APO-VORTIOXETINE

1 Dosing Considerations • APO-VORTIOXETINE is not indicated for use in patients below the age of 18 (see 7 WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm). 2 Recommended Dose and Dosage Adjustment Adults The starting and recommended dose of APO-VORTIOXETINE is 10 mg vortioxetine once daily for adults less than 65 years of age.

Depending on individual patient response, the dose may be increased to a maximum of 20 mg vortioxetine once daily, as tolerated. A dose decrease to a minimum of 5 mg vortioxetine once daily may be considered for patients who do not tolerate higher doses.

APO-VORTIOXETINE (Vortioxetine Tablets) Page 6 of 57 In clinical trials conducted outside the United States, efficacy was demonstrated with 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day. 1 Clinical Trials by Indication, Study Results).

The efficacy and safety of doses greater than 20 mg/day were not evaluated in controlled clinical trials. 1 Clinical Trials by Indication, Study Results). During long-term therapy, the dosage should be maintained at the lowest effective level and patients should be periodically reassessed to determine the need to continue treatment.

• Pediatrics (<18 years of age) Health Canada has not authorized an indication for pediatric use. • Geriatrics (>65 years of age) The lowest effective dose of 5 mg/day vortioxetine should always be used as the starting dose for patients of 65 years of age or older.

1 Clinical Trials by Indication, Study Results). Dosage Adjustment Patients with Renal Impairment No dose adjustment is recommended for patients with renal impairment or for patients with end- stage renal disease. 3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).

Patients with Hepatic Impairment No dose adjustment is recommended for patients with hepatic impairment. 3 Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency). g. 4 Drug- Drug Interactions). g. 4 Drug-Drug Interactions).

2 Clinical Trial Adverse Reactions, Discontinuation Symptoms). Patients should be monitored for discontinuation symptoms when discontinuing treatment with APO-VORTIOXETINE. A gradual reduction in the dose, rather than an abrupt cessation, is recommended whenever possible.

). Gastrointestinal and gynaecological bleeding have also been reported following treatment with vortioxetine tablets. 1 Pregnant Women). g. thrombocytopenia or coagulation disorders). 2 Drug Interactions Overview). 3 Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency).

However, due to extensive hepatic metabolism of vortioxetine, caution is advised when APO-VORTIOXETINE is prescribed in patients with moderate or severe hepatic impairment. Musculoskeletal Bone Fracture Risk Elderly patients, patients with osteoporosis and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal.

Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs and other newer antidepressants. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment.

The possibility of fracture should be considered in the care of patients treated with APO-VORTIOXETINE. Preliminary data from observational studies show association of Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) and low bone mineral density in older men and women.

Until further information becomes available, a possible effect on bone mineral density with long- term treatment with SSRIs and other newer antidepressants including APO-VORTIOXETINE, cannot be excluded. Neurologic Seizures Seizures are a potential risk with antidepressant drugs.

1% of patients that received vortioxetine tablets compared to 0% that received placebo. As with other antidepressants, APO-VORTIOXETINE should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy.

1 Clinical Trial Adverse Reactions – Pediatrics). 1 Clinical Trials by Indication, Study Results). 2 CONTRAINDICATIONS APO-VORTIOXETINE is contraindicated in: • patients who are hypersensitive to vortioxetine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Angioedema has been reported in patients treated with vortioxetine tablets. For a complete listing of excipients, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. 2 Drug APO-VORTIOXETINE (Vortioxetine Tablets) Page 5 of 57 Interactions Overview; 7 WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Toxicity/Neuroleptic Malignant Syndrome).

Monoamine Oxidase Inhibitors (MAOIs) Vortioxetine increases serotonergic neurotransmission and must not be used concomitantly in patients taking MAOIs, including linezolid, an antibiotic, methylene blue, a dye used in certain surgeries, or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions.

These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome or serotonin toxicity, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

Therefore, at least 14 days should be allowed after discontinuing treatment with a MAOI before starting treatment with vortioxetine. 2 Drug Interactions Overview). 3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions • Increased risk of self-harm, harm to others, suicidal thinking and behavior with antidepressants use.

Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of agitation type and/or suicidal thoughts and behaviors (see 7 WARNINGS AND PRECAUTIONS, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).

APO-VORTIOXETINE is contraindicated in: • patients who are hypersensitive to vortioxetine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. Angioedema has been reported in patients treated with vortioxetine tablets.

For a complete listing of excipients, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. 2 Drug APO-VORTIOXETINE (Vortioxetine Tablets) Page 5 of 57 Interactions Overview; 7 WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Toxicity/Neuroleptic Malignant Syndrome).

Monoamine Oxidase Inhibitors (MAOIs) Vortioxetine increases serotonergic neurotransmission and must not be used concomitantly in patients taking MAOIs, including linezolid, an antibiotic, methylene blue, a dye used in certain surgeries, or in patients who have taken MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions.

These interactions have been associated with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome or serotonin toxicity, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma.

Therefore, at least 14 days should be allowed after discontinuing treatment with a MAOI before starting treatment with vortioxetine. 2 Drug Interactions Overview).