused by ethanol. However, as with other drugs acting on the central nervous system, patients should be advised to avoid alcohol while taking Elifor.
Effect of the drug on laboratory test results
False-positive urine immunoassays for phencyclidine and amphetamine have been reported in patients taking desvenlafaxine. This is due to the lack of specificity of the screening tests. False-positive test results can be expected for several days after desvenlafaxine is discontinued. Confirmatory tests, such as gas chromatography/mass spectrometry, can distinguish desvenlafaxine from phencyclidine and amphetamine.
Application features
Suicidal thoughts and behavior in children, adolescents, and young adults
Patients with MND, both adults and children, whether or not they are taking antidepressants, may experience worsening depression, suicidal ideation and behavior (suicidality), or unusual changes in behavior, and this risk may persist until sustained remission occurs. Depression and some other psychiatric disorders are known to be risk factors for suicide; these disorders themselves are strong predictors of suicide. However, antidepressants may play a role in worsening depression and suicidality in some patients early in treatment. Pooled analyses of short-term placebo-controlled trials of antidepressants (SSRIs and others) have shown that these drugs increase the risk of suicidal ideation and behavior (suicidality) in children, adolescents, and young adults (aged 18 to 24 years) with MND and other psychiatric disorders. Short-term studies do not show an increased risk of suicidality with antidepressants compared to placebo in adults aged 24 years and older; there has been a decreased risk of suicidality with antidepressants compared to placebo in adults aged 65 years and older.
A pooled analysis of placebo-controlled trials in children and adolescents with ADHD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressants involving over 4,400 patients. A pooled analysis of placebo-controlled trials in adults with ADHD or other psychiatric disorders included a total of 295 short-term trials (mean duration 2 months) of 11 antidepressants involving over 77,000 patients. There were significant differences in the risk of suicidality between drugs, but with a trend toward an increase in younger patients for almost all drugs studied. There were differences in the absolute risk of suicidality across indications; the highest level was observed in ADHD. However, the differences in risk (drugs versus placebo) were relatively stable across age groups and across indications. No suicides occurred in any of the pediatric studies. Suicides were observed in adult studies, but the numbers were insufficient to draw any conclusions about the effects of the drugs on suicides.
It is not known whether the risk of suicidality extends to long-term use, i.e., beyond a few months. However, there is substantial evidence from placebo-controlled trials in adult patients with depression that antidepressant use may delay relapse of depression.
All patients treated with antidepressants for any indication should be closely monitored and observed for clinical deterioration, suicidality, and unusual changes in behavior, especially during the first few months of treatment or during dose changes (increase or decrease).
Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults and children treated with antidepressants for the treatment of MDD and other psychiatric and non-psychiatric indications. Although a causal relationship between the occurrence of these symptoms and worsening of depression and/or suicidal ideation has not been established, there is concern that such symptoms may be a precursor to suicidality.
A change in the therapeutic regimen, including possible discontinuation of the drug, should be considered for patients whose depression is persistently worsening or who develop suicidality or symptoms that may be harbingers of worsening depression or suicidality, especially if these symptoms are severe, have an abrupt onset, or were not observed in the patient before treatment.
If the decision has been made to discontinue treatment, the drug should be discontinued by gradually reducing the dose as quickly as possible, but bearing in mind that abrupt discontinuation may be associated with certain symptoms (see “Method of administration and dosage”).
Families and caregivers of patients taking antidepressants and being treated for ADHD or other psychiatric and nonpsychiatric conditions should be warned to monitor patients for agitation, irritability, unusual changes in behavior, and other symptoms described above, as well as suicidality, and to report such symptoms immediately to healthcare professionals.
An episode of bipolar disorder may be the initial symptom of bipolar disorder. It is thought (although not established in controlled trials) that treatment of such an episode with antidepressants alone may increase the likelihood of a mixed/manic episode in patients at risk of developing bipolar disorder. It is not known whether the symptoms described above demonstrate the likelihood of this acceleration. However, before starting antidepressant treatment, patients with symptoms of depression should be appropriately evaluated to determine whether they are at risk of bipolar disorder; such evaluation should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Elifor is not indicated for the treatment of bipolar depression.
Serotonin syndrome
Serotonin syndrome, a potentially life-threatening condition, has been reported with the use of SSRIs and SSRIs, including Elifor, alone, but especially with concomitant use with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's wort), as well as with drugs that reduce serotonin metabolism (in particular, MAO inhibitors, which are prescribed to treat psychiatric disorders, and others such as linezolid and methylene blue for intravenous use).
Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, blood pressure fluctuations, dizziness, sweating, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the development of serotonin syndrome.
The concomitant use of Elifor with MAO inhibitors intended for the treatment of psychiatric disorders is contraindicated. Elifor should also not be prescribed to patients undergoing treatment with MAO inhibitors such as linezolid or intravenous methylene blue. All reports of methylene blue that included information on the routes of administration concerned intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. There are no reports of the use of methylene blue by other routes (e.g. oral tablets or local injections) or at lower doses. If it is necessary to use MAO inhibitors such as linezolid or intravenous methylene blue, the patient using Elifor should discontinue Elifor before starting treatment with MAO inhibitors (see “Contraindications”, “Method of administration and dosage”).
If concomitant use of Elifor with other serotonergic agents, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's wort, is clinically warranted, patients should be informed of the possible increased risk of serotonin syndrome, particularly at the beginning of treatment and with dose increases.
Treatment with Elifor with concomitant use of serotonergic agents should be discontinued immediately if the above symptoms occur and appropriate symptomatic treatment should be initiated.
High blood pressure
Patients receiving Elifor should have their blood pressure monitored regularly, as increases in blood pressure have been observed in clinical trials (see Adverse Reactions). Blood pressure should be monitored in patients with a history of hypertension before starting treatment with Elifor. Caution should be exercised when treating patients with pre-existing hypertension, cardiovascular and cerebrovascular disorders, which may be aggravated by increased blood pressure. Cases of increased blood pressure requiring immediate treatment have been reported during the use of Elifor.
A persistent increase in blood pressure may have adverse effects. For patients who experience a persistent increase in blood pressure while taking Elifor, a dose reduction or discontinuation of therapy should be considered (see “Adverse Reactions”).
Abnormal bleeding
SSRIs and SNRIs, including Elifor, may increase the risk of bleeding. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin and other anticoagulants may increase this risk. Case reports and epidemiological studies (case-control and cohort studies) have shown an association between the use of drugs that affect serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events associated with SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis and petechiae to life-threatening bleeding. Patients should be aware of the risk of bleeding associated with the concomitant use of Elifor and NSAIDs, aspirin or other drugs that affect coagulation or bleeding.
Narrow-angle glaucoma
Mydriasis has been reported in association with the use of Elifor, therefore patients with elevated intraocular pressure or at risk of angle-closure glaucoma (narrow-angle glaucoma) should be monitored.
In all phase 2 and phase 3 VDR studies, mania was observed in approximately 0.02% of patients treated with Elifor. Activation of mania/hypomania has also been observed in a small number of patients with major affective disorder treated with other licensed antidepressants. As with all antidepressants, Elifor should be used with caution in patients with a personal or family history of mania or hypomania.
Withdrawal syndrome
Withdrawal symptoms have been evaluated in systematic and prospective studies in patients treated with Elifor in clinical trials of VDR. Abrupt discontinuation or dose reduction has been associated with the development of new symptoms, including dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and sweating. In general, withdrawal symptoms were more frequent with longer-term therapy.
During the use of SSRIs and SSRIs, spontaneous reports of adverse reactions occurring after discontinuation of these drugs, especially abrupt, have been received, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these reactions were usually self-limiting, severe withdrawal symptoms have been reported.
These symptoms should be monitored in patients who discontinue treatment with Elifor. Gradual dose reduction rather than abrupt discontinuation is recommended, if possible. If intolerable symptoms occur after dose reduction or discontinuation, resumption of the previously prescribed dose should be considered. Subsequently, the doctor may continue to reduce the dose, but more gradually (see “Method of administration and dosage”, “Adverse reactions”).
Convulsive seizures
Cases of seizures have been reported in pre-marketing clinical studies of Elifor. Systematic analysis of the effects of Elifor was not conducted in patients with epilepsy. Patients with a history of seizures were excluded from pre-marketing clinical studies. Elifor should be administered with caution to patients with epilepsy.
Hyponatremia
Hyponatraemia may occur as a result of treatment with SSRIs and SNRIs, including Elifor. In many cases, hyponatraemia is the result of the syndrome of inappropriate antidiuretic hormone secretion. Cases of serum sodium levels below 110 mmol/l have not been reported. Elderly patients are at greater risk of developing hyponatraemia during treatment with SSRIs and SNRIs. In addition, patients taking diuretics or dehydrated for other reasons are also at increased risk of hyponatraemia (see section “
Method of administration and dosage” subsections “Use in special groups” and “Pharmacological properties”). For patients with symptoms of hyponatremia, Elifor may need to be discontinued and appropriate medical measures taken.
Symptoms of hyponatremia include: headache, difficulty concentrating, memory impairment, confusion, weakness, and loss of balance, which may lead to falls. Symptoms associated with more severe and/or acute cases have included: hallucinations, fainting, seizures, coma, respiratory arrest, and death.
Interstitial lung disease and eosinophilic pneumonia
Interstitial lung disease and eosinophilic pneumonia have been reported rarely in association with the use of venlafaxine (the parent compound of Elifor). The possibility of these adverse reactions should be considered in patients taking Elifor who present with progressive dyspnea, cough, or chest discomfort. Such patients should receive prompt medical evaluation and discontinuation of Elifor should be considered.
Use in elderly patients
Of the 4158 patients who participated in pre-marketing clinical studies of Elifor, 6% were 65 years of age or older. Overall, no differences in safety and efficacy were observed between these patients and younger patients; however, in short-term placebo-controlled studies, a higher rate of systolic orthostatic hypotension was observed in patients ≥ 65 years of age compared to patients < 65 years of age treated with Elifor. For elderly patients, the possible limited renal clearance of Elifor should be considered when determining the dose.
SSRIs and SNRIs, including Elifor, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at increased risk of these adverse reactions.
Use during pregnancy or breastfeeding
Pregnancy (category C)
There are no adequate and well-controlled studies of the effects of Elifor in pregnant women. In animal reproduction studies of desvenlafaxine succinate, no evidence of teratogenicity was observed at doses up to 30 times the human dose of 100 mg/day (based on mg/m2). Increased pup mortality was observed during the first 4 days of lactation when desvenlafaxine succinate was used during pregnancy and lactation at doses 10 times the human dose of 100 mg/day (based on mg/m2). Elifor should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
A prospective, long-term study of 201 women with a history of VDR who were euthymic at the start of pregnancy demonstrated that women who discontinued antidepressants during pregnancy were more likely to suffer a relapse of major depression than women who continued to use antidepressants.
Neonates exposed to SSRIs or SSRIs late in the third trimester have had complications requiring prolonged hospitalization, mechanical ventilation, and tube feeding. These complications may occur immediately after delivery. Respiratory depression, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypotension, hypertension, hyperreflexia, tremor, nervousness, irritability, and persistent crying have been reported. These features are consistent with either direct toxicity of SSRIs and SSRIs or possibly drug withdrawal syndrome. It should be noted that in some cases the clinical picture is consistent with serotonin syndrome (see “Special instructions”).
Breast-feeding
Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Elifor, 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.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies of the effect of the drug on the reaction rate when driving vehicles or other mechanisms have not been conducted. When deciding whether to drive vehicles or other mechanisms, the possibility of adverse reactions should be taken into account.
Method of administration and doses
The recommended dose of Elifor is 50 mg once daily, regardless of meals.
Elifor should be taken at about the same time each day. The tablets should be swallowed whole with liquid and should not be broken, crushed, chewed or dissolved.
In clinical studies, doses of 50 to 400 mg per day were effective, no additional effect was observed with doses above 50 mg per day, and adverse reactions and the risk of withdrawal syndrome were more frequent at higher doses. If the physician, based on the results of the clinical assessment of the patient's condition, decides that an increase in the dose above 50 mg per day is appropriate for a particular patient, the maximum recommended dose should not exceed 100 mg per day.
When discontinuing therapy, gradual dose reduction is recommended, if possible, to minimize withdrawal symptoms.
Application in special groups
Patients with renal impairment
The maximum recommended dose for patients with moderate renal impairment (creatinine clearance [CC] 30 to 50 mL/min) is 50 mg daily. The maximum recommended dose for patients with severe renal impairment (CC < 30 mL/min) or end-stage renal disease is 50 mg every other day. The dose should not be increased in patients undergoing dialysis.
Patients with hepatic impairment
The recommended dose for patients with moderate to severe hepatic impairment is 50 mg/day. Increasing the dose above 100 mg/day is not recommended.
Supportive therapy
It is generally accepted that acute episodes of VDR require continuous drug therapy for several months or longer. The efficacy of long-term use of Elifor (50-400 mg) has been established in two maintenance therapy studies. The patient should be periodically reassessed to determine the need for continued therapy.
Elifor drug withdrawal
Symptoms associated with discontinuation of Elifor, other SSRIs and SSRIs have been reported. Patients who discontinue treatment should be monitored for withdrawal symptoms. Gradual dose reduction rather than abrupt discontinuation is recommended whenever possible. If intolerable symptoms occur after dose reduction or discontinuation, the previously prescribed dose may need to be resumed. The doctor may then continue to reduce the dose, but more gradually.
Switching patients from other antidepressants to Elifor
Withdrawal symptoms have been reported when patients are switched from other antidepressants, including venlafaxine, to Elifor. A reduction in the dose of the original antidepressant may be necessary to minimize withdrawal symptoms.
MAO inhibitor therapy for the treatment of psychiatric disorders
At least 14 days should elapse between discontinuing an MAO inhibitor used to treat psychiatric disorders and starting Elifor therapy, and at least 7 days should elapse after discontinuing Elifor before starting therapy with an MAO inhibitor used to treat psychiatric disorders.
Using Elifor with other MAO inhibitors such as linezolid or methylene blue
In some cases, a patient already receiving Elifor may require urgent treatment with linezolid or intravenous methylene blue. If there is no acceptable alternative to linezolid or methylene blue and the potential benefit of using these drugs outweighs the risks of serotonin syndrome in the individual patient, Elifor should be discontinued immediately and treatment with linezolid or intravenous methylene blue should be initiated. The patient should be monitored for symptoms of serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Elifor therapy may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.
The risk of concomitant use of methylene blue, either intravenously or in other forms (e.g., oral tablets or local injection), at doses significantly below 1 mg/kg is unknown. The physician should be aware of the possibility of serotonin syndrome symptoms with such use.
Children.
Safety and efficacy in children have not been established, so the drug is not used in this age group of patients.
Overdose
Clinical experience with overdose of desvenlafaxine succinate in humans is limited. However, desvenlafaxine (Elifor) is the major active metabolite of venlafaxine. The following are reports of overdose with venlafaxine.
In post-marketing experience, overdoses of venlafaxine have occurred primarily in combination with alcohol and/or other drugs. The most common symptoms were tachycardia, altered level of consciousness (ranging from drowsiness to coma), mydriasis, convulsions, and vomiting. Electrocardiogram changes (e.g., QT prolongation, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, acute skeletal muscle necrosis, dizziness, hepatic necrosis, serotonin syndrome, and death have been reported.
Published retrospective studies suggest that venlafaxine overdose may be associated with an increased risk of fatal outcomes compared with SSRI antidepressants, but the risk of fatal outcomes with venlafaxine is lower than with tricyclic antidepressants. Epidemiological studies have shown that patients receiving venlafaxine have higher levels of pre-existing risk factors for suicide than patients receiving SSRIs. The extent to which the increased risk of fatal outcomes can be attributed to venlafaxine toxicity in overdose is unclear, unlike some other toxicity measures in patients receiving venlafaxine.
Treatment of overdose. Specific antidotes to Elifor are not known. Symptomatic and supportive therapy, monitoring of heart rate and vital signs are recommended.
Adverse reactions
The safety of desvenlafaxine has been established in clinical studies involving 7785 patients with ADHD who received at least one dose of desvenlafaxine over a dose range of 10 to 400 mg/day. Long-term safety has been evaluated in more than 2000 subjects with ADHD who received desvenlafaxine for at least 6 months and in 400 patients who received desvenlafaxine for 1 year.
In most cases, adverse reactions were most frequently observed during the first week of treatment and were mild to moderate in severity. The incidence of adverse reactions was generally dose-dependent.
The following adverse reactions have been reported in pre-marketing clinical trials with desvenlafaxine at doses ranging from 10 to 400 mg for the treatment of BDD. The frequency of adverse reactions is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to ≤ 1/1,000); very rare (≥ 1/10,000 to ≤ 1/1,000).
