Venlafaxine Other names: Venlafaxine hydrochloride Βενλαξαφίνη

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.

Relevant classes include:

• Class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide).
• Some antipsychotics (e.g. thioridazine).
• Some macrolides (e.g. erythromycin).
• Some antihistamines.
• Some quinolone antibiotics (e.g. moxifloxacin).

The above list is not exhaustive and other individual medicinal products known to significantly increase QT interval should be avoided.

Reversible, selective MAO-A inhibitor (moclobemide): 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.

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.

In patients with mild and moderate hepatic impairment, in general a 50% dose reduction should be considered. However, due to inter-individual variability in clearance, individualisation of dosage may be desirable.

There are limited data in patients with severe hepatic impairment. Caution is advised, and a dose reduction by more than 50% should be considered. The potential benefit should be weighed against the risk in the treatment of patients with severe hepatic impairment.

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.

If concomitant treatment of venlafaxine with a 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.

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.

Although no change in dosage is necessary for patients with glomerular filtration rate (GFR) between 30-70ml/minute, caution is advised.

For patients that require haemodialysis and in patients with severe renal impairment (GFR <30ml/min), the dose should be reduced by 50%. Because of inter-individual variability in clearance in these patients, individualisation of dosage may be desirable.

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.

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.

A pharmacokinetic study with haloperidol has shown a 42% decrease in total oral clearance, a 70% increase in AUC, an 88% increase in C_max, 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 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 indinavir has shown a 28% decrease in AUC and a 36% decrease in C_max for indinavir. Indinavir did not affect the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine. 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.

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.

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.

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.

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 preexisting hypertension should be controlled before initation 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.

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.

As with other antidepressants, venlafaxine should be used cautiously in patients with a history or family history of bipolar disorder.

In patients with diabetes, treatment with a SSRI or venlafaxine may alter glycaemic control. Insulin and/or oral antidiabetic dosage may need to be adjusted.

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.

There are no adequate data from the use of venlafaxine in pregnant women. Studies in animals have shown reproductive toxicity. Venlafaxine must only be administered to pregnant women if the expected benefits outweigh any possible risk.

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).

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.

The following symptoms may be observed in neonates if the mother has used a 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.

Venlafaxine and its active metabolite, O-desmethylvenlafaxine, are excreted in breast milk. There have been post-marketing 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 to the child and the benefit of venlafaxine therapy to the woman.

Fertility

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.

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,frequency category and decreasing order of medical seriousness within each frequency category.

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).

Blood and lymphatic system disorders

Rare: Agranulocytosis*, Aplastic anaemia*, Pancytopaenia*, Neutropaenia*

Very Rare: Thrombocytopaenia*

Immune system disorders

Rare: Anaphylactic reaction*

Endocrine disorders

Rare: Inappropriate antidiuretic hormone secretion*

Very Rare: Blood prolactin increased*

Metabolism and nutrition disorders

Common: Decreased appetite

Rare: Hyponatraemia*

Psychiatric disorders

Very Common: Insomnia

Common: Confusional state*, Depersonalization*, Abnormal dreams, Nervousness, Libido decreased, Agitation*, Anorgasmia,

Uncommon: Mania, Hypomania, Hallucination, Derealization, Abnormal orgasm, Bruxism*, Apathy

Rare: Delirium*

Not Known: Suicidal ideation and suicidal behaviours^a, Aggression

Nervous system disorders

Very Common: Headache^*c, Dizziness, Sedation

Common: Akathisia*, Tremor, Paraesthesia, Dysgeusia

Uncommon: Syncope, Myoclonus, Balance disorder*, Coordination abnormal*, Dyskinaesia*

Rare: Neuroleptic Malignant Syndrome (NMS), Serotonin syndrome, Convulsion, Dystonia*

Very Rare: Tardive dyskinaesia*

Eye disorders

Common: Visual impairment, Accommodation disorder, including vision blurred, Mydriasis

Rare: Angle-closure glaucoma*

Ear and labyrinth disorders

Common: Tinnitus*

Not Known: Vertigo

Cardiac disorders

Common: Tachycardia, Palpitations*

Rare: Torsade de pointes*, Ventricular tachycardia*, Ventricular fibrillation, Electrocardiogram QT prolonged*

Vascular disorders

Common: Hypertension, Hot flush

Uncommon: Orthostatic hypotension, Hypotension*

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea*, Yawning

Rare: Interstitial lung disease*, Pulmonary eosinophilia*

Gastrointestinal disorders

Very Common: Nausea, Dry mouth, Constipation

Common: Diarrhoea*, Vomiting

Uncommon: Gastrointestinal haemorrhage

Rare: Pancreatitis*

Hepatobiliary disorders

Uncommon: Liver function test abnormal*

Rare: Hepatitis*

Skin and subcutaneous tissue disorders

Very Common: Hyperhidrosis* (including night sweats)*

Common: Rash, Pruritus*

Uncommon: Urticaria*, Alopecia*, Ecchymosis, Angioedema*, Photosensitivity reaction,

Rare: Stevens-Johnson syndrome*, Toxic epidermal necrolysis*, Erythema multiforme*

Musculoskeletal and connective tissue disorders

Common: Hypertonia

Rare: Rhabdomyolysis*

Renal and urinary disorders

Common: Urinary hesitation, Urinary retention, Pollakiuria*

Uncommon: Urinary incontinence*

Reproductive system and breast disorders

Common: Menorrhagia*, Metrorrhagia*, Erectile dysfunction, Ejaculation disorder

Not Known: Postpartum haemorrhage**

General disorders and administration site conditions

Common: Fatigue, Asthenia, Chills*

Very Rare: Mucosal haemorrhage*

Investigations

Common: Weight decreased, Weight increased, Blood cholesterol increased

Very Rare: Bleeding time prolonged*

* ADR identified post-marketing

^a Cases of suicidal ideation and suicidal behaviours have been reported during venlafaxine therapy or early after treatment discontinuation.
^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 and flu syndrome 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.

Paediatric patients

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.

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.