Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Sun Pharmaceutical Industries Europe B.V., Polarisavenue 87, 2132 JH Hoofddorp, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. Sunveniz XL must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI.
Sunveniz XL must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see sections 4.4. and 4.5).
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which venlafaxine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.
Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour, and to seek medical advice immediately if these symptoms present.
Venlafaxine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, amphetamines, lithium, sibutramine, St. John’s Wort [Hypericum perforatum], fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicinal agents that impair metabolism of serotonin (such as MAOIs e.g. methylene blue), with serotonin precursors (such as tryptophan supplements) or with antipsychotics or other dopamine antagonists (see sections 4.3 and 4.5).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea). Serotonin syndrome in its most severe form, can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes.
If concomitant treatment with venlafaxine and other agents that may affect the serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended.
Mydriasis may occur in association with venlafaxine. It is recommended that patients with raised intraocular pressure or patients at risk for acute narrow-angle glaucoma (angle-closure glaucoma) be closely monitored.
Dose-related increases in blood pressure have been commonly reported with venlafaxine. In some cases, severely elevated blood pressure requiring immediate treatment has been reported in postmarketing experience. All patients should be carefully screened for high blood pressure and pre-existing hypertension should be controlled before initiation of treatment. Blood pressure should be reviewed periodically, after initiation of treatment and after dose increases. Caution should be exercised in patients whose underlying conditions might be compromised by increases in blood pressure, e.g., those with impaired cardiac function.
Increases in heart rate can occur, particularly with higher doses. Caution should be exercised in patients whose underlying conditions might be compromised by increases in heart rate.
Venlafaxine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, it should be used with caution in these patients.
In postmarketing experience, cases of QTc prolongation, Torsade de Pointes (TdP), ventricular tachycardia, and fatal cardiac arrhythmias have been reported with the use of venlafaxine, especially in overdose or in patients with other risk factors for QTc prolongation/TdP. The balance of risks and benefits should be considered before prescribing venlafaxine to patients at high risk of serious cardiac arrhythmia or QTc prolongation (see section 5.1).
Convulsions may occur with venlafaxine therapy. As with all antidepressants, venlafaxine should be introduced with caution in patients with a history of convulsions, and concerned patients should be closely monitored. Treatment should be discontinued in any patient who develops seizures.
Cases of hyponatraemia and/or the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion may occur with venlafaxine. This has most frequently been reported in volume-depleted or dehydrated patients. Elderly patients, patients taking diuretics, and patients who are otherwise volume-depleted may be at greater risk for this event.
Medicinal products that inhibit serotonin uptake may lead to reduced platelet function. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to gastrointestinal and life-threatening haemorrhages. The risk of haemorrhage may be increased in patients taking venlafaxine. As with other serotonin-reuptake inhibitors, venlafaxine should be used cautiously in patients predisposed to bleeding, including patients on anticoagulants and platelet inhibitors.
Clinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treated patients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlled clinical trials. Measurement of serum cholesterol levels should be considered during long-term treatment.
The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including phentermine, have not been established. Co-administration of venlafaxine and weight loss agents is not recommended. Venlafaxine is not indicated for weight loss alone or in combination with other products.
Mania/hypomania may occur in a small proportion of patients with mood disorders who have received antidepressants, including venlafaxine. As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.
Aggression may occur in a small number of patients who have received antidepressants, including venlafaxine. This has been reported under initiation, dose changes and discontinuation of treatment.
As with other antidepressants, venlafaxine should be used cautiously in patients with a history of aggression.
Discontinuation effect are well known to occur with antidepressants, and sometimes these effects can be protracted and severe. Suicide/suicidal thoughts and aggression have been observed in patients during changes in venlafaxine dosing regimen, including during discontinuation. Therefore, patients should be closely monitored when the dose is reduces or during discontinuation (see above in section 4.4 – Suicide/suicidal thoughts or clinical worsening, and Aggression). Withdrawal symptoms, when treatment is discontinued, are common, particularly if discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on treatment discontinuation (tapering and post-tapering) occurred in approximately 31% of patients treated with venlafaxine and 17% of patients taking placebo.
The risk of withdrawal symptoms may be dependent on several factors, including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache, visual impairment and hypertension are the most commonly reported reactions. Generally, these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally, these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that venlafaxine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see section 4.2). In some patients, discontinuation could take months or longer.
Serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs.
The use of venlafaxine has been associated with development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move often accompanied by inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Dry mouth is reported in 10% of patients treated with venlafaxine. This may increase the risk of caries, and patients should be advised upon the importance of dental hygiene.
In patients with diabetes, treatment with an SSRI or venlafaxine may alter glycaemic control. Insulin and/or oral antidiabetic dosage may need to be adjusted.
Venlafaxine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medication.
False-positive urine immunoassay screening for phencyclidine (PCP) and amphetamine have been reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of venlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from PCP and amphetamine.
SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6, 4.8).
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
Venlafaxine must not be used in combination with irreversible non-selective MAOIs. Venlafaxine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Venlafaxine must be discontinued for at least 7 days before starting treatment with an irreversible non-selective MAOI (see sections 4.3 and 4.4).
Due to the risk of serotonin syndrome, the combination of venlafaxine with a reversible and selective MAOI, such as moclobemide, is not recommended. Following treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of venlafaxine treatment. It is recommended that venlafaxine should be discontinued for at least 7 days before starting treatment with a reversible MAOI (see section 4.4).
The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with venlafaxine (see section 4.4).
Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI and started on venlafaxine or have recently had venlafaxine therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.
As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition may occur with venlafaxine treatment, particularly with concomitant use of other agents that may affect the serotonergic neurotransmitter system (including triptans, SSRIs, SNRIs, amphetamines, lithium, sibutramine, St. John’s Wort [Hypericum perforatum]), fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, pethidine, methadone and pentazocine), with medicinal products which impair metabolism of serotonin (such as MAOIs e.g. methylene blue), or with serotonin precursors (such as tryptophan supplements) or with antipsychotics or other dopamine antagonists (see sections 4.3 and 4.4).
If concomitant treatment with venlafaxine and an SSRI, an SNRI or a serotonin receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine with serotonin precursors (such as tryptophan supplements) is not recommended (see section 4.4).
The risk of using venlafaxine in combination with other CNS-active substances has not been systematically evaluated. Consequently, caution is advised when venlafaxine is taken in combination with other CNS-active substances.
Venlafaxine has been shown not to increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active substances, patients should be advised to avoid alcohol consumption.
The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased with concomitant use of other medicinal products which prolong the QTc interval. Co-administration of such medicinal products should be avoided (see section 4.4).
Relevant classes include:
The above list is not exhaustive and other individual medicinal products known to significantly increase QT interval should be avoided.
A pharmacokinetic study with ketoconazole in CYP2D6 extensive (EM) and poor metabolisers (PM) resulted in higher AUC of venlafaxine (70% and 21% in CYP2D6 PM and EM subjects, respectively) and O-desmethylvenlafaxine (33% and 23% in CYP2D6 PM and EM subjects, respectively) following administration of ketoconazole. Concomitant use of CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, voriconazole, posaconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, telithromycin) and venlafaxine may increase levels of venlafaxine and O-desmethylvenlafaxine. Therefore, caution is advised if a patient’s therapy includes a CYP3A4 inhibitor and venlafaxine concomitantly.
Serotonin syndrome may occur with the concomitant use of venlafaxine and lithium (see Serotonin syndrome).
Venlafaxine has no effects on the pharmacokinetics and pharmacodynamics of diazepam and its active metabolite, desmethyldiazepam. Diazepam does not appear to affect the pharmacokinetics of either venlafaxine or O-desmethylvenlafaxine. It is unknown whether a pharmacokinetic and/or pharmacodynamic interaction with other benzodiazepines exists.
Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine. There was a dose-dependent increase of 2-OH-desipramine AUC by 2.5 to 4.5-fold when venlafaxine 75 mg to 150 mg daily was administered. Imipramine did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown. Caution should be exercised with co-administration of venlafaxine and imipramine.
A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in Cmax, but no change in half-life for haloperidol. This should be taken into account in patients treated with haloperidol and venlafaxine concomitantly. The clinical significance of this interaction is unknown.
Venlafaxine increased the risperidone AUC by 50%, but did not significantly alter the pharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone). The clinical significance of this interaction is unknown.
Concomitant administration of venlafaxine and metoprolol to healthy volunteers in a pharmacokinetic interaction study for both medicinal products resulted in an increase of plasma concentrations of metoprolol by approximately 30-40% without altering the plasma concentrations of its active metabolite, α-hydroxymetoprolol. The clinical relevance of this finding in hypertensive patients is unknown. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O-desmethylvenlafaxine. Caution should be exercised with co-administration of venlafaxine and metoprolol.
A pharmacokinetic study with indinavir has shown a 28% decrease in AUC and a 36% decrease in Cmax for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. The clinical significance of this interaction is unknown.
In vivo studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP3A4 (alprazolam and carbamazepine), CYP1A2 (caffeine), and CYP2C9 (tolbutamide) or CYP2C19 (diazepam) in vivo.
In post-marketing experience unintended pregnancies have been reported in subjects taking oral contraceptives while on venlafaxine. There is no clear evidence these pregnancies were a result of drug interaction with venlafaxine. No interaction study with hormonal contraceptives has been performed.
There are no adequate data from the use of venlafaxine in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risk.
As with other serotonin reuptake inhibitors (SSRIs/SNRIs), discontinuation symptoms may occur in the newborns if venlafaxine is used until or shortly before birth. Some newborns exposed to venlafaxine late in the third trimester have developed complications requiring tube-feeding, respiratory support or prolonged hospitalisation. Such complications can arise immediately upon delivery.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated an association of PPHN to SNRI treatment, this potential risk cannot be ruled out with venlafaxine taking into account the related mechanism of action (inhibition of the re-uptake of serotonin).
The following symptoms may be observed in neonates if the mother has used an SSRI/SNRI late in pregnancy: irritability, tremor, hypotonia, persistent crying, and difficulty in sucking or in sleeping. These symptoms may be due to either serotonergic effects or exposure symptoms. In the majority of cases, these complications are observed immediately or within 24 hours after partus.
Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see sections 4.4, 4.8).
Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in breast milk. There have been reports of breast-fed infants who experienced crying, irritability, and abnormal sleep patterns. Symptoms consistent with venlafaxine drug discontinuation have also been reported after stopping breast-feeding. A risk to the suckling child cannot be excluded. Therefore, a decision to continue/discontinue breast feeding or to continue/discontinue therapy with venlafaxine should be made, taking into account the benefit of breast feeding for the child and the benefit of venlafaxine therapy to the woman.
Reduced fertility was observed in a study in which both male and female rats were exposed to O-desmethylvenlafaxine. The human relevance of this finding is unknown (see section 5.3).
Any psychoactive medicinal product may impair judgment, thinking and motor skills. Therefore, any patient receiving venlafaxine should be cautioned about their ability to drive or operate hazardous machinery.
The most commonly (>1/10) reported adverse reactions in clinical studies were nausea, dry mouth, headache and sweating (including night sweats).
Adverse reactions are listed below by system organ class and frequency.
Frequencies are defined as: 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), not known (cannot be estimated from the available data).
| Body System | Very common | Common | Uncommon | Rare | Very rare | Not known |
|---|---|---|---|---|---|---|
| Blood and lymphatic system disorders | Agranulocytosis*, aplastic anaemia*, pancytopaenia*, neutropaenia* | Thrombocytopaenia* | ||||
| Immune system disorders | Anaphylactic reaction* | |||||
| Endocrine disorders | Inappropriate antidiuretic hormone secretion* | Blood prolactin increased* | ||||
| Metabolism and nutrition disorders | Decreased appetite | Hyponatraemia* | ||||
| Psychiatric disorders | Insomnia | Confusional state*, depersonalization*, abnormal dreams, nervousness, libido decreased, agitation*, anorgasmia | Mania, hypomania, hallucination, derealisation, abnormal orgasm, bruxism*. apathy | Delirium* | Suicidal ideations and suicidal behavioursa, aggressionb | |
| Nervous system disorders | Headache*c, dizziness, sedation | Akathisia*, tremor, paraesthesia, dysgeusia | Syncope, myoclonus, balance disorder*, coordination abnormal*, dyskinaesia | Neuroleptic malignant syndrome* (NMS), serotonin syndrome*, convulsion, dystonia* | Tardive dyskinaesia* | |
| Eye disorders | Visual impairment, accommodation disorder, including vision blurred, mydriasis | Angle-closure glaucoma* | ||||
| Ear and labyrinth disorders | Tinnitus* | Vertigo | ||||
| Cardiac disorders | Tachycardia, palpitations* | Torsade de pointes*, ventricular tachycardia*, ventricular fibrillation, electrocardiogram QT prolonged* | Stress cardiomyopathy* (takotsubo cardiomyopathy) | |||
| Vascular disorders | Hypertension, hot flush | Orthostatic hypotension, hypotension* | ||||
| Respiratory, thoracic and mediastinal disorders | Dyspnoea*, yawning | Interstitial lung disease*, pulmonary eosinophilia* | ||||
| Gastro-intestinal disorders | Nausea, dry mouth, constipation | Vomiting, diarrhoea* | Gastrointestinal haemorrhage* | Pancreatitis* | ||
| Hepatobiliary disorders | Liver function test abnormal* | Hepatitis* | ||||
| Skin and subcutaneous tissue disorders | Hyperhidrosis* (including night sweats*) | Rash, pruritis* | Urticaria*, alopecia*, ecchymosis, angioedema*, photosensitivity reaction | Stevens-Johnson syndrome*, Toxic epidermal necrolysis*, Erythema multiforme* | ||
| Musculo-skeletal and connective tissue disorders | Hypertonia | Rhabdomyolysis* | ||||
| Renal and urinary disorders | Urinary hesitation, urinary retention, pollakiuria* | Urinary incontinence* | ||||
| Reproductive system and breast disorders | Menorrhagia*, metrorrhagia*, ejaculation disorderb, erectile dysfunctionb | Postpartum haemorrhage** | ||||
| General disorders and administration site conditions | Asthenia, fatigue, chills* | Mucosal haemorrhage* | ||||
| Investigations | Weight decreased, weight increased, blood cholesterol increased | Bleeding time prolonged* |
* ADR identified post marketing
** This event has been reported for the therapeutic class of SSRIs/SNRIs (see sections 4.4, 4.6).
a Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation (see section 4.4).
b See section 4.4.
c In pooled clinical trials, the incidence of headache with venlafaxine and placebo were similar.
Discontinuation of venlafaxine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraethesia), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, vertigo, headache flu syndrome, visual impairment and hypertension are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting; however in some patients, they may be severe and/or prolonged. It is therefore advised that when venlafaxine treatment is no longer required, gradual discontinuation by dose tapering should be carried out. However, in some patients severe aggression, and suicidal ideation occurred when the dose was reduced or during discontinuation (see sections 4.2 and 4.4).
In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical trials) in children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed (see section 4.4).
In paediatric clinical trials the adverse reaction suicidal ideation was observed. There were also increased reports of hostility and, especially in major depressive disorder, self-harm.
Particularly, the following adverse reactions were observed in paediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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