When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Section 2 – Update to qualitative and quantitative description
Section 6.4 – Update to storage conditions
Section 6.5 – Inclusion of additional pack sizes
Section 10 – Date of revision
Section 1: Update to pharmaceutical form
Section 2: Update to pharmaceutical form
Section 3: Update to pharmaceutical form
Section 4: Addition of Treatment of social anxiety disorder and other indications reworded.
Section 4.2: New information and other information reworded.
Section 4.3: Information reworded
Section 4.4: New information and other information reworded.
Section 4.5: New information and other information reworded.
Section 4.6: New information and other information reworded.
Section 4.7: Information reworded
Section 4.8: Additional adverse events added, adverse events deleted, adverse events reformatted to MEDRA.
Section 4.9: New information
Section 5.1: New information and other information reworded.
Section 5.2: New information and other information reworded.
Section 4.8
Reinsertion of a paragraph deleted in error:
Particularly, the following adverse reactions were observed in pediatric patients: abdominal pain, agitation, dyspepsia, ecchymosis, epistaxis and myalgia.
Section 4.9
General supportive and symptomatic measures are recommended; cardiac rhythm and vital signs must be monitored.
When there is a risk of aspiration, induction of emesis is not recommended.
Gastric Lavage may be indicated if performed soon after ingestion or in symptomatic patients.
Administration of activated charcoal may also limit drug absorption.
Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
Section 4.4 Special warnings and precautions for use - additional information on Suicide/suicidal thoughts or clinical worsening
Section 1 – inclusion of additional strength information
Section 2 - inclusion of additional strength information
Section 3 - inclusion of additional strength information
Section 4.1 – addition of indication for the treatment of panic disorder, with or without agoraphobia
Section 4.2 – addition of dosage and Maintenance/Continuation/Extended Treatment instructions for panic disorder, with or without agoraphobia
Section 4.3 – reworded
Section 4.4 – addition of precaution for concomitant use of (serotonin re-uptake inhibitors/ nefazodone /trazodone/ triptans) and herbal preparations containing St John’s Wort (Hypericum perforatum)
Section 4.5 – rewording of MAOI, Imipramine/desipramine, Metoprolol, Cimetidine and Warfarin interaction paragraphs
Section 4.6 – rewording of section
Section 4.7 - rewording of section
Section 4.8 – rewording of adverse events from paediatric clinical trials section
Section 4.9 – rewording of section
Section 6.5 – addition of 7-day pack for Efexor 37.5mg
Section 6.6 - inclusion of additional strength information
Section 8 - inclusion of additional strength information
Section 4.2
Elderly Patients – dosage adjustment statement reworded
Section 4.3
Maintenance/Continuation, extended treatment – New information added for General Anxiety Disorder
Section 4.4
Precaution added regarding concomitant use of SSRIs and St Johns Wort
Section 4.5
MAOI – paragraph reworded
Imipramine/desipramine – paragraph reworded
Metoprolol – paragraph reworded and new information added
Cimetidine – paragraph reworded
Warfarin – paragraph reworded
Section 4.6
Section reworded
Section 4.7
Adverse events from paediatric clinical trials – paragraph reworded and new information added
Present
Proposed
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.
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.
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.
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…
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…
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.
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.
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.
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.
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.
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:…
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 Cmax increased by 26% in EM subjects and 48% in PM subjects. Cmax 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.
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.
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).
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.
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.
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.
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.
Special senses - Common: abnormal vision/ accommodation, mydriasis, tinnitus; Uncommon: altered taste sensation.
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.
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…
A clinical study demonstrated that in hepatically impaired patients the mean plasma half-life of venlafaxine is approximately doubled (see Section 4.2)
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.
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.
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The following highlighted sections have been changed
4.3 Contra-indications
1. Known hypersensitivity to venlafaxine or any other component of the product.
2. Concomitant use of venlafaxine with monoamine oxidase inhibitors (See Interactions with other Medicaments and Other Forms of Interactions).
3. Efexor should not be used in children and adolescents under the age of 18 years with Major Depressive Disorder. (see section 4.8, Undesirable Effects)
4.4 Special Warnings and Special Precautions for Use
17. Use in children and adolescents under 18 years of age: Efexor 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.
Adverse events from paediatric clinical trials:
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 MDD clinical trials the following adverse events were reported at a frequency of at least 2% of patients and occurred at a rate of at least twice that of placebo: abdominal pain, chest pain, tachycardia, anorexia, weight loss, constipation, dyspepsia, nausea, ecchymosis, epistaxis, mydriasis, myalgia, dizziness, emotional lability, tremor, hostility and suicidal ideation.