EFEXOR^®- Combining the powerful effects of Serotonin and Noradrenaline Reuptake Inhibition¹

• A potent serotonin and norepinephrine reuptake inhibitor (SNRI)¹
• The mechanism of the antidepressant action of EFEXOR^® in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS¹
• Potent inhibitor of neuronal serotonin and norepinephrine reuptake and weak inhibitor of dopamine reuptake¹

EFEXOR^® Mode of action - Targeting two important neurotransmitters involved in anxiety/depressive disorders^1,2

SNRI mode of actions: In this figure, the dual actions of the serotonin–norepinephrine reuptake inhibitors (SNRIs) are shown. Both the serotonin reuptake inhibitor (SRI) portion of the SNRI molecule (left panel) and the norepinephrine reuptake inhibitor (NRI) portion of the SNRI molecule (right panel) are inserted into their respective reuptake pumps. Consequently, both pumps are blocked, and the drug mediates an antidepressant effect.²

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In 2014, EFEXOR^® XR received the American Chemical Society’s Heroes of Chemistry award for innovation in research & development for first SNRI.¹

EFEXOR^® XR has been shown to be an effective and generally well-tolerated treatment option in MDD patients with depressive symptoms.²

EFEXOR^® XR rapid and powerful improvements of depressive symptoms in patients with MDD.^2*

Significant improvements in mean Clinical Global Impression of Severity (CGI-S) scores vs placebo were observed with EFEXOR^® XR as early as Week 2.^2*

Mean CGI-S Scores Over Time^2*

Adapted from Thase ME, et al. J Clin Psychiatry. 1997 Sep;58(9):393-398.

* A randomized, double-blind, placebo-controlled trial in 197 outpatients with major depression. Patients were randomized 1:1 to receive EFEXOR^® XR 75-225 mg or placebo for up to 8 weeks. Eligible patients had a HAM-D₂₁ score ³20 with no more than a 20% decrease in score between screening and baseline. The primary efficacy variables included HAM-D₂₁ total score and CGI scales. For HAM-D₂₁ response was defined as a decrease in total score of ³50% from baseline. For CGI response was defined as a score of 1 (very much improved) or 2 (much improved) on the CGI-I item.

EFEXOR^® XR achieved significantly higher response rates vs placebo at Week 6 and Week 8, as measured by the 21-item Hamilton Rating Scale for Depression (HAM-D₂₁) and the CGI Improvement (CGI-I) scale.^2*

Response rates at Week 6 and Week 8^2*

Adapted from Thase ME, et al. J Clin Psychiatry. 1997 Sep;58(9):393-398.

* A randomized, double-blind, placebo-controlled trial in 197 outpatients with major depression. Patients were randomized 1:1 to receive EFEXOR^® XR 75-225 mg or placebo for up to 8 weeks. Eligible patients had a HAM-D₂₁ score ³20 with no more than a 20% decrease in score between screening and baseline. The primary efficacy variables included HAM-D₂₁ total score and CGI scales. For HAM-D₂₁, response was defined as a decrease in total score of ³50% from baseline. For CGI, response was defined as a score of 1 (very much improved) or 2 (much improved) on the CGI-I item.

6 to 12 months of maintenance treatment with EFEXOR^® XR demonstrated response vs placebo in preventing recurrence of MDD among patients with recurrent unipolar depression who had achieved a prior medication response.³

EFEXOR^® XR maintenance therapy reduced the risk of recurrence in moderate-to-severe MDD.^4,5*

Among patients who initially responded to treatment with EFEXOR^® XR…The estimated probability of relapse was significantly lower with EFEXOR^® XR vs placebo at 2 years.^4,5*

EFEXOR^® XR reduced the risk of relapse by 82% vs placebo during the second year of maintenance treatment. EFEXOR^® XR (8.0%) vs placebo (44.8%).^4*†

Time to recurrence (second year of maintenance treatment)⁴

Adapted from Keller MB, et al. J Clin Psychiatry.2007;68:1246-1256.

* Patients were initially randomized to double-blind treatment with EFEXOR^® XR or fluoxetine for 10 weeks of acute treatment. Responders then received 6 months of double-blind continuation treatment. Those who remained responders were then enrolled into 2 consecutive 12-month maintenance periods, during which EFEXOR^® XR responders were randomly assigned to receive double-blind treatment with EFEXOR^® XR or placebo. Recurrence was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D₁₇) total score ³12 and ≤50% reduction from baseline (acute phase) at 2 consecutive visits or at the last valid visit prior to discontinuation. Data are for the second year of maintenance treatment and derived from primary definition of the probability of recurrence after 12 months.

EFEXOR^® XR sustained response in moderate-to-severe MDD.^4,5*

Among patients who initially responded to treatment with EFEXOR^® XR, the rate of response or remission was significantly higher with EFEXOR^® XR vs placebo at 2 years.^4,5*

Rate of HAM-D₂₁ response or remission at 2 years

(Second year of maintenance treatment)^4†

Adapted from Keller MB, et al. J Clin Psychiatry.2007;68:1246-1256.

*Patients were initially randomized to double-blind treatment with EFEXOR^® XR or fluoxetine for 10 weeks of acute treatment. Responders then received 6 months of double-blind continuation treatment. Those who remained responders were then enrolled into 2 consecutive 12-month maintenance periods, during which EFEXOR^® XR responders were randomly assigned to receive double-blind treatment with EFEXOR^® XR or placebo. Response was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D17) total score ≤12 and ≥50% reduction from baseline (acute phase) at 2 consecutive visits or at the last valid visit prior to discontinuation. Remission was defined as HAM-D17 total score ≤7.Data are for the second year of maintenance treatment and derived from primary definition of the probability of recurrence after 12 months.

EFEXOR^® improvements in depressive symptoms in MDD with comorbid anxiety vs a standard SSRI.^6*

EFEXOR^® provided significant improvements in depressive symptoms vs fluoxetine at Week 12, as measured by the 21-item Hamilton Rating Scale for Depression (HAM-D₂₁).^6*

Change from baseline in HAM-D₂₁ total score at Week 12⁶

Adapted from De Nayer A, et al. Int J Neuropsychopharmacol. 2002;5:115-120.

* A randomized, double-blind, active-controlled phase 4 study in 146 patients with MDD, a HAM-D₂₁ score of 18-25 inclusive, and a Covi Anxiety Scale score ³8. Patients were randomized to receive treatment with EFEXOR^® 75-150 mg/day or fluoxetine 20-40 mg/day for 12 weeks. The primary efficacy variables were the final on-therapy and HAM-D₂₁ and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores, and the final on-therapy Clinical Global Impression (CGI) severity score.

EFEXOR^® XR powerful and sustained relief of anxiety symptoms in patients with GAD.^7*

EFEXOR^® XR demonstrated significantly higher Hamilton Rating Scale for Anxiety (HAM-A) remission rates vs placebo at 6 months.^7*

HAM-A remission at 6 months by baseline social impairment⁷

Adapted from Boyer P, et al. Eur Psychiatry. 2004;19(5):272-279.

* A randomized, double-blind, placebo-controlled study in 544 outpatients with GAD, a baseline HAM-A Score of ³20, and a score of ³2 on HAM-A item (anxious mood) and item 2 (tension). Patients also had to have a Covi Anxiety Scale total score higher than their Raskin Depression Scale total score, and a Raskin Depression Scale total score <9. The primary observer rating scales were the HAM-A and Clinical Global Impression (CGI) scores. Data for EFEXOR^® XR 37.5 mg/day not shown.

EFEXOR^® XR can also be used to treat other anxiety disorders such as:⁸

• Social anxiety disorder (SAD)
• Panic disorder

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EFEXOR^® XR well tolerated across all indications.¹

In 12-week clinical studies, EFEXOR^® XR demonstrated a low incidence of adverse events.¹

Adverse events with ≥5% incidence and greater than placebo¹

EFEXOR^® XR has a demonstrated long-term safety profile.²

Among patients with MDD who received maintenance therapy, EFEXOR^® XR demonstrated a low incidence of adverse events during the second year.²

Only 1 patient discontinued treatment in the EFEXOR^® XR group vs 4 patients in the placebo group (2% vs 10%).²

Adverse reactions with ≥10% incidence in any group^2*

* Data shown are for the second maintenance phase of a double-blind, placebo-controlled, 3-phase study in patients with recurrent moderate or severe unipolar major depression. Patients were initially randomized to double-blind treatment with EFEXOR^® XR or fluoxetine for 10 weeks of acute treatment. Responders then received 6 months of double-blind continuation treatment. Those who remained responders were then enrolled into 2 consecutive 12-month maintenance periods, during which EFEXOR^® XR responders were randomly assigned to receive double blind treatment with EFEXOR^® XR or placebo.

EFEXOR^® XR drug interaction profile¹

The risk of using EFEXOR^® in combination with other CNS-active drugs has not been systematically evaluated. Caution is advised when EFEXOR^® is taken in combination with other CNS-active drugs¹

Severe adverse reactions or drug interactions have been reported or are likely with monoamine oxidase inhibitors (MAOIs), serotonergic and dopaminergic medicines, and drugs that prolong QT-interval¹

Caution is advised when EFEXOR^® XR is co-administered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid, lithium, tramadol, or St. John’s wort¹

The use of psychotropic drugs that interfere with serotonin reuptake is associated with the occurrence of upper gastrointestinal bleeding and concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin may potentiate this risk of bleeding¹ Co-administration of EFEXOR^® XR and weight loss agents is not recommended¹ Pharmacokinetic data suggest drug-drug interactions between EFEXOR^® and the following medications: indinavir, haloperidol, cimetidine, imipramine, ketoconazole, metoprolol, and risperidone. The clinical significance of these interactions has not been determined in all cases¹

DISCLAIMER: Please refer to local prescribing information for more information on potential drug-drug interactions.

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EFEXOR^® XR provides flexible, once-daily dosing.¹

EFEXOR^® XR’s flexible, once-daily dosing for patients with major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder.^1,2

Recommended dosing schedule¹

Recommended as optimal treatment for most MDD patients by APA guidelines and as first-line treatment of MDD with Level 1 evidence by the CANMAT guidelines.^3,4

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Note: Please refer to the full prescribing information before prescribing

EFEXOR^®XR

Content: Venlafaxine Hydrochloride.

Indication: Depression including depression with associated anxiety in hospitalized patients, anxiety or generalized anxiety disorder(GAD) including long-term treatment, social anxiety disorder (SAD or social phobia), panic disorder including prevention of relapse. Prevention of relapse of an episode of depression or recurrence of new depressive episodes.

Dosing: 75mg once daily. Increase in increments of 75 mg/day at intervals of not less than 4 days. Maximum dose: 225mg/day for moderate depression and 375 mg/day for severe depression. Patients with panic disorder 37.5 mg/day for the 1^st 4-7 days. Increase to 75mg once a day.

Administration: Take at the same time with food each day. Swallow whole, do not chew/ crush/ divide/ dissolve. Cap may be carefully opened and entire contents should be sprinkled on a spoonful of applesauce. Drug and food mixture can be swallowed with or without chewing immediately after preparation.

Contraindications: Hypersensitivity to venlafaxine hydrochloride. Concomitant use with monoamine oxidase inhibitors (MAOIs). Initiate for at least 14 days after discontinuation of treatment with a monoamine oxidase inhibitors (MAOIs). Discontinue for at least 7 days before starting treatment with any MAOIs.

Special precautions: Closely monitor for clinical worsening, suicidality, other unusual changes in behaviors, worsening of depression or suicidal ideation. Concomitant use of serotonergic agents may increase risk of bone fractures in patients receiving serotonin reuptake inhibitors. Monitor serotonin syndrome or neuroleptic malignant syndrome-like reactions. Increased intraocular pressure and take caution for patients at risk for acute narrow-angle glaucoma. Caution should be taken for patients with recent history of myocardial infarction or unstable heard disease. Consider cardiovascular assessment during treatment with dose above 150-200 mg daily. Reduce or discontinue the dose in patients with sustained increase in blood pressure. Patients with risk factors for QTc prolongation/Torsades de Pointes, ventricular tachycardia or sudden death should be cautioned. Caution should be taken for patients with history of convulsions, bipolar disorder or aggression. Avoid concomitant use with serotonin precursors such as tryptophan supplements or diuretics and weight loss agents such as phentermine. Elderly patients taking diuretics, volume depleted or dehydrated. Patients predisposed to bleeding including those on anticoagulant or platelet inhibitor therapy should be cautioned. Consider measurement of serum cholesterol levels during long-term treatment. Avoid abrupt withdrawal. Patients with renal or hepatic insufficiency should be cautioned. There may be false positive urine immunoassay screening tests for phencyclidine and amphetamine. It may affect the ability to drive or operate machinery. Caution should be taken for pregnant and lactating women as well as children and adolescents below 18 years old.

Adverse Reactions: Insomnia, headache, dizziness, sedation, nausea, dry mouth, constipation, hyperhidrosis; decreased appetite, abnormal dreams, nervousness, decreased libido, agitation, anorgasmia, akathisia, tremor, paraesthesia, dysgeusia, visual impairment, accommodation disorder, mydriasis, tinnitus, tachycardia, palpitations, hypertension, hot flush, dyspnea, yawning , diarrhea, vomiting, rash, pruritus, night sweats, hypertonia, urinary hesitation and retention, pollakiuria, erectile dysfunction, ejaculation disorder, fatigue, asthenia, chills, decreased or increase weight.

Drug Interactions: Interaction with monoamine oxidase inhibitors (MAOIs), and increases the risk of severe adverse reaction. Caution when taken in combination with other CNS-active drugs and alcohol. Interaction with other serotonergic agents such as triptans, SSRIs, other SNRIs, amphetamines, lithium, sibutramine, fentanyl and its analogues, tramadol, dextromethorphan, tapentadol, meperidine, methadone, pentazocine or St. John’s wart. Interaction with drugs which impair serotonin’s metabolism such as linezolid and methylene blue or serotonin precursors such as tryptophan supplements. Increased risk of QTc prolongation and/or ventricular arrhythmias with some antipsychotics and antibiotics. Decreased AUC and C max of indinavir. Increased AUC and C max of haloperidol. May have increased first-pass metabolism with cimetidine in the elderly. Increased AUC, C max, and C min of desipramine. Increased plasma concentration with ketoconazole. Increased plasma concentration and reduced blood pressure lowering effect of metoprolol. Increased AUC of risperidone. Reduced metabolism with CYP2D6 inhibitors and increased venlafaxine levels with CYP3A4 inhibitors.

Presentation and Packing: Enteric release capsule 75mg x 28’s.

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