The SPC: Updated as follows,

Section 4.8 has been updated with the addition of adverse drug reaction (ADR) ‘takotsubo cardiomyopathy’ to Section 4.8 “Undesirable effects” of the venlafaxine hydrochloride Summary of Product Characteristics (SmPC) in line with the company Core Data Sheet (CDS) for the above products. PIL has been updated accrodingly.

4.2    Posology and Method of Administration

…

Patients with Renal or Hepatic Impairment:

For patients with mild renal impairment (GFR > 30ml/minute) or mild hepatic impairment, no change in dosage is necessary.

For patients with moderate renal impairment (GFR 10-30ml/minute) or moderate hepatic impairment, the dose should be reduced by 50%.  For patients requiring a lower daily dose than 75mg, treatment may be provided with Efexor Tablets.

Insufficient data are available to support the use of Efexor XL in patients with severe renal impairment (GFR < 10ml/minute) or severe hepatic impairment.

…

4.2     Posology and Method of Administration

…

Patients with Renal or Hepatic Impairment:

For patients with mild renal impairment (GFR > 30ml/minute), no change in dosage is necessary.  For patients with moderate renal impairment (GFR 10-30ml/minute) the dose should be reduced by 50%.

For patients with mild to moderate hepatic impairment (PT < 18 seconds), the dose should be reduced by 50%.  Reductions of more than 50% may be appropriate for some patients. For patients requiring a lower daily dose than 75mg, treatment may be provided with Efexor Tablets.

Insufficient data are available to support the use of Efexor XL in patients with severe renal impairment (GFR < 10ml/minute) or severe hepatic impairment.

…

4.4    Special Warnings and Special Precautions For Use

…

2.      Activation of mania or hypomania has been reported rarely in patients who have received antidepressants, including venlafaxine.  As with all antidepressants, Efexor should be used with caution in patients with a history of mania.

…

4.4     Special Warnings and Precautions For Use

…

2.        Activation of mania or hypomania has been reported rarely in patients who have received antidepressants, including venlafaxine.  As with all antidepressants, Efexor should be used with caution in patients with a history or family history of bipolar disorder.

…

4.4    Special Warnings and Special Precautions For Use

…

2.      Activation of mania…

3.      Venlafaxine has not been evaluated…

4.      Efexor XL should be introduced…

5.      Dose-related increases in blood…

6.      Due to the possibility of…

7.      When considering the…

8.      Increases in heart rate…

9.      Dosage should be reduced…

10.     Postural hypotension has…

11.     Hyponatraemia (usually in…

12.     Mydriasis has been…

13.     There have been reports…

14.     Clinically relevant increases…

15.     The safety and efficacy…

16.     As with SSRIs…

17.     Discontinuation effects…

18.     Use in children…

4.4     Special Warnings and Precautions For Use

…

2.        Activation of mania…

3.       Aggression may occur in a small proportion of patients who have received antidepressants including venlafaxine treatment, dose reduction or discontinuation.  As with other antidepressants, venlafaxine should be used cautiously in patients with a history of depression

4.       Venlafaxine has not been evaluated…

5.       Efexor XL should be introduced…

6.       Dose-related increases in blood…

7.       Due to the possibility of…

8.       When considering the…

9.       Increases in heart rate…

10.     Dosage should be reduced…

11.     Postural hypotension has…

12.     Hyponatraemia (usually in…

13.     Mydriasis has been…

14.     There have been reports…

15.     Clinically relevant increases…

16.     The safety and efficacy…

17.     As with SSRIs…

18.     Discontinuation effects…

19.     Use in children…

4.4    Special Warnings and Special Precautions For Use

…

5.      Dose-related increases in blood pressure have been reported particularly in patients receiving daily doses greater than 200mg.  Measurement of blood pressure is therefore recommended for patients receiving venlafaxine.  The presence of treated hypertension or elevated blood pressure at baseline did not seem to predispose patients to further increases during venlafaxine therapy.

…

4.4     Special Warnings and Precautions For Use

…

6.       Dose-related increases in blood pressure have been reported particularly in patients receiving daily doses greater than 200mg.  Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience.  Measurement of blood pressure is therefore recommended for patients receiving venlafaxine.  Pre­‑existing hypertension should be controlled before treatment with venlafaxine.  The presence of treated hypertension or elevated blood pressure at baseline did not seem to predispose patients to further increases during venlafaxine therapy.

…

4.4    Special Warnings and Special Precautions For Use

…

12.     Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at a risk of narrow angle glaucoma should be monitored closely.

…

4.4     Special Warnings and Precautions For Use

…

13.     Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at a risk of narrow angle glaucoma (angle closure glaucoma) should be monitored closely.

…

4.4    Special Warnings and Special Precautions For Use

…

13.     There have been reports of cutaneous bleeding abnormalities, such as ecchymosis and purpura, with serotonin-reuptake inhibitors (SSRIs).  Other bleeding manifestations (e.g. gastrointestinal bleeding and mucous membrane bleeding) have been reported.  Caution is advised in patients predisposed to bleeding due to factors such as age, underlying medical conditions or concomitant medications.

…

4.4     Special Warnings and Precautions For Use

…

14.     Drugs that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. The risk of cutaneous and mucous membrane bleeding may be increased in patients taking venlafaxine. Bleeding abnormalities, such as ecchymosis and purpura have been reported, as have other bleeding manifestations (e.g. gastrointestinal bleeding and mucous membrane bleeding).  Caution is advised in patients predisposed to bleeding.

…

4.5    Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Haloperidol:…

4.5     Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Ketoconazole: A pharmacokinetic study with ketoconazole in extensive (EM) and poor metabolizers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in most subjects following administration of ketoconazole.  Venlafaxine C_max increased by 26% in EM subjects and 48% in PM subjects.  C_max values for ODV increased by 14% and 29% in EM and PM subjects respectively.  Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects.  AUC values of ODV increased by 23% and 141% in EM and PM subjects, respectively.

Haloperidol:…

4.5    Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Haloperidol:…

4.5     Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Ketoconazole: …

Metoprolol: In a pharmacokinetic interaction study for both venlafaxine and metoprolol, the plasma concentration of metoprolol increased by approximately 30 ‑ 40% without altering the plasma concentrations of its active metabolite, a‑hydroxymetoprolol.  Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O‑desmethylvenlafaxine.

Haloperidol:…

4.5    Interactions with Other Medicinal Products and Other Forms of Interaction

…

Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9 or CYP3A4.  This was confirmed by in vivo studies with the following drugs: alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine, diazepam (CYP3A4 and CYP2C19).

…

4.5     Interactions with Other Medicinal Products and Other Forms of Interaction

…

Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9 or CYP3A4.  This was confirmed by in vivo studies with the following drugs: alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine (CYP3A4), diazepam (CYP3A4 and CYP2C19) and tolbutamide (CYP2C9).

…

4.8              Undesirable Effects

…

Neurological disorders  - Very common: dizziness, dry mouth, insomnia, nervousness, somnolence; Common: abnormal dreams, agitation, anxiety, confusion, hypertonia, paraesthesia, tremor; Uncommon: apathy, hallucinations, myoclonus; Rare:  ataxia and disorders of balance and coordination, speech disorders including dysarthria, mania or hypomania (see section 4.4), neuroleptic malignant syndrome-like effects, seizures (see section 4.4), serotonergic syndrome; Very rare: delirium, extrapyramidal disorders including dyskinesia and dystonia, tardive dyskinesia.

…

4.8              Undesirable Effects

…

Neurological disorders  - Very common: dizziness, dry mouth, insomnia, nervousness, somnolence; Common: abnormal dreams, agitation, anxiety, confusion, hypertonia, paraesthesia, tremor; Uncommon: apathy, hallucinations, myoclonus; Rare:  akathisia, ataxia and disorders of balance and coordination, speech disorders including dysarthria, mania or hypomania (see section 4.4), neuroleptic malignant syndrome-like effects, seizures (see section 4.4), serotonergic syndrome; Very rare: delirium, extrapyramidal disorders including dyskinesia and dystonia, tardive dyskinesia.

…

4.8        Undesirable Effects

…

Skin and subcutaneous tissue disorders -Very common: sweating (including night sweats); Common: pruritus, rash; Uncommon: angioedema, maculopapular eruptions, urticaria, photosensitivity reactions, alopecia; Rare: erythema multiforme, Stevens Johnson syndrome.

…

4.8           Undesirable Effects

…

Skin and subcutaneous tissue disorders -Very common: sweating (including night sweats); Uncommon: rash, angioedema, maculopapular eruptions, photosensitivity reactions, alopecia; Rare: erythema multiforme, Stevens Johnson syndrome, pruritus, urticaria.

…

4.8        Undesirable Effects

…

Special senses - Common:  abnormal vision/ accommodation, mydriasis, tinnitus; Uncommon:  altered taste sensation.

…

4.8           Undesirable Effects

…

Special senses - Common:  abnormal vision/ accommodation, mydriasis; Uncommon:  altered taste sensation, tinnitus; Very rare: Narrow Angle glaucoma.

…

4.9    Overdose

Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia and seizures, hypotension and changes in level of consciousness have been reported in association with overdosage of venlafaxine usually when in combination with alcohol and/or other CNS drugs.

…

4.9    Overdose

Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia and seizures, hypotension and changes in level of consciousness (ranging from somnolence to coma) have been reported in association with overdosage of venlafaxine usually when in combination with alcohol and/or other CNS drugs.

…

5.2    Pharmacokinetic Properties

…

The half lives of venlafaxine…

Administration of Efexor XL…

5.2    Pharmacokinetic Properties

…

The half lives of venlafaxine…

A clinical study demonstrated that in hepatically impaired patients the mean plasma half-life of venlafaxine is approximately doubled (see Section 4.2)

Administration of Efexor XL…

5.3    Preclinical Safety Data

…

Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV).  This exposure was approximately 2 to 3 times that of a human dose of 225mg/day.

…

5.3    Preclinical Safety Data

…

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m² basis.  Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV).  This ODV exposure was approximately 2 to 3 times that of a human dose of 225mg/day.

…

4.2    Posology and Method of Administration

…

Patients with Renal or Hepatic Impairment:

For patients with mild renal impairment (GFR > 30ml/minute) or mild hepatic impairment, no change in dosage is necessary.

For patients with moderate renal impairment (GFR 10-30ml/minute) or moderate hepatic impairment, the dose should be reduced by 50%.  For patients requiring a lower daily dose than 75mg, treatment may be provided with Efexor Tablets.

Insufficient data are available to support the use of Efexor XL in patients with severe renal impairment (GFR < 10ml/minute) or severe hepatic impairment.

…

4.2     Posology and Method of Administration

…

Patients with Renal or Hepatic Impairment:

For patients with mild renal impairment (GFR > 30ml/minute), no change in dosage is necessary.  For patients with moderate renal impairment (GFR 10-30ml/minute) the dose should be reduced by 50%.

For patients with mild to moderate hepatic impairment (PT < 18 seconds), the dose should be reduced by 50%.  Reductions of more than 50% may be appropriate for some patients. For patients requiring a lower daily dose than 75mg, treatment may be provided with Efexor Tablets.

Insufficient data are available to support the use of Efexor XL in patients with severe renal impairment (GFR < 10ml/minute) or severe hepatic impairment.

…

4.4    Special Warnings and Special Precautions For Use

…

2.      Activation of mania or hypomania has been reported rarely in patients who have received antidepressants, including venlafaxine.  As with all antidepressants, Efexor should be used with caution in patients with a history of mania.

…

4.4     Special Warnings and Precautions For Use

…

2.        Activation of mania or hypomania has been reported rarely in patients who have received antidepressants, including venlafaxine.  As with all antidepressants, Efexor should be used with caution in patients with a history or family history of bipolar disorder.

…

4.4    Special Warnings and Special Precautions For Use

…

2.      Activation of mania…

3.      Venlafaxine has not been evaluated…

4.      Efexor XL should be introduced…

5.      Dose-related increases in blood…

6.      Due to the possibility of…

7.      When considering the…

8.      Increases in heart rate…

9.      Dosage should be reduced…

10.     Postural hypotension has…

11.     Hyponatraemia (usually in…

12.     Mydriasis has been…

13.     There have been reports…

14.     Clinically relevant increases…

15.     The safety and efficacy…

16.     As with SSRIs…

17.     Discontinuation effects…

18.     Use in children…

4.4     Special Warnings and Precautions For Use

…

2.        Activation of mania…

3.       Aggression may occur in a small proportion of patients who have received antidepressants including venlafaxine treatment, dose reduction or discontinuation.  As with other antidepressants, venlafaxine should be used cautiously in patients with a history of depression

4.       Venlafaxine has not been evaluated…

5.       Efexor XL should be introduced…

6.       Dose-related increases in blood…

7.       Due to the possibility of…

8.       When considering the…

9.       Increases in heart rate…

10.     Dosage should be reduced…

11.     Postural hypotension has…

12.     Hyponatraemia (usually in…

13.     Mydriasis has been…

14.     There have been reports…

15.     Clinically relevant increases…

16.     The safety and efficacy…

17.     As with SSRIs…

18.     Discontinuation effects…

19.     Use in children…

4.4    Special Warnings and Special Precautions For Use

…

5.      Dose-related increases in blood pressure have been reported particularly in patients receiving daily doses greater than 200mg.  Measurement of blood pressure is therefore recommended for patients receiving venlafaxine.  The presence of treated hypertension or elevated blood pressure at baseline did not seem to predispose patients to further increases during venlafaxine therapy.

…

4.4     Special Warnings and Precautions For Use

…

6.       Dose-related increases in blood pressure have been reported particularly in patients receiving daily doses greater than 200mg.  Cases of elevated blood pressure requiring immediate treatment have been reported in post marketing experience.  Measurement of blood pressure is therefore recommended for patients receiving venlafaxine.  Pre­‑existing hypertension should be controlled before treatment with venlafaxine.  The presence of treated hypertension or elevated blood pressure at baseline did not seem to predispose patients to further increases during venlafaxine therapy.

…

4.4    Special Warnings and Special Precautions For Use

…

12.     Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at a risk of narrow angle glaucoma should be monitored closely.

…

4.4     Special Warnings and Precautions For Use

…

13.     Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular pressure or at a risk of narrow angle glaucoma (angle closure glaucoma) should be monitored closely.

…

4.4    Special Warnings and Special Precautions For Use

…

13.     There have been reports of cutaneous bleeding abnormalities, such as ecchymosis and purpura, with serotonin-reuptake inhibitors (SSRIs).  Other bleeding manifestations (e.g. gastrointestinal bleeding and mucous membrane bleeding) have been reported.  Caution is advised in patients predisposed to bleeding due to factors such as age, underlying medical conditions or concomitant medications.

…

4.4     Special Warnings and Precautions For Use

…

14.     Drugs that inhibit serotonin uptake may lead to abnormalities of platelet aggregation. The risk of cutaneous and mucous membrane bleeding may be increased in patients taking venlafaxine. Bleeding abnormalities, such as ecchymosis and purpura have been reported, as have other bleeding manifestations (e.g. gastrointestinal bleeding and mucous membrane bleeding).  Caution is advised in patients predisposed to bleeding.

…

4.5    Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Haloperidol:…

4.5     Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Ketoconazole: A pharmacokinetic study with ketoconazole in extensive (EM) and poor metabolizers (PM) of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and ODV in most subjects following administration of ketoconazole.  Venlafaxine C_max increased by 26% in EM subjects and 48% in PM subjects.  C_max values for ODV increased by 14% and 29% in EM and PM subjects respectively.  Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects.  AUC values of ODV increased by 23% and 141% in EM and PM subjects, respectively.

Haloperidol:…

4.5    Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Haloperidol:…

4.5     Interactions with Other Medicinal Products and Other Forms of Interaction

…

Imipramine/desipramine:…

Ketoconazole: …

Metoprolol: In a pharmacokinetic interaction study for both venlafaxine and metoprolol, the plasma concentration of metoprolol increased by approximately 30 ‑ 40% without altering the plasma concentrations of its active metabolite, a‑hydroxymetoprolol.  Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active metabolite, O‑desmethylvenlafaxine.

Haloperidol:…

4.5    Interactions with Other Medicinal Products and Other Forms of Interaction

…

Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9 or CYP3A4.  This was confirmed by in vivo studies with the following drugs: alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine, diazepam (CYP3A4 and CYP2C19).

…

4.5     Interactions with Other Medicinal Products and Other Forms of Interaction

…

Studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9 or CYP3A4.  This was confirmed by in vivo studies with the following drugs: alprazolam (CYP3A4), caffeine (CYP1A2), carbamazepine (CYP3A4), diazepam (CYP3A4 and CYP2C19) and tolbutamide (CYP2C9).

…

4.8              Undesirable Effects

…

Neurological disorders  - Very common: dizziness, dry mouth, insomnia, nervousness, somnolence; Common: abnormal dreams, agitation, anxiety, confusion, hypertonia, paraesthesia, tremor; Uncommon: apathy, hallucinations, myoclonus; Rare:  ataxia and disorders of balance and coordination, speech disorders including dysarthria, mania or hypomania (see section 4.4), neuroleptic malignant syndrome-like effects, seizures (see section 4.4), serotonergic syndrome; Very rare: delirium, extrapyramidal disorders including dyskinesia and dystonia, tardive dyskinesia.

…

4.8              Undesirable Effects

…

Neurological disorders  - Very common: dizziness, dry mouth, insomnia, nervousness, somnolence; Common: abnormal dreams, agitation, anxiety, confusion, hypertonia, paraesthesia, tremor; Uncommon: apathy, hallucinations, myoclonus; Rare:  akathisia, ataxia and disorders of balance and coordination, speech disorders including dysarthria, mania or hypomania (see section 4.4), neuroleptic malignant syndrome-like effects, seizures (see section 4.4), serotonergic syndrome; Very rare: delirium, extrapyramidal disorders including dyskinesia and dystonia, tardive dyskinesia.

…

4.8        Undesirable Effects

…

Skin and subcutaneous tissue disorders -Very common: sweating (including night sweats); Common: pruritus, rash; Uncommon: angioedema, maculopapular eruptions, urticaria, photosensitivity reactions, alopecia; Rare: erythema multiforme, Stevens Johnson syndrome.

…

4.8           Undesirable Effects

…

Skin and subcutaneous tissue disorders -Very common: sweating (including night sweats); Uncommon: rash, angioedema, maculopapular eruptions, photosensitivity reactions, alopecia; Rare: erythema multiforme, Stevens Johnson syndrome, pruritus, urticaria.

…

4.8        Undesirable Effects

…

Special senses - Common:  abnormal vision/ accommodation, mydriasis, tinnitus; Uncommon:  altered taste sensation.

…

4.8           Undesirable Effects

…

Special senses - Common:  abnormal vision/ accommodation, mydriasis; Uncommon:  altered taste sensation, tinnitus; Very rare: Narrow Angle glaucoma.

…

4.9    Overdose

Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia and seizures, hypotension and changes in level of consciousness have been reported in association with overdosage of venlafaxine usually when in combination with alcohol and/or other CNS drugs.

…

4.9    Overdose

Electrocardiogram changes (e.g. prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia and seizures, hypotension and changes in level of consciousness (ranging from somnolence to coma) have been reported in association with overdosage of venlafaxine usually when in combination with alcohol and/or other CNS drugs.

…

5.2    Pharmacokinetic Properties

…

The half lives of venlafaxine…

Administration of Efexor XL…

5.2    Pharmacokinetic Properties

…

The half lives of venlafaxine…

A clinical study demonstrated that in hepatically impaired patients the mean plasma half-life of venlafaxine is approximately doubled (see Section 4.2)

Administration of Efexor XL…

5.3    Preclinical Safety Data

…

Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV).  This exposure was approximately 2 to 3 times that of a human dose of 225mg/day.

…

5.3    Preclinical Safety Data

…

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to 2 times on a mg/m² basis.  Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV).  This ODV exposure was approximately 2 to 3 times that of a human dose of 225mg/day.

…