Elifor

Instructions for Medical Use of the Medicinal Product ELIFORE (ELIFORE)

Composition:

Active substance: desvenlafaxine succinate;

One prolonged-release tablet contains desvenlafaxine succinate 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, polyethylene glycol, titanium dioxide (E 171), talc, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake (E 110), iron oxide red (E 172)); for 50 mg tablets: Opadry® II, 85F94487 (polyvinyl alcohol, polyethylene glycol, titanium dioxide (E 171), talc, iron oxide yellow (E 172), iron oxide red (E 172)).

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

50 mg tablets: light pink, square-shaped, film-coated tablets, with an imprint "W" above "50" on one flat side and a pyramid-shaped indentation on the other side;

100 mg tablets: reddish-orange, square-shaped, film-coated tablets, with an imprint "W" above "100" on one flat side and a pyramid-shaped indentation on the other side.

Pharmacotherapeutic group. Antidepressants. ATC code: N06AX23.

Pharmacological Properties

Pharmacodynamics

The precise mechanism of the antidepressant action of desvenlafaxine is unknown, but it is believed to be related to the 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 serotonin and norepinephrine reuptake inhibitor (SNRI).

Desvenlafaxine showed no significant affinity for various receptors, including muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Desvenlafaxine also did not exhibit clear inhibitory activity against monoamine oxidase (MAO).

Pharmacokinetics

The pharmacokinetics of a single dose of desvenlafaxine are linear and dose-proportional over a dose range of 50 mg to 600 mg (1–12 times the recommended approved dose) per day. At a once-daily dosing regimen, steady-state plasma concentrations are achieved within approximately 4–5 days. At steady state, multiple-dose accumulation of desvenlafaxine is linear and predictable, consistent with the pharmacokinetic profile of a single dose.

Absorption

The absolute bioavailability of Elifor after oral administration is approximately 80%.

Effect of Food Intake

Consumption of a high-fat meal (containing 800 to 1000 kilocalories) resulted in an approximately 16% increase in Cmax of desvenlafaxine and had no effect on AUC.

Distribution

The volume of distribution of desvenlafaxine at steady state is 3.4 L/kg. Plasma protein binding of desvenlafaxine is 30% and is independent of drug concentration.

Elimination

Metabolism

Desvenlafaxine is primarily metabolized via conjugation [mediated by uridine-5-diphosphate (UDP) isoenzymes], with a lesser extent of oxidative metabolism. CYP3A4 is involved in the oxidative metabolism (N-demethylation) of desvenlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine were similar in patients who are poor and extensive metabolizers of CYP2D6.

Excretion

Approximately 45% of desvenlafaxine is excreted unchanged in urine within 72 hours after oral administration. Approximately 19% of the administered dose is excreted as a glucuronide metabolite and < 5% as an oxidative metabolite (N,O-didesmethylvenlafaxine) in urine.

Use in Special Patient Populations

No clinically significant differences in desvenlafaxine exposure were observed based on race (in Caucasian, African American, or Hispanic populations).

In vitro studies

Based on in vitro data, drugs that inhibit the CYP1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1 isoenzymes are not expected to have a significant effect on the pharmacokinetic profile of desvenlafaxine.

Desvenlafaxine does not inhibit the CYP1A2, 2A6, 2C8, 2C9, 2C19, CYP2D6, or CYP3A4 isoenzymes.

Desvenlafaxine is also not an inducer of CYP3A4.

Desvenlafaxine is neither a substrate nor an inhibitor of the P-glycoprotein (P-gp) transporter.

Clinical characteristics.

Indications.

Treatment of major depressive disorder (MDD) in adults.

Contraindications.

• Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride, or to any excipients of Elifor.
• Concomitant use of monoamine oxidase inhibitors (MAOIs) indicated for the treatment of psychiatric disorders, or their use within 7 days after discontinuation of Elifor. Use of Elifor within 14 days after discontinuation of MAOIs indicated for the treatment of psychiatric disorders.
• Concomitant treatment with MAOIs such as linezolid, or intravenous methylene blue therapy.

Interaction with other medicinal products and other forms of interaction.

Medicinal products that have clinically important interactions with Elifor

Monoamine oxidase inhibitors (MAOIs), such as selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue.

Concomitant use of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including Elifor, with MAOIs increases the risk of serotonin syndrome (see "Method of administration and dosage", "Contraindications", "Special precautions").

Other serotonergic agents, such as other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium preparations, tramadol, buspirone, amphetamines, tryptophan, and St. John's wort.

Concomitant use of Elifor with other serotonergic agents increases the risk of serotonin syndrome.

Monitoring for symptoms of serotonin syndrome is required when Elifor is used concomitantly with other agents that may affect serotonergic neurotransmitter systems. If serotonin syndrome develops, consider discontinuing treatment with Elifor and/or the concomitant serotonergic agents (see "Special precautions").

Drugs affecting hemostasis, including nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, warfarin, and others.

Concomitant use of Elifor with antiplatelet or anticoagulant agents increases the risk of bleeding. This may be due to the effect of Elifor on platelet serotonin release.

Careful monitoring for signs of bleeding is required in patients receiving antiplatelet or anticoagulant agents when initiating or discontinuing treatment with Elifor (see "Special precautions").

Drugs primarily metabolized by CYP2D6, such as desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine.

Concomitant use of Elifor increases Cmax and AUC of drugs primarily metabolized by CYP2D6, increasing the risk of toxicity of CYP2D6 substrate drugs.

When coadministered with Elifor at a dose of 100 mg, drugs metabolized by CYP2D6 should be initiated at the usual or lower starting dose. The dose of these drugs should be reduced by half when coadministered with 400 mg of Elifor.

Medicinal products that do not have clinically important interactions with Elifor

According to pharmacokinetic studies, dose adjustment is not required for medicinal products primarily metabolized by CYP3A4 (e.g., midazolam), or medicinal products metabolized by both CYP2D6 and CYP3A4 isoenzymes (e.g., tamoxifen, aripiprazole) when used concomitantly with Elifor (see "Pharmacological properties").

Alcohol

Elifor does not increase ethanol-induced impairment of mental and motor skills. However, as with other centrally acting agents, patients should be advised to avoid alcohol consumption during treatment with Elifor.

Effect of the medicinal product on laboratory test results

False-positive immunoassay screening tests for phencyclidine and amphetamines in urine have been reported in patients taking desvenlafaxine. This is due to the lack of specificity of screening tests. False-positive results may be expected for several days after discontinuation of desvenlafaxine. Confirmatory tests, such as gas chromatography/mass spectrometry, can differentiate desvenlafaxine from phencyclidine and amphetamines.

Special precautions.

Suicidal thoughts and behavior in children, adolescents, and young adults

Patients with MDD, both adults and children, whether or not they are taking antidepressants, may experience worsening of depression, emergence of suicidal ideation and behavior (suicidality), or unusual changes in behavior, and this risk may persist until a sustained remission occurs. It is well established that depression and certain other psychiatric disorders are risk factors for suicide; these disorders themselves are clear precursors of suicide. However, antidepressants may play a role in increasing depression and the emergence of suicidality in some patients during the early stages of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressants (SSRIs and others) have demonstrated that these drugs increase the risk of suicidal thoughts and behavior (suicidality) in children, adolescents, and young adults (aged 18 to 24 years) with MDD and other psychiatric disorders. Short-term trials did not show an increased risk of suicidality during antidepressant treatment compared to placebo in adults aged 24 years and older; a reduction in suicidality risk was observed during antidepressant treatment compared to placebo in adults aged 65 years and older.

A combined analysis of placebo-controlled trials involving children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressants involving more than 4,400 patients. A combined analysis of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (mean duration 2 months) of 11 antidepressants involving more than 77,000 patients. Significant differences in suicidality risk among drugs were observed, but with a trend toward increased risk in younger patients with almost all studied drugs. Differences in absolute risk of suicidality were observed across indications, with the highest rates seen in MDD. However, differences in risk (drugs versus placebo) were relatively stable across age groups and indications.

These risk differences (the difference between drugs and placebo in the number of suicidality cases per 1000 treated patients) are presented in the table below.

Age range	Difference between active drug and placebo in number of suicide cases per 1000 patients treated
	Increased compared to placebo
< 18	14 additional cases
18-24	5 additional cases
	Decreased compared to placebo
25-64	1 fewer case
≥ 65	6 fewer cases

No suicides occurred in any of the pediatric studies. Suicides were observed in adult studies, but the number was insufficient to draw any conclusion about the effect of the drugs on suicides.

It is unknown whether the risk of suicidality extends to long-term use, i.e., longer than several months. However, data from placebo-controlled studies in adult patients with depression provide substantial evidence that antidepressant treatment may delay the recurrence of depression. All patients receiving antidepressants for any indication should be appropriately monitored and observed for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of treatment or during dose adjustments (increases or decreases).

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adults and children treated with antidepressants for MDD as well as for other psychiatric and non-psychiatric indications. Although a causal link between the emergence of such symptoms and worsening of depression and/or the emergence of suicidal impulses has not been established, there are concerns that such symptoms may be precursors to the emergence of suicidality.

Therapeutic regimen changes, including possible discontinuation of the drug, should be considered for patients whose depression is persistently worsening or who experience suicidality or symptoms that may be harbingers of worsening depression or suicidality, especially if these symptoms are severe, have a sudden onset, or were not present prior to treatment.

If a decision is made to discontinue treatment, the drug should be tapered gradually, reducing the dose as rapidly as possible while considering that abrupt discontinuation may be associated with certain symptoms (see "Dosage and Administration" and "Special Warnings").

Patients' families and caregivers being treated with antidepressants for MDD or other psychiatric and non-psychiatric conditions should be advised to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and other symptoms described above, as well as the emergence of suicidality, and to immediately report such symptoms to healthcare professionals.

Prescriptions for Elifor should be issued for the smallest number of tablets necessary for adequate patient treatment to reduce the risk of overdose.

Screening patients for bipolar disorder

A major depressive episode may be an initial presentation of bipolar disorder. It is believed (although not established in controlled studies) that treating such an episode with antidepressants alone may increase the likelihood of precipitating a mixed/manic episode in patients at risk for bipolar disorder. It is unknown whether the symptoms described above indicate a likelihood of such precipitation. However, appropriate screening of patients with depressive symptoms should be conducted prior to initiating antidepressant treatment to determine whether they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including family history of suicide, bipolar disorder, and depression. Elifor should not be used for the treatment of bipolar depression.

Serotonin syndrome

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), including Elifor, may cause serotonin syndrome, a potentially life-threatening condition. The risk increases when used concomitantly with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's wort) and drugs that impair serotonin metabolism, particularly monoamine oxidase inhibitors (MAOIs) (see "Contraindications," "Drug Interactions and Other Interactions"). Serotonin syndrome may also occur with the use of these drugs alone.

Symptoms of serotonin syndrome may include changes in mental status (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, fluctuations in blood pressure, dizziness, sweating, flushing, hyperthermia), neuromuscular manifestations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Concomitant use of Elifor with MAO inhibitors is contraindicated. Elifor should not be prescribed to patients receiving MAO inhibitors such as linezolid or intravenous methylene blue. Reports of methylene blue use by other routes (e.g., oral tablets or local injections) are lacking. If treatment with MAO inhibitors such as linezolid or intravenous methylene blue is required, the patient should discontinue Elifor prior to initiating MAOI treatment (see "Contraindications," "Drug Interactions and Other Interactions").

All patients taking Elifor must be monitored for the emergence of serotonin syndrome. If the above symptoms occur, treatment with Elifor and any concomitant serotonergic agents should be immediately discontinued, and appropriate symptomatic treatment initiated. If concomitant use of Elifor with other serotonergic agents is clinically justified, patients should be informed of the increased risk of serotonin syndrome and monitored for early signs of serotonin syndrome.

Elevated blood pressure

Patients receiving Elifor should have their blood pressure monitored regularly, as increased blood pressure has been observed in clinical trials (see "Adverse Reactions"). Prior to initiating Elifor treatment, blood pressure should be controlled in patients with a history of hypertension. Caution should be exercised when treating patients with pre-existing hypertension, cardiovascular, and cerebrovascular disorders, which may be exacerbated by increased blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported during Elifor use.

Persistent elevation of blood pressure may have adverse consequences. For patients who develop persistent elevated blood pressure during Elifor treatment, consideration should be given to reducing the dose or discontinuing therapy (see "Adverse Reactions").

Increased risk of bleeding

Drugs that inhibit serotonin reuptake, including Elifor, increase the risk of bleeding. SSRIs and SNRIs may increase the risk of postpartum hemorrhage (see "Use in Pregnancy or Breastfeeding" and "Adverse Reactions"). 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 demonstrated an association between the use of drugs affecting 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 hemorrhage.

Patients should be informed of the risk of bleeding associated with concomitant use of Elifor and antiplatelet or anticoagulant agents. If a patient is taking warfarin, careful monitoring of coagulation parameters is required during initiation, titration, or discontinuation of Elifor.

Angle-closure glaucoma

Mydriasis, which may occur during treatment with many antidepressants, including Elifor, may precipitate an acute attack of angle-closure glaucoma in patients with anatomically narrow angles who have not undergone a peripheral iridectomy. Antidepressants, including Elifor, should be avoided in patients with untreated anatomically narrow angles.

Activation of mania/hypomania

In all Phase 2 and Phase 3 MDD studies, mania was observed in approximately 0.02% of patients receiving Elifor. Activation of mania/hypomania has also been observed in a small number of patients with major affective disorder receiving other approved antidepressants. As with all other antidepressants, Elifor should be used with caution in patients with a personal or family history of mania or hypomania.

Withdrawal syndrome

Adverse reactions following discontinuation of serotonergic antidepressants, particularly abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures (see "Adverse Reactions").

During post-marketing use of Elifor, reports of serious withdrawal symptoms, which may be prolonged and severe, have been received. During dose reduction of Elifor, including discontinuation of treatment, completed suicide, suicidal thoughts, and severe aggression (including hostility, rage, and homicidal ideation) have been observed in patients. Other reports during post-marketing use describe visual disturbances (such as blurred vision or focusing problems) and elevated blood pressure following discontinuation or dose reduction of Elifor.

Patients should be monitored when discontinuing Elifor. Gradual dose reduction is recommended rather than abrupt discontinuation. If intolerable symptoms occur after dose reduction or after discontinuation of treatment, consideration may be given to reinstating Elifor at the previously prescribed dose. The physician may then continue to reduce the dose, but more gradually. Some patients may require tapering over several months (see "Dosage and Administration").

Seizures

Seizures have been reported in pre-marketing clinical trials of Elifor. Systematic analysis of the effect of Elifor has not been conducted in patients with epilepsy. Patients with a history of seizures were excluded from pre-marketing clinical trials. Elifor should be prescribed with caution to patients with epilepsy.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Elifor. In many cases, hyponatremia is due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium levels below 110 mmol/L have not been reported. Elderly patients are at greater risk of developing hyponatremia during treatment with SSRIs and SNRIs. Additionally, the risk of hyponatremia is also increased in patients taking diuretics or those with dehydration from other causes (see "Dosage and Administration," subsection "Use in Special Populations," and "Pharmacological Properties"). For patients with symptoms of hyponatremia, discontinuation of Elifor and appropriate medical interventions may be required.

Symptoms of hyponatremia include: headache, difficulty concentrating, memory impairment, confusion, weakness, and loss of balance, which may lead to falls. In more severe and/or acute cases, hallucinations, unconsciousness, seizures, coma, respiratory arrest, and fatal outcomes have been observed.

Lung interstitial disease and eosinophilic pneumonia

Rare cases of interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the active substance of Elifor) have been reported. 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 undergo immediate medical evaluation, and discontinuation of Elifor should be considered.

Sexual dysfunction

Use of SNRIs, including Elifor, may cause symptoms of sexual dysfunction (see "Adverse Reactions"). In men, use of SNRIs may cause delayed or absent ejaculation, decreased libido, and erectile dysfunction. In women, use of SNRIs may lead to decreased libido and delayed or absent orgasm.

It is important that physicians prescribing the drug inquire about the patient's sexual function prior to starting Elifor and, particularly, changes in sexual function during treatment, as spontaneous reports of sexual function may be absent. When evaluating changes in sexual function, obtaining a detailed history (including onset of symptoms) is important, as symptoms related to the sexual system may have other causes, including the underlying psychiatric disorder. Potential treatment strategies should be discussed to support patients in making informed treatment decisions.

Use in elderly patients

Of the 4158 patients who participated in pre-marketing clinical trials of Elifor, 6% were aged 65 years or older. Overall, no differences in safety and efficacy profiles were observed between these patients and younger patients, although in short-term placebo-controlled trials, a higher incidence of systolic orthostatic hypotension was observed in patients aged ≥65 years compared to patients aged <65 years receiving Elifor. For elderly patients, the possibility of reduced renal clearance of Elifor should be considered when determining dosage.

SSRIs and SNRIs, including Elifor, have been associated with cases of clinically significant hyponatremia in elderly patients, who may have an increased risk of developing these adverse reactions.

Use during pregnancy or breastfeeding

Summary of risks

There are no published studies on the use of Elifor in pregnant women. However, published epidemiological studies on the effects of the parent compound—venlafaxine—on pregnant women have not reported a clear association with adverse pregnancy outcomes. Risks are associated with untreated depression in pregnant women as well as with the effects of SNRIs and SSRIs, including Elifor, during pregnancy.

The estimated background risk of major congenital malformations and pregnancy loss in the general population is unknown. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes.

Maternal and/or embryofetal risk associated with the disease

A prospective long-term study involving 201 women with a history of major depressive disorder (MDD), who were euthymic at the beginning of pregnancy, demonstrated that women who discontinued antidepressants during pregnancy experienced more frequent relapses of major depression than women who continued antidepressant treatment.

Information on drug effects on mother and fetus/newborn

Exposure to SNRIs during mid and late pregnancy increases the risk of preeclampsia, and SNRI exposure shortly before delivery increases the risk of postpartum hemorrhage.

Observational data indicate an increased risk (less than two-fold) of postpartum hemorrhage following SSRI/SNRI use within one month of delivery (see "Special Warnings" and "Adverse Reactions").

Newborns whose mothers took Elifor during the third trimester of pregnancy should be monitored for signs of drug withdrawal syndrome. Use of SNRIs or SSRIs in late pregnancy increases the risk of complications in newborns requiring prolonged hospitalization, mechanical ventilation, and tube feeding. Such complications may occur immediately after delivery. Reports include respiratory depression, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypotonia, hypertension, hyperreflexia, tremor, restlessness, irritability, and persistent crying. These features may correspond to either direct toxic effects of SSRIs and SNRIs or, possibly, drug withdrawal syndrome. It should be noted that in some cases, the clinical picture corresponds to serotonin syndrome (see "Special Warnings").

Published epidemiological studies on the effects of the parent compound—venlafaxine—on pregnant women have not reported a clear association with major congenital malformations or pregnancy loss. However, these studies cannot confirm or exclude any risk associated with drug use during pregnancy.

Oral administration of desvenlafaxine succinate to pregnant rats and rabbits during organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, did not reveal teratogenic effects. These doses were associated with plasma concentrations (AUC) 19 times higher (rats) and 0.5 times higher (rabbits) than the concentration at a 100 mg daily dose in adults. However, reduced fetal weight and delayed skeletal ossification were observed in rats, associated with maternal toxicity at the highest dose. The AUC at the non-toxic dose was 4.5 times higher than the AUC at a 100 mg daily dose in adults.

Oral administration of desvenlafaxine succinate to pregnant rats throughout gestation and lactation resulted in reduced offspring body weight and increased mortality during the first four days of lactation. The cause of these deaths is unknown.

Breastfeeding

Available limited data from scientific publications indicate low levels of desvenlafaxine in breast milk and show no adverse reactions in breastfed infants. There is no information on the effect of desvenlafaxine on breast milk production.

The benefits of breastfeeding for the child's development and health, the mother's clinical need for Elifor treatment, and any potential adverse effects on the breastfed infant from the mother's underlying condition and Elifor use should be carefully evaluated.

Ability to affect reaction speed when operating vehicles or other machinery

Patients should not operate complex machinery, including vehicles, until they are certain that Elifor does not impair their ability to engage in such activities.

Method of Administration and Dosage.

The recommended dose of Elifor is 50 mg once daily, independent of food intake.

Elifor should be taken at approximately the same time each day. Tablets should be swallowed whole with liquid and must not be broken, crushed, chewed, or dissolved.

In clinical studies, doses ranging from 50 to 400 mg daily were effective; however, no additional benefit was observed with doses exceeding 50 mg daily, while adverse reactions and the risk of withdrawal syndrome were more frequent at higher doses. If a physician, based on clinical assessment of the patient's condition, determines that increasing the dose above 50 mg daily is appropriate for a particular patient, the maximum recommended dose should not exceed 100 mg daily.

When discontinuing therapy, gradual dose reduction is recommended, if possible, to minimize withdrawal symptoms.

Use in Special Patient Populations

Patients with Renal Impairment

The maximum recommended dose for patients with moderate renal impairment (creatinine clearance [CrCl] 30–50 mL/min over 24 hours, calculated by the Cockcroft–Gault formula) is 50 mg daily. The maximum recommended dose for patients with severe renal impairment (CrCl 15–29 mL/min) or end-stage renal disease (ESRD, CrCl < 15 mL/min) is 50 mg every other day. Additional doses should not be administered after dialysis (see "Pharmacological Properties").

Patients with Hepatic Impairment

The recommended dose for patients with moderate to severe hepatic impairment (Child–Pugh score 7–15) is 50 mg daily. Dose escalation above 100 mg daily is not recommended (see "Pharmacological Properties").

Maintenance Therapy

It is generally accepted that acute episodes of MDD require continuous pharmacological treatment for several months or longer. The efficacy of long-term use of Elifor (50–400 mg) has been demonstrated in two maintenance therapy studies. Periodic assessment of the patient should be conducted to determine the need for continued treatment.

Discontinuation of Elifor

Upon discontinuation of Elifor, adverse reactions may occur (see "Special Warnings and Precautions for Use"). Gradual dose reduction of Elifor is recommended rather than abrupt discontinuation. Some patients may require tapering over several months.

Switching Patients from Other Antidepressants to Elifor

Withdrawal symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to Elifor. Dose reduction of the initial antidepressant may be necessary to minimize withdrawal symptoms.

MAOI Therapy for Psychiatric Disorders

At least 14 days must elapse between discontinuation of an MAOI indicated for psychiatric disorders and initiation of Elifor therapy. At least 7 days must pass after discontinuation of Elifor before initiating therapy with an MAOI indicated for psychiatric disorders.

Use of Elifor with Other MAOIs, Such as Linezolid or Methylene Blue

Elifor therapy should not be initiated in patients receiving linezolid or intravenous methylene blue due to the increased risk of serotonin syndrome. For patients requiring urgent psychiatric treatment, alternative approaches, including hospitalization, should be considered.

In some cases, a patient already receiving Elifor may require urgent treatment with linezolid or intravenous methylene blue. If no acceptable alternative to linezolid or methylene blue exists and the potential benefit outweighs the risk of serotonin syndrome in a specific patient, Elifor should be discontinued immediately and treatment with linezolid or intravenous methylene blue initiated. The patient should be monitored for symptoms of serotonin syndrome for 7 days or for 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 intravenous methylene blue or other forms (e.g., oral tablets or local injection) at doses substantially lower than 1 mg/kg is unknown. Physicians should consider the potential for serotonin syndrome symptoms with such use.

Pediatric Use

The safety and efficacy of Elifor for the treatment of major depressive disorder in children have not been established; therefore, the drug is not recommended for use in this patient population.

Efficacy was not demonstrated in two adequate and well-controlled 8-week randomized, double-blind, placebo-controlled, parallel-group studies involving 587 patients (aged 7 to 17 years) with MDD.

Antidepressants such as Elifor increase the risk of suicidal thoughts and behaviors in children (see "Special Warnings and Precautions for Use").

In placebo-controlled trials, Elifor use was associated with weight loss in children with MDD. The incidence of weight loss (≥ 3.5% from baseline weight) was 22%, 14%, and 7% in patients receiving low-dose Elifor, high-dose Elifor, and placebo, respectively.

The risk associated with long-term use of Elifor was evaluated in 6-month open-label extension studies in children aged 7 to 17 years with MDD. In children aged 7 to 17 years, mean changes in body weight were within the expected range based on data from age- and sex-matched peers.

In clinical studies, compared to adults receiving the same dose of Elifor, desvenlafaxine exposure was similar in adolescents aged 12 to 17 years and approximately 30% higher in children aged 7 to 11 years.

Overdose.

Clinical experience with desvenlafaxine succinate overdose in humans is limited. However, desvenlafaxine (Elifor) is the primary active metabolite of venlafaxine. The following reports pertain to venlafaxine overdose.

During post-marketing use, overdoses occurred predominantly in combination with alcohol and/or other drugs. The most common symptoms included tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Reports included ECG changes (e.g., QT interval prolongation, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, acute rhabdomyolysis, dizziness, hepatic necrosis, serotonin syndrome, and fatal outcomes.

Published retrospective studies suggest that venlafaxine overdose may be associated with an increased risk of fatal outcomes compared to SSRIs, but this risk is lower than with tricyclic antidepressants. Epidemiological studies have shown that patients receiving venlafaxine have a higher prevalence of pre-existing suicide risk factors than those receiving SSRIs. The extent to which the increased risk of fatal outcomes is attributable to venlafaxine toxicity in overdose, as opposed to other patient-related toxicity factors, remains unclear.

Treatment of Overdose. There are no known specific antidotes for Elifor. Recommended treatment includes symptomatic and supportive care, with cardiac rhythm and vital sign monitoring.

Adverse Reactions

The safety of desvenlafaxine was established in clinical studies involving 7785 patients with MDD who received at least one dose of desvenlafaxine in the dose range of 10 to 400 mg/day. The safety of long-term use was evaluated in more than 2000 subjects with MDD who received desvenlafaxine for at least 6 months, and in 400 patients who took desvenlafaxine for 1 year.

In most cases, adverse reactions occurred primarily during the first week of treatment and were of mild to moderate severity. The incidence of adverse reactions was generally dose-dependent.

The adverse reactions listed below were reported during pre-registration clinical trials of desvenlafaxine at doses of 10 to 400 mg for the treatment of MDD. The frequency of adverse reactions is classified according to the following scale: very common – ≥ 1/10; common – ≥ 1/100 and < 1/10; uncommon – ≥ 1/1000 and < 1/100; rare – ≥ 1/10000 and ≤ 1/1000; very rare – < 1/10000; frequency not known – cannot be estimated based on available data. Adverse reactions with frequency < 1% were calculated manually; reactions with frequency ≥ 1% were classified as indicated below.

Within each frequency category, adverse reactions are listed in order of decreasing frequency.

Immune system disorders: uncommon – hypersensitivity.

Metabolism and nutrition disorders: common – decreased appetite; rare – hyponatraemia.

Psychiatric disorders: very common – insomnia; common – anxiety, nervousness, anorgasmia, decreased libido, unusual dreams; uncommon – depersonalization, unusual orgasm, withdrawal syndrome; rare – hallucinations, hypomania, mania.

Nervous system disorders: very common – dizziness, headache; common – somnolence, tremor, attention disturbance, paraesthesia, dysgeusia; uncommon – syncope; rare – seizures, dystonia; frequency not known – serotonin syndrome**.

Eye disorders: uncommon – mydriasis, blurred vision.

Ear and labyrinth disorders: common – tinnitus, vertigo.

Cardiac disorders: common – tachycardia, palpitations; frequency not known – Takotsubo cardiomyopathy**.

Vascular disorders: common – hot flushes; uncommon – cold extremities, orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: common – yawning; uncommon – epistaxis.

Gastrointestinal disorders: very common – nausea, dry mouth, constipation; common – vomiting, diarrhoea; frequency not known – acute pancreatitis**.

Skin and subcutaneous tissue disorders: very common – hyperhidrosis; common – rash; uncommon – alopecia; rare – angioneurotic oedema**, photosensitivity reaction; frequency not known – Stevens-Johnson syndrome**.

Musculoskeletal and connective tissue disorders: uncommon – musculoskeletal rigidity.

Renal and urinary disorders: uncommon – proteinuria, urinary retention, difficulty in micturition.

Reproductive system and breast disorders: common – erectile dysfunction*, delayed ejaculation*, absence of ejaculation*; uncommon – sexual dysfunction, ejaculation disorder*; frequency not known – postpartum haemorrhage***.

General disorders: common – fatigue, asthenia, chills, feeling of anxiety, irritability.

Investigations: common – increased blood pressure, weight increase, weight decrease; uncommon – liver function test abnormal, increased blood triglycerides, increased blood prolactin levels, increased blood cholesterol levels.

* Frequency calculated only from data obtained in males.

** Adverse reactions identified during post-marketing use of the medicinal product.

*** This phenomenon has been reported for the therapeutic class of SSRIs/SNRIs (see "Special precautions for use" and "Use during pregnancy or breastfeeding").

Cardiac ischaemic adverse reactions

In clinical studies, ischaemic cardiac adverse reactions including myocardial ischaemia, myocardial infarction, and coronary vessel occlusion requiring revascularization were occasionally reported in patients with multiple concomitant risk factors for cardiac disease. These events were observed in a greater number of patients during treatment with desvenlafaxine compared to placebo.

Reactions upon discontinuation of the drug

Discontinuation (especially abrupt) of SSRIs/SNRIs, including desvenlafaxine, usually leads to a discontinuation syndrome. Adverse reactions reported in association with abrupt discontinuation, dose reduction, or gradual tapering of the drug in MDD clinical trials with a frequency ≥ 2% included: dizziness, discontinuation syndrome, nausea, and headache. Overall, withdrawal symptoms occurred more frequently with higher doses and longer duration of treatment. These reactions were generally mild or moderate in severity and resolved spontaneously; however, in some patients, they could be severe and/or prolonged. Therefore, desvenlafaxine treatment is recommended to be discontinued gradually by dose tapering.

Adverse reactions leading to discontinuation of the drug

In combined 8- to 12-week placebo-controlled MDD studies, 8% of 3335 patients receiving desvenlafaxine (10 to 400 mg) and 4% of 1873 patients receiving placebo discontinued treatment due to adverse reactions.

The most common adverse reaction leading to discontinuation in at least 2% of patients treated with desvenlafaxine in short-term studies (up to 12 weeks) was nausea (2%). In a long-term study (up to 11 months) during the double-blind phase, adverse reactions occurred more frequently in patients treated with desvenlafaxine than in those receiving placebo, but no single event led to discontinuation in at least 2% of patients.

With a 50 mg dose of desvenlafaxine, the frequency of discontinuation due to an adverse reaction (4%) was similar to that with placebo (4%). At doses of 100 mg and 200 mg of desvenlafaxine, the frequency of discontinuation due to an adverse reaction was 8% and 15%, respectively.

Use in elderly patients

In clinical studies of MDD, of the 7785 patients treated with desvenlafaxine, 5% were aged 65 years or older. Overall, there were no differences in safety and efficacy between these patients and younger patients. However, in short-term placebo-controlled studies, more cases of systolic orthostatic hypotension were observed, and in both short-term and long-term placebo-controlled studies, an increase in systolic blood pressure was noted in patients aged > 65 years compared to adults aged ≤ 65 years treated with desvenlafaxine.

Adverse reactions reported with use of other SNRIs

Although gastrointestinal bleeding is not considered an adverse reaction to desvenlafaxine, it is an adverse reaction associated with other SNRIs and may also occur with desvenlafaxine use.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions in accordance with applicable requirements of the reporting system.

Shelf life.

3 years.

Storage conditions. Store at temperatures not exceeding 25°C.

Keep out of reach and sight of children.

Packaging.

Extended-release tablets 50 mg No. 28: cardboard box containing 2 blisters; 14 tablets per blister;

extended-release tablets 100 mg No. 28: cardboard box containing 2 blisters; 14 tablets per blister.

Prescription status. Prescription only.

Manufacturer.

Pfizer Manufacturing Deutschland GmbH

Manufacturer's location and address of place of business.

Mooswaldallee 1, 79108 Freiburg im Breisgau, Germany