Fetzima Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ...................................................................................................... 2

TABLE OF CONTENTS ........................................................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION ................................................................................ 5

1 INDICATIONS ....................................................................................................................... 5

1.1 Pediatrics .............................................................................................................................. 5

1.2 Geriatrics .............................................................................................................................. 5

2 CONTRAINDICATIONS .......................................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS box ....................................................................... 6

4 DOSAGE AND ADMINISTRATION .......................................................................................... 6

4.1 Dosing Considerations ......................................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment .................................................................... 6

4.4 Administration ..................................................................................................................... 7

4.5 Missed Dose ......................................................................................................................... 8

5 OVERDOSAGE ...................................................................................................................... 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................................ 8

7 WARNINGS AND PRECAUTIONS ............................................................................................ 9

7.1 Special Populations ............................................................................................................15

7.1.1 Pregnant Women ........................................................................................................15

7.1.2 Breast-feeding .............................................................................................................16

7.1.3 Pediatrics .....................................................................................................................16

7.1.4 Geriatrics .....................................................................................................................17

8 ADVERSE REACTIONS ......................................................................................................... 17

8.1 Adverse Reaction Overview ...............................................................................................17

8.2 Clinical Trial Adverse Reactions .........................................................................................17

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ...............................................................20

8.3 Less Common Clinical Trial Adverse Reactions ..................................................................21

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data 22

8.5 Post-Market Adverse Reactions .........................................................................................22

9 DRUG INTERACTIONS ......................................................................................................... 22

9.1 Serious Drug Interactions ...................................................................................................22

9.2 Drug Interactions Overview ...............................................................................................22

9.3 Drug-Behavioural Interactions ...........................................................................................22

9.4 Drug-Drug Interactions ......................................................................................................23

9.5 Drug-Food Interactions ......................................................................................................25

9.6 Drug-Herb Interactions ......................................................................................................25

9.7 Drug-Laboratory Test Interactions .....................................................................................25

10 CLINICAL PHARMACOLOGY ................................................................................................ 25

10.1 Mechanism of Action ...................................................................................................25

10.2 Pharmacodynamics .....................................................................................................26

10.3 Pharmacokinetics ........................................................................................................27

11 STORAGE, STABILITY AND DISPOSAL ................................................................................... 28

12 SPECIAL HANDLING INSTRUCTIONS .................................................................................... 28

PART II: SCIENTIFIC INFORMATION ................................................................................................. 29

13 PHARMACEUTICAL INFORMATION ..................................................................................... 29

14 CLINICAL TRIALS ................................................................................................................. 30

14.1 Clinical Trials by Indication ..........................................................................................30

Major Depressive Disorder ...........................................................................................................30

15 MICROBIOLOGY ................................................................................................................. 32

16 NON-CLINICAL TOXICOLOGY ............................................................................................... 32

PATIENT MEDICATION INFORMATION ............................................................................................ 36

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

FETZIMA® (levomilnacipran extended release capsules) is indicated for the symptomatic relief of major depressive disorder (MDD).

1.1 Pediatrics

Pediatrics (< 18 years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of FETZIMA in pediatric patients has not been established; therefore Health Canada has not authorized an indication for pediatric use. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Potential association with behavioural and emotional changes, including self-harm and 7.1.3 Pediatrics.

1.2 Geriatrics

Caution should be exercised in treating the elderly. Clinical studies of FETZIMA did not include sufficient numbers of subjects over 65 years of age to determine whether they respond differently from younger subjects. Dose selection for elderly patients should be cautious. See 7.1.4 Geriatrics.

2 CONTRAINDICATIONS

• Hypersensitivity: FETZIMA is contraindicated in patients who are hypersensitive to levomilnacipran, milnacipran or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Serotonin toxicity and Monoamine Oxidase Inhibitors (MAOIs): FETZIMA should not be used in combination with MAOIs, including linezolid, an antibiotic, methylene blue, a dye used in certain surgeries, or within two weeks of terminating treatment with MAOIs. Treatment with MAOIs should not be started until 2 weeks after discontinuation of FETZIMA therapy. Co-administration of MAOIs with selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) treatment or with other serotonergic drugs can lead to serious, sometimes fatal, drug interactions. Symptoms include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. See 4.1 Dosing Considerations, Serotonin toxicity / serotonin syndrome, and 9.4 Drug-Drug Interactions.

• Cardiovascular: FETZIMA should not be used in patients with:

  • myocardial infarction or cardiac intervention within the past 12 months
  • NYHA Class III or IV congestive heart failure
  • uncontrolled tachyarrhythmia
  • uncontrolled hypertension
  • a history of cerebrovascular accident

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Switching to or from Monoamine Oxidase Inhibitor (MAOI) Antidepressants

  At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with FETZIMA. Conversely, at least 14 days should be allowed after stopping FETZIMA before starting an MAOI antidepressant. See 2 CONTRAINDICATIONS and 9.4 Drug-Drug Interactions.

• Use of FETZIMA with Other Drugs that Inhibit Monoamine Oxidase such as Linezolid or Methylene Blue

  Do not start FETZIMA in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin toxicity. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. See 2 CONTRAINDICATIONS, 9.4 Drug-Drug Interactions and Serotonin toxicity / serotonin syndrome.

  In some cases, a patient already receiving FETZIMA therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, FETZIMA should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with FETZIMA may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

  The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with FETZIMA is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use. See Serotonin toxicity / serotonin syndrome.

4.2 Recommended Dose and Dosage Adjustment

Initiating Treatment

Adults: The recommended dose range for FETZIMA is 40 mg to 120 mg once daily. FETZIMA should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily.

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 Potential association with behavioural and emotional changes, including self-harm.

In clinical studies, added benefit was not consistently demonstrated for doses greater than 40 mg/day. If the physician, based on clinical judgment, decides a dose increase above 40 mg/day is warranted for an individual patient, the dose may be increased in increments of 40 mg. The maximum recommended dose should not exceed 120 mg/day.

Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Long-term efficacy of FETZIMA for up to 26 weeks, following response during 20 weeks of acute, open-label treatment, was established in a placebo-controlled trial.

Physicians choosing to use FETZIMA should periodically reassess patients to determine the need for continued treatment.

Dosing in Special Populations and Conditions

Hepatic Impairment: No dose adjustment is required in patients with mild, moderate or severe hepatic impairment. See 10.3 Pharmacokinetics.

Renal Impairment: Based on a population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild renal impairment (creatinine clearance of 60-89 mL/min). For patients with moderate renal impairment (creatinine clearance of 30-59 mL/min), the dose should not exceed 80 mg/day. For patients with more severe renal impairment (creatinine clearance of 15-29 mL/min) the dose should not exceed 40 mg/day. See 10.3 Pharmacokinetics. FETZIMA is not recommended for patients with end stage renal disease.

Geriatric Patients (> 65 years of age): No dose adjustment is required in geriatric patients on the basis of age. See 10.3 Pharmacokinetics.

In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure (C_max by 24% and AUC by 26%) of levomilnacipran than younger subjects (18-45 years).

Because levomilnacipran is predominately excreted by the kidney, renal clearance of levomilnacipran should be considered when determining the dose.

Pediatrics (< 18 years of age): Health Canada has not authorized an indication for pediatric use. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Potential association with behavioural and emotional changes, including self-harm and 7.1.3 Pediatrics.

Sex: No dose adjustment is required based on sex. See 10.3 Pharmacokinetics.

Discontinuing Treatment

Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as FETZIMA. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible. Monitor patients for these symptoms when discontinuing FETZIMA. If intolerable symptoms occur following a dose decrease or upon discontinuation of treatment, consider resuming the previously prescribed dose and decreasing the dose at a more gradual rate. See Discontinuation Symptoms.

4.4 Administration

FETZIMA should be taken at approximately the same time each day. FETZIMA should be swallowed whole. Do not open, chew or crush the capsule. FETZIMA can be taken with or without food. See 9.5 Drug-Food Interactions.

4.5 Missed Dose

In the event that a dose is missed, the patient should take the missed dose as soon as they remember. If it is almost time for the next dose, the patient should skip the missed dose and take the next dose at the regular time. The patient should not take two doses of FETZIMA at the same time.

5 OVERDOSAGE

There is limited clinical experience with FETZIMA overdose in humans. In clinical trials, cases of ingestions up to 360 mg daily were reported with none being fatal.

No specific antidotes for FETZIMA are known. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be considered. The high volume of distribution of levomilnacipran suggests that dialysis will not be effective in reducing levomilnacipran plasma concentrations.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 - Dosage Forms, Strengths, Composition and Packaging

FETZIMA is available as capsules for oral administration, containing levomilnacipran hydrochloride equivalent to 20 mg, 40 mg, 80 mg and 120 mg of levomilnacipran.

20 mg: Each capsule has a yellow cap imprinted with “FL” in black ink, and a white body imprinted with “20” in black ink.

40 mg: Each capsule has a yellow cap imprinted with “FL” in black ink, and a yellow body imprinted with “40” in black ink.

80 mg: Each capsule has a pink cap imprinted with “FL” in black ink, and a white body imprinted with “80” in black ink.

120 mg: Each capsule has a pink cap imprinted with “FL” in black ink, and a pink body imprinted with “120” in black ink.

Packaging: FETZIMA is supplied in the following configurations:

Bottles of 30 capsules: 20 mg, 40 mg, 80 mg and 120 mg

7 WARNINGS AND PRECAUTIONS

Discontinuation Symptoms

Patients currently taking FETZIMA should NOT be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

Discontinuation of treatment with FETZIMA:

There have been reports of adverse events occurring upon discontinuation of serotonergic antidepressants, particularly when discontinuation is abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Monitor patients for these symptoms when discontinuing FETZIMA. Reduce the dose gradually whenever possible. See Discontinuing Treatment .

General

Bone Fracture Risk

Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including SSRIs/SNRIs. 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 FETZIMA. Elderly patients 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. Preliminary data from observational studies show association of SSRIs/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/SNRIs, including FETZIMA, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.

Cardiovascular

Inhibition of the reuptake of norepinephrine (NE) and serotonin (5-HT) can lead to cardiovascular effects. Patients with severe cardiac function impairment or with an identified risk of a serious cardiac arrhythmia, uncontrolled hypertension, or severe or unstable coronary heart disease were excluded from clinical trials with FETZIMA.

Elevated Blood Pressure and Hypertension

In short-term, placebo-controlled studies in patients with MDD, FETZIMA (40 mg – 120 mg) was associated with mean increases of 3.0 mmHg in systolic blood pressure (SBP) and 3.2 mmHg in diastolic blood pressure (DBP) after 8 to 10 weeks of treatment, compared to a mean decrease of 0.4 mmHg SBP and no change in DBP in placebo-treated patients. Approximately 10% of FETZIMA-treated patients experienced a categorical shift in blood pressure from normotensive/prehypertension to Stage I/Stage II hypertension, compared to 7% of placebo-treated patients.

In healthy subjects who had serial blood pressure assessments during steady-state treatment with 120 mg levomilnacipran, the mean difference from placebo in SBP ranged from 3.8 to 7.2 mmHg and the mean difference from placebo in DBP ranged from 6.1 to 8.1 mmHg. See 10.2 Pharmacodynamics.

In patients exposed to one-year, open-label treatment of FETZIMA (doses from 40-120 mg/day), the mean increase from initiation of treatment in SBP was 3.9 mmHg and DBP was 3.3 mmHg. Upward shifts from normal or prehypertension to Stage 1 or 2 hypertension was experienced by 104/800 (13%) of patients.

Sustained Hypertension: Instances of sustained hypertension were more frequent in FETZIMA–treated patients (see Table 2). Dose-dependency was not evident over the 40-120 mg dose range studied. For patients who experience a sustained increase in blood pressure while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered.

Table 2 - Incidence of Patients with Sustained Hypertension for All Short-Term Clinical Studies

FETZIMA was associated with an increase in blood pressure in pediatric patients with MDD. These increases in blood pressure led to a higher proportion of pediatric patients developing new-onset and sustained hypertension when compared to adults. See 7.1.3 Pediatrics.

Concomitant use of FETZIMA with drugs that increase blood pressure has not been evaluated and such combination should be used with caution. See 9.4 Drug-Drug Interactions.

Blood pressure should be measured prior to initiating treatment and periodically throughout FETZIMA treatment. See 7 WARNINGS AND PRECAUTIONS. Pre-existing hypertension and other cardiovascular disease should be treated and stabilized before starting therapy with FETZIMA. Centrally acting antihypertensives (clonidine, methyldopa, etc.) were not permitted in the clinical studies and may interact with FETZIMA. See 9.4 Drug-Drug Interactions.

Elevated Heart Rate

SNRIs, including FETZIMA, have been associated with increased heart rate.

In short-term placebo-controlled clinical studies in patients with MDD, with periodic steady-state ECG assessments at unspecified time points in relation to dosing, FETZIMA treatment was associated with mean increases in heart rate of 7.2 beats per minute (bpm) for 40 mg and 80 mg/day and 9.1 bpm for

120 mg/day, compared to a mean decrease of 0.3 bpm in placebo-treated patients. In patients exposed to one-year, open-label treatment of FETZIMA (doses from 40-120 mg/day), the mean change from initiation of treatment in heart rate was 9.1 bpm.

In an ECG assessment study in healthy subjects, with serial ECG data collection over the course of a dosing interval, FETZIMA 120 mg/day was associated with a maximum placebo-adjusted increase from baseline in heart rate of 20.2 bpm. See 10.2 Pharmacodynamics.

Concomitant use of FETZIMA with drugs that increase heart rate has not been evaluated and the possibility of additive effects should be considered. FETZIMA has not been systematically evaluated in patients with a cardiac rhythm disorder. Heart rate should be measured prior to initiating treatment and periodically measured throughout FETZIMA treatment. See Monitoring and Laboratory Tests. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with FETZIMA. Patients with serious or uncontrolled tachyarrhythmias, ischemic heart disease, or congestive heart failure should not receive FETZIMA. See 2 CONTRAINDICATIONS. For patients who experience an increase in heart rate while receiving FETZIMA discontinuation or other appropriate medical intervention should be considered.

Dependence/Tolerance

FETZIMA has not been systematically studied in animals or humans for its potential for abuse or dependence. There was no evidence suggestive of drug-seeking behavior in the clinical studies. It is not possible to predict on the basis of clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of FETZIMA (e.g., development of tolerance or drug-seeking behavior).

Driving and Operating Machinery

Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that FETZIMA therapy does not adversely affect their ability to engage in such activities.

Endocrine and Metabolism

Diabetic Patients

FETZIMA has not been systematically evaluated in diabetic patients. Insulin use was not permitted in premarket clinical trials. Treatment with antidepressants in patients with diabetes may alter glycemic control (hypoglycemia and hyperglycemia). FETZIMA should be used with caution in diabetic patients on insulin or other antidiabetic drugs. See Monitoring and Laboratory Tests.

Genitourinary

Urinary Hesitation, Retention and Dysuria

The noradrenergic effect of SNRIs including FETZIMA, can affect urethral resistance. In the controlled short-term studies, rates of obstructive uropathies were higher in patients treated with levomilnacipran (8%) compared to the placebo arm (1%). Dose dependent increases in urinary hesitation (3.6% in 40 mg/day; 4.9% in 80 mg/day; 6.1% in 120 mg/day) were observed, compared to no patients in the placebo group.

Almost all events of dysuria and urinary hesitation occurred in male patients. Caution is advised in the use of FETZIMA with concomitant medications that may affect voiding (e.g., anticholinergics) and in patients with a history of obstructive urinary disorders and dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders.

If symptoms of urinary hesitation, urinary retention, or dysuria develop during treatment with FETZIMA, discontinuation or dose-reduction should be considered.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk. Discontinuation of FETZIMA in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Hematologic

Abnormal Bleeding

SSRIs and SNRIs, including FETZIMA, may increase the risk of bleeding events by causing abnormal platelet aggregation. Concomitant use of acetylsalicylic acid (ASA), nonsteroidal anti-inflammatory drugs (NSAIDS), warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. SSRIs/SNRIs, including FETZIMA, may increase the risk of postpartum hemorrhage. See 7.1.1 Pregnant Women.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of FETZIMA and NSAIDs, ASA, or other drugs that affect coagulation. See 9.4 Drug-Drug Interactions. Caution is advised in patients with a history of bleeding disorder or predisposing conditions (e.g., thrombocytopenia).

Monitoring and Laboratory Tests

Self-Harm

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and Potential association with behavioural and emotional changes, including self-harm.

Heart Rate and Blood Pressure

Heart rate and blood pressure should be measured prior to initiating treatment with FETZIMA and periodically throughout treatment. For patients who experience a sustained increase in blood pressure or heart rate while receiving FETZIMA, discontinuation or other appropriate medical intervention should be considered.

Patients should be told to consult their doctors if they have symptoms associated with acute severe hypertension such as headache (particularly in the back of head/neck when waking up), stronger heartbeat and possibly more rapid, palpitations, dizziness, easy fatigability, blurred vision, chest pain. See Cardiovascular.

Serum Cholesterol

Clinically relevant increases in total serum cholesterol were recorded in 5% of patients receiving 40-120 mg/day of FETZIMA in short-term clinical trials, and in 7% of patients exposed to one-year, open-label treatment (doses from 40-120 mg/day). Periodic measurement of serum cholesterol levels (including a complete lipid profile/fractionation and an assessment of the patient’s individual risk factors) should be considered.

Serum Glucose

Cases of altered glycemic control and new onset diabetes mellitus have been reported in patients receiving antidepressants, including FETZIMA. Patients should be monitored for signs and symptoms of glucose fluctuations. Diabetic patients especially should have their glycaemia carefully monitored.

Neurologic

Seizures

FETZIMA has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies. One case of encephalopathy and convulsion was reported in clinical studies with FETZIMA. Like other antidepressants, FETZIMA should be prescribed with caution in patients with a seizure disorder.

Serotonin toxicity / serotonin syndrome

Serotonin toxicity also known as serotonin syndrome is a potentially life-threatening condition and has been reported with SSRIs and SNRIs, including FETZIMA, particularly during combined use with other serotonergic drugs. See 2 CONTRAINDICATIONS, 9.4 Drug-Drug Interactions.

Serotonin toxicity is characterised by neuromuscular excitation, autonomic stimulation (e.g. tachycardia, flushing) and altered mental state (e.g. anxiety, agitation, hypomania). In accordance with the Hunter Criteria, serotonin toxicity diagnosis is likely when, in the presence of at least one serotonergic agent, one of the following is observed:

• Spontaneous clonus
• Inducible clonus or ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia and body temperature >38°C and ocular clonus or inducible clonus.

The concomitant use of FETZIMA with serotonin precursors (such as tryptophan) is not recommended. See 9.4 Drug-Drug Interactions. If concomitant treatment with FETZIMA and other serotonergic agents, including a 5-hydroxytryptamine receptor agonist (triptan), is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. See 9.4 Drug-Drug Interactions. If serotonin toxicity is suspected, discontinuation of the serotonergic agents should be considered.

The concomitant use of FETZIMA with MAOIs intended to treat psychiatric disorders is contraindicated. FETZIMA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking FETZIMA. FETZIMA should be discontinued before initiating treatment with the MAOI. See 2 CONTRAINDICATIONS, 9.4 Drug-Drug Interactions, and 4.1 Dosing Considerations.

Ophthalmologic

Angle-Closure Glaucoma

As with other antidepressants, FETZIMA can cause mydriasis which may trigger an angle-closure attack in patients with anatomically narrow ocular angles. Healthcare providers should inform patients to seek immediate medical assistance if they experience eye pain, changes in vision or swelling or redness in or around the eye.

Psychiatric

Potential Association with Behavioural and Emotional Changes, Including Self-Harm

• Pediatrics: Placebo-Controlled Clinical Trial Data

Recent analyses of placebo-controlled clinical trial safety databases from selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

The small denominators in the clinical trials database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

• Adults and Pediatrics: Additional Data

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.

An FDA meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients aged 18 to 24 years with psychiatric disorder showed an increased risk of suicidal behaviour with antidepressants compared to placebo.

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behaviour, worsening of depression, and suicidal ideation, especially when initiating therapy or during any change in dose or dosage regimen. The risk of suicide attempt must be considered, especially in depressed patients.

Suicide

The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision of patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization of high-risk patients.

The risk of suicide attempt must be considered, especially in depressed patients; the smallest quantity of drug, consistent with good patient management, should be provided to reduce the risk of overdose with this drug. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and Potential association with behavioural and emotional changes, including self-harm.

Activation of Mania/Hypomania

Symptoms of mania/hypomania were reported in 0.2% of FETZIMA-treated patients and 0.2% of placebo-treated patients in clinical studies. Activation of mania/hypomania has also been reported in a small proportion of patients with mood disorders who were treated with other antidepressants. As with all antidepressants, use FETZIMA cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania.

A major depressive episode may be the initial presentation of bipolar disorder. Patients with bipolar disorder may be at an increased risk of experiencing manic episodes when treated with antidepressants alone. Therefore, the decision to initiate symptomatic treatment of depression should be made only after patients have been adequately assessed to determine if they are at risk for bipolar disorder. It should be noted that FETZIMA is not approved for use in treating bipolar depression.

Renal

For patients with moderate to severe renal impairment, the pharmacokinetic disposition of levomilnacipran is significantly altered. Dosage adjustment is necessary in these patients. See Dosing in Special Populations and Conditions.

Reproductive Health: Female and Male Potential

• Function

Serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see 8.2 Clinical Trial Adverse Reactions, Sexual Function). Patients should be informed that there have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRIs. It is important for prescribers to inquire about sexual function prior to initiation of FETZIMA and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.

7.1 Special Populations

7.1.1 Pregnant Women

There are no adequate and well-controlled studies in pregnant women. In pre-market clinical studies, serious adverse events were reported in two pregnant women exposed to FETZIMA (one premature birth and one preeclampsia) out of 6 confirmed pregnancies with adequate follow-up. The causal relationship between FETZIMA and the emergence of these events has not been established. FETZIMA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Complications following late third trimester exposure to SNRIs

Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum hemorrhage following SSRI/SNRI exposure within the month prior to birth. See Hematologic.

Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. See Serotonin toxicity / serotonin syndrome.

Labour and Delivery

The effect of FETZIMA on labour and delivery in humans is unknown. FETZIMA should be used during labour and delivery only if the potential benefits outweigh the potential risks.

7.1.2 Breast-feeding

There are no adequate and well-controlled studies in nursing mothers. It is not known if FETZIMA is excreted in human milk. Studies have shown that levomilnacipran is excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FETZIMA, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. Breast feeding by women treated with FETZIMA should be considered only if the potential benefits outweigh the potential risks to the child.

7.1.3 Pediatrics

Pediatrics (< 18 years): Based on data submitted and reviewed by Health Canada, the safety and efficacy of FETZIMA in pediatric patients has not been established; therefore Health Canada has not authorized an indication for pediatric use.

FETZIMA was not superior to placebo in two adequate and well-controlled 8-week studies conducted in pediatric Major Depressive Disorder patients; one in patients 7 to 17 years and the second in patients 12 to 17 years.

The most commonly observed adverse reactions with FETZIMA-treated pediatric MDD patients were nausea, tachycardia, vomiting and decreased appetite. See 8.2.1 Clinical Trial Adverse Reactions - Pediatrics.

In these studies, treatment with FETZIMA was associated with the occurrence of new-onset hypertension (two systolic and/or diastolic BP measurements in the stage I hypertension range and/or one measurement in the stage II range) in 36.2% of treated patients compared with 20.7% of patients randomized to placebo. Elevations in either systolic or diastolic BP leading to measures at or above the stage II hypertension threshold occurred in 12.1% of pediatric patients treated with FETZIMA and 7.5% of patients randomized to placebo. Sustained hypertension (three or more consecutive systolic or diastolic BP measurements at or above the stage I hypertension threshold) occurred in 15% of pediatric patients treated with FETZIMA and 4 % of patients randomized to placebo.

Antidepressants may increase the risk of suicidal thoughts and behaviours in pediatric patients. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX and Potential association with behavioural and emotional changes, including self-harm.

7.1.4 Geriatrics

Of the total number of FETZIMA-treated subjects in the short-term clinical studies, only 2.8% of patients were 65 or older.

SSRIs and SNRIs, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. See Hyponatremia and 10.3 Pharmacokinetics.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

The safety of FETZIMA was evaluated in 3317 patients (18-78 years of age) diagnosed with MDD who participated in clinical studies. Among the 3317 FETZIMA-treated patients, 1,583 were exposed to FETZIMA in short-term, placebo-controlled studies.

A total of 895 patients were exposed to FETZIMA for at least 6 months and 367 were exposed for one year. In these studies, FETZIMA was given at doses ranging from 40-120 mg once daily and was given without regard to food.

The most commonly observed adverse events in FETZIMA-treated MDD patients in placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were: nausea, heart rate increased, erectile dysfunction, hyperhidrosis, constipation, tachycardia, vomiting, and palpitations.

Adverse Events Reported as Reasons for Discontinuation of Treatment

In the short-term placebo-controlled pre-marketing studies for MDD, 9% of the 1,583 patients who received FETZIMA (40-120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo-treated patients in those studies. The most common adverse event leading to discontinuation in at least 1% of FETZIMA-treated patients in the short-term placebo-controlled studies was nausea (1.5%).

Blood Pressure and Heart Rate

In placebo-controlled clinical studies for change from baseline to endpoint, FETZIMA treatment was associated with mean increases in blood pressure and heart rate. See Cardiovascular. The most commonly reported cardiovascular adverse events among FETZIMA-treated patients in the short-term clinical studies included heart rate increased, tachycardia, palpitations, hypertension, hypotension, and blood pressure increased (see Table 3).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Table 3 shows the incidence of adverse events that occurred in ≥ 2% of FETZIMA-treated MDD patients (and greater than placebo-treated patients) in the short-term, placebo-controlled studies.

Table 3 - Adverse Events Occurring in ≥ 2% of FETZIMA-Treated Patients and Greater than Placebo Treated Patients in Five, Short-term, Phase 3 Placebo-Controlled Studies

Dose-Related Adverse Events

In pooled data from the short-term placebo-controlled fixed-dose studies, there were no dose-related adverse events (greater than 2% overall incidence) in patients treated with FETZIMA across the dose range 40-120 mg/day, with the exception of erectile dysfunction and urinary hesitation (see Table 4).

Table 4 - Dose-Related Adverse Events in Two Fixed-Dose, Phase 3, Placebo-Controlled Studies

Sexual Function

While sexual dysfunction is often part of depression and other psychiatric disorders, there is increasing evidence that treatment with selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine-reuptake inhibitors (SNRIs) may induce sexual side effects. This is a difficult area to study because patients may not spontaneously report symptoms of this nature.

Table 5 shows the incidence of adverse events associated with sexual dysfunction in FETZIMA-treated patients in placebo controlled short-term studies.

Table 5 - Adverse Events Associated With Sexual Dysfunction by Sex in Five, Short-term Phase 3 Placebo-Controlled Studies

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

• Pediatrics (<18 years): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of FETZIMA in pediatric patients has not been established; therefore Health Canada has not authorized an indication for pediatric use.
• Two adequate and well-controlled 8-week studies were conducted in pediatric MDD patients, one in patients 7 to 17 years and the second in patients 12 to 17 years. Both studies did not meet both primary and secondary endpoints.
• The most commonly observed adverse reactions with FETZIMA-treated pediatric MDD patients were nausea, tachycardia, vomiting and decreased appetite.
• FETZIMA was associated with an increase in blood pressure in pediatric patients with MDD. These increases in blood pressure led to a higher proportion of pediatric patients developing new-onset and sustained hypertension when compared to adults. See 7.1.3 Pediatrics.

8.3 Less Common Clinical Trial Adverse Reactions

The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than

1/1000 patients:

Cardiac disorders: frequent: postural orthostatic tachycardia syndrome; infrequent: angina pectoris; supraventricular and ventricular extrasystoles

Eye disorders: infrequent: dry eye; mydriasis; vision blurred; rare: conjunctival hemorrhage

General disorders and administration site conditions: infrequent: chest pain; thirst; rare: drug withdrawal syndrome

Gastrointestinal disorders: frequent: flatulence; infrequent: hematochezia

Injury, poisoning and procedural complications: infrequent: ankle fracture; contusion; hand fracture; joint dislocation; joint injury; laceration; limb injury; post-traumatic neck syndrome; radius fracture; skeletal injury

Investigations: frequent: weight decreased; infrequent: blood cholesterol increased; liver function test abnormal

Nervous System disorders: frequent: migraine; paraesthesia; infrequent: syncope; rare: convulsion; extrapyramidal disorder

Psychiatric disorders: infrequent: agitation; anger; bruxism; worsening of depression; hypomania; panic attack; suicidality (including ideation, behavior, attempt); tension; rare: aggression; self-injurious behavior; mania

Renal and urinary disorder: frequent: dysuria; pollakiuria; urinary retention; infrequent: hematuria; rare: proteinuria

Reproductive system and breast disorders: rare: postmenopausal hemorrhage

Respiratory, thoracic and mediastinal disorders: infrequent: epistaxis; yawning

Skin and subcutaneous tissue disorders: frequent: rash; infrequent: dry skin; pruritus; urticaria; increased tendency to bruise

Vascular disorders: frequent: orthostatic hypotension; infrequent: hypotension; rare: orthostatic hypertension

Weight

In short-term clinical studies, FETZIMA-treated patients experienced a mean weight loss of 0.59 kg compared to a gain of 0.02 kg for placebo-treated patients. The proportion of patients with a weight gain > 7% was 0.6% in the FETZIMA group and 0.9% in the placebo group. No dose-related weight changes were observed. Results from a one-year open-label study were consistent with the findings from the placebo-controlled studies.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Slight elevations of liver enzyme levels (ALT, AST, and ALP) were noted among FETZIMA-treated patients in clinical studies. Mean increases (U/L) across all studies ranged from 2.1 to 2.7 for ALT, from 1.1 to 2.3 for AST, and from 1.9 to 3.6 for ALP. Few FETZIMA-treated patients experienced potentially clinically significant (PCS) criteria for ALT (0.7%), compared to placebo (0.1%). While a few patients were discontinued due to changes in liver function parameters, other patients with elevations continued on FETZIMA with enzyme levels returning to normal during on-going treatment. No patient had concurrent PCS elevations in ALT or AST and total bilirubin.

8.5 Post-Market Adverse Reactions

Cases of acute pancreatitis have been reported with SSRIs and SNRIs, including levomilnacipran. Although causality could not be established due to confounding factors, a role for levomilnacipran could not be excluded.

The following adverse reaction has been identified during post-approval use of FETZIMA or other selective serotonin and norepinephrine reuptake inhibitors. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: Takotsubo cardiomyopathy

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

In vitro and in vivo studies showed that FETZIMA has low potential to be involved in clinically significant pharmacokinetic drug interactions.

9.3 Drug-Behavioural Interactions

Alcohol

As with other psychotropic medications, the use of alcohol by patients taking FETZIMA is not recommended.

9.4 Drug-Drug Interactions

Monoamine Oxidase Inhibitors (MAOIs)

FETZIMA is contraindicated in patients taking MAOIs, or within at least 14 days of discontinuation. See 2 CONTRAINDICATIONS, Serotonin toxicity / serotonin syndrome and 4.1 Dosing Considerations.

Serotonergic Drugs

Based on the known mechanism of action of levomilnacipran and the potential for serotonin toxicity, also known as serotonin syndrome, caution is advised when FETZIMA is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, tryptophan, triptans, fentanyl and its analogues, dextromethorphan, tramadol, tapentadol, meperidine, methadone and pentazocine). See Serotonin toxicity / serotonin syndrome.

Drug that Increase Heart Rate and/or Blood Pressure

FETZIMA increases heart rate and blood pressure. FETZIMA may exacerbate the hemodynamic effects of other drugs that also increase heart rate and/or blood pressure (e.g., sympathomimetics).

Central Nervous System (CNS) Active Agents

The risk of using FETZIMA in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised when FETZIMA is prescribed in combination with other CNS-active drugs.

Drugs Affecting Platelet Function (e.g., NSAIDS, ASA and other anticoagulants)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, ASA or other anticoagulants may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when FETZIMA is initiated or discontinued. See Hematologic.

Potential for Other Drugs to Affect FETZIMA

Table 6 - Summary of Effect of Co-administered Drugs on Exposure to Levomilnacipran

Potential for FETZIMA to Affect Other Drugs

Table 7 - Summary of Effect of FETZIMA on Exposure to Co-administered Drugs

9.5 Drug-Food Interactions

Food has no clinically meaningful effect on the bioavailability of levomilnacipran. FETZIMA may be taken with or without food. However, tolerability was improved when taken with food particularly with respect to gastrointestinal adverse events (vomiting and nausea were markedly reduced).

9.6 Drug-Herb Interactions

In common with other SSRIs and SNRIs, pharmacodynamic interactions between FETZIMA and the herbal remedy St. John’s Wort may occur and may result in an increase in undesirable effects. Interactions with other herbs have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

FETZIMA is a potent and selective serotonin and norepinephrine reuptake inhibitor (SNRI). The exact mechanism of the antidepressant effect of levomilnacipran is unknown but is thought to be related to the potentiation of these neurotransmitters in the central nervous system.

10.2 Pharmacodynamics

Nonclinical studies have shown that levomilnacipran binds with high affinity to the norepinephrine (NE) and serotonin (5-HT) transporters (K_i = 71-91 nM and 11 nM respectively at human transporters). Levomilnacipran inhibits the uptake of both NE and 5-HT in vitro and in vivo; preferentially inhibiting reuptake of NE over 5-HT by approximately 2-fold. Levomilnacipran does not directly affect the uptake of dopamine or other neurotransmitters.

Levomilnacipran has no significant affinity for serotonergic (5-HT1-7), α- and β-adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, and γ-aminobutyric acid (GABA) receptors in vitro.

Levomilnacipran has no significant affinity for Ca⁺⁺, K⁺, Na⁺ and Cl^– channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.

Cardiac Electrophysiology and Hemodynamics

Levomilnacipran at 120 mg daily (maximum therapeutic dose) and 300 mg daily (supratherapeutic dose) was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg), parallel-group, thorough ECG study in 170 healthy subjects. Subjects randomized to levomilnacipran treatment received escalating once-daily doses on Day 1 to Day 24. Serial ECG data were collected on Day -2 (baseline), Day 11 (120 mg dose) and Day 24 (300 mg dose) at predose, and 1, 2, 3, 4, 6, 8, 12, 16, 20, and 23 hours postdose.

No clinically significant changes in QTcF interval (QTcF=QT/RR^0.33) were noted in this study.

Levomilnacipran caused an increase in heart rate. The mean change from baseline in heart rate in the levomilnacipran treatment group on Day 11 (120 mg dose) was significantly greater than the placebo group at multiple timepoints, ranging from 15 to 20 bpm with a maximum mean difference from placebo of 20.2 bpm (90% CI 18.0, 22.4) at 6 h. The effect was somewhat greater in the levomilnacipran treatment group on Day 24 (300 mg dose), with mean differences in heart rate ranging from 19-22 bpm with a maximum mean difference from placebo of 22.1 bpm (90% CI 19.8, 24.3) at 6 h.

On Day 11, the proportion of subjects with heart rate values >90 bpm at any recorded timepoint was 2.7% with placebo and 50.6% with levomilnacipran (120 mg dose). On Day 24, the corresponding values were 2.8% with placebo and 60.0% with levomilnacipran (300 mg dose).

None of the placebo-treated subjects had heart rate values >100 bpm on Days 11 or 24; however, heart rate values >100 bpm at any recorded timepoint were observed in 20.2% of subjects receiving levomilnacipran 120 mg on Day 11 and 26.3% receiving levomilnacipran 300 mg on Day 24.

Blood pressure in this thorough ECG study was measured using automatic blood pressure monitors at baseline (one measurement), and at predose, and 2, 3, 6, 8, and 24 hours postdose on Days 11 (120 mg dose), and 24 (300 mg dose). Levomilnacipran showed increases in blood pressure from baseline at recorded time points on Days 11 and 24.

As shown in Table 8Error! Reference source not found., the difference from placebo in SBP ranged from 3.8 to 7.2 mmHg for levomilnacipran (120 mg dose) on Day 11. The mean difference from placebo in SBP ranged from 5.4 to 7.9 mmHg for levomilnacipran (300 mg dose) on Day 24.

The mean difference from placebo in DBP ranged from 6.1 to 8.1 mmHg for levomilnacipran (120 mg dose) on Day 11. The mean difference from placebo in DBP ranged from 7.9 to 10.6 mmHg for levomilnacipran (300 mg dose) on Day 24.

Table 8 - Change from Baseline in Blood Pressure

10.3 Pharmacokinetics

Following an oral administration, the mean apparent total clearance of levomilnacipran is 21-29 L/h and the apparent volume of distribution is 387-473 L. The pharmacokinetics of levomilnacipran (25-300 mg once daily) are dose-proportional. Steady-state concentrations of levomilnacipran are predictable from single-dose data. Elimination of levomilnacipran is predominantly by renal excretion with a terminal elimination half-life of approximately 12 hours. After daily dosing of FETZIMA 120 mg, the mean C_max value is 341 ng/mL, and the mean steady-state AUC value is 5196 ng·h/mL. Interconversion between levomilnacipran and its stereoisomer does not occur in humans.

Absorption

Peak concentration of levomilnacipran is reached at a median of 6-8 hours (T_max) after oral administration. The absolute oral bioavailability of levomilnacipran is >80% and is not affected by food.

Distribution

Levomilnacipran is widely distributed with an apparent volume of distribution of 387-473 L; plasma protein binding is 22%.

Metabolism

Levomilnacipran undergoes desethylation to form desethyl levomilnacipran and hydroxylation to form p-hydroxy-levomilnacipran. Both oxidative metabolites undergo further conjugation with glucuronide to form conjugates. The desethylation is catalyzed primarily by CYP3A4 with minor contribution by CYP2C8, 2C19, 2D6, and 2J2. In human studies, ketoconazole, a potent inhibitor of CYP3A4, and carbamazepine, a potent inducer of CYP3A4, did not result in clinically significant drug-drug interactions when administered with levomilnacipran. See 9.4 Drug-Drug Interactions.

Elimination

Levomilnacipran and its metabolites are eliminated primarily by renal excretion. Following oral administration of ¹⁴C-levomilnacipran solution, approximately 58% of the dose is excreted in urine as unchanged levomilnacipran. N-desethyl levomilnacipran is the major metabolite excreted in the urine and accounted for approximately 18% of the dose. Other identifiable metabolites excreted in the urine are levomilnacipran glucuronide (4%), desethyl levomilnacipran glucuronide (3%), p-hydroxy levomilnacipran glucuronide (1%), and p-hydroxy levomilnacipran (1%). The metabolites are inactive.

Special Populations and Conditions

• Pediatrics: Based on the data submitted and reviewed by Health Canada, the safety and efficacy of FETZIMA in pediatric patients has not been established; therefore Health Canada has not authorized an indication for pediatric use. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Potential association with behavioural and emotional changes, including self-harm and 7.1.3 Pediatrics.
• Geriatrics: No dose adjustment is recommended on the basis of age. In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure (C_max by 24% and AUC by 26%) of levomilnacipran than younger subjects (18-45 years).
• Sex: The systemic exposure in females is slightly higher (C_max by 17% and AUC by 14%) than that in males; however, no dose adjustment is necessary.

• Hepatic Insufficiency: Hepatic elimination of levomilnacipran is low. In mild, moderate, and severe hepatic impairment, no dose adjustment is necessary.

  The presence of mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment increased the apparent clearance of levomilnacipran by 7%, and decreased by 8% and 25%, respectively, without significant change in terminal elimination half-life.

• Renal Insufficiency: Renal excretion plays a predominant role in the elimination of levomilnacipran. In mild (creatinine clearance of 50 - 79 ml/min), moderate (creatinine clearance of 30 - 49 ml/min), or severe (creatinine clearance <30 ml/min) renal impairment, AUC increased by 23%, 93%, or 180%, respectively, the apparent clearance of levomilnacipran decreased by 19%, 49%, or 64%, respectively and terminal elimination half-life increased by 28%, 43%, or 105%, respectively, relative to healthy subjects with normal renal function. Dosing adjustment is necessary for patients with moderate or severe renal impairment. See Dosing in Special Populations and Conditions.

11 STORAGE, STABILITY AND DISPOSAL

FETZIMA should be stored at controlled room temperature (15-30°C).

12 SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Levomilnacipran hydrochloride

Chemical name: (1S,2R)-2-(aminomethyl)-N,N-diethyl-1- phenylcyclopropanecarboxamide hydrochloride

Molecular formula and molecular mass: C₁₅H₂₂N₂O ·HCl and 282.8 g/mol

Structural formula:

. N NH₂ O HCl

Physicochemical properties: Levomilnacipran hydrochloride is a white to off-white powder that is very soluble in water and 0.1M HCl and freely soluble in ethanol.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Major Depressive Disorder

Table 9 - Summary of patient demographics for clinical studies supporting efficacy of FETZIMA in the Treatment of Major Depressive Disorder

The efficacy of FETZIMA (levomilnacipran extended-release capsules) for the treatment of major depressive disorder (MDD) was studied in four 8-week randomized, double-blind, placebo-controlled studies (at doses of 40-120 mg once daily) in adult (18-78 years of age) outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. Of the total number of FETZIMA-treated subjects in short-term clinical studies, only 2.8% of patients were 65 or older. Two of the studies were fixed dose (Study LVM-MD-01 and Study LVM-MD-10) and two were flexible dose (Study LVM-MD-02 and Study LVM-MD-03). The designs of the studies are summarized in Table 9.

The primary efficacy endpoint in all studies was mean change from baseline to Week 8-endpoint on the Montgomery Asberg Depression Rating Scale (MADRS). All studies included a 1-week single-blind placebo lead-in period, followed by an 8-week, double-blind treatment period.

In three of the four studies (LVM-MD-01, LVM-MD-10, and LVM-MD-03), FETZIMA demonstrated statistical superiority over placebo in the improvement of depressive symptoms as measured by the mean change from baseline to Week 8 in the MADRS total score (see Table 10).

Table 10 - Summary of the Least Square Mean Difference from Placebo in Change from Baseline for MADRS Score, in Placebo-Controlled Studies for Major Depressive Disorder (ITT Population)

Results from subgroup analyses by gender were not consistent across the pivotal trials; however, clinical studies with FETZIMA were not designed with adequate power to detect a gender difference. Both fixed-dose trials showed better response to treatment in male subjects. Females in these studies either had a reduced treatment response at doses above 40 mg/day compared to males (Study LVM-MD-01) or failed to demonstrate clinically significant improvements in study outcomes over placebo (Study LVM-MD-10). Female subjects, however, outperformed male subjects in the positive flexible-dose study (Study LVM-MD-03).

Fixed-dose studies failed to demonstrate a clear dose-response relationship for either male or female subjects.

The key secondary instrument was the Sheehan Disability Scale (SDS), a validated scale that measures the extent emotional symptoms disrupt patients functioning in 3 life domains: (work/school, social life and family life).

FETZIMA demonstrated superiority over placebo in functional improvement as measured by mean change from baseline to Week 8 in the SDS total score in studies LVM-MD-01, LVM-MD-10 and LVM-MD-03.

Additional efficacy parameters in the studies included HAMD-17 (17 item Hamilton Rating Scale for Depression), CGI-S (Clinical Global Impressions - Severity Scale) and MADRS-CR (Montgomery-Åsberg Depression Rating Scale - Clinician Rated) response and remission rates. In addition CGI-I (Clinical Global Impressions - Improvement Scale) was assessed in studies LVM-MD-01 and LVM-MD-03 and MEI-SF (Motivation and Energy Inventory - Short Form) was assessed in Study LVM-MD-03. Results of the additional efficacy parameters were generally supportive of the primary efficacy result.

Maintenance Study

The efficacy of FETZIMA for the maintenance treatment of MDD was demonstrated in a multicenter, randomized, double-blind, placebo-controlled trial of adult patients meeting DSM-V criteria for MDD (baseline MADRS total score of 32.2). Patients received flexible dose titration of FETZIMA (40 mg, 80 mg, or 120 mg/day) during the first 8 weeks (run-in phase) of an open-label treatment phase (OLTP), responders were eligible to enter a 12-week, open-label, fixed-dose stabilization phase (SP). Three hundred twenty-four (324) patients who met the response criteria (MADRS of 12 or less) after 20 weeks of open-label treatment were randomized to the double-blind treatment phase (DBTP) (baseline mean MADRS total score of 4.7) for 26 weeks. The primary efficacy endpoint was the time to first relapse during the DBTP, defined as the number of days from the randomization date to the relapse date. Recurrence of depressive episode was defined as a MADRS total score ≥ 18 at 2 consecutive visits or insufficient therapeutic response as judged by the investigator. Patients on FETZIMA experienced a statistically significantly longer time to have recurrence of depressive episodes than did patients on placebo. In the placebo group 39 of 159 patients experienced relapse (24.5%) while 24 of 165 FETZIMA-treated patients experienced relapse (14.5%).

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Safety Pharmacology Studies

Levomilnacipran was studied in a core battery of acute, nonclinical safety pharmacology studies to determine the effects on CNS, respiratory, and cardiovascular function. Acute, nonclinical safety findings are described as follows:

• The effect of levomilnacipran on hERG K+ currents was studied in vitro in CHO-K1 cells stably expressing the hERG channel. Levomilnacipran (0.001, 0.01, 0.1, 1, and 10 μM) produced a concentration-dependent inhibition of the maximum tail current amplitude, with an estimated IC50 > 10 μM.

• The effect of levomilnacipran (0.01, 0.1, 1, and 10 μM) on cardiac action potential physiology was assessed in vitro in canine Purkinje fiber preparations at both a normal stimulation rate (1 Hz) and a low stimulation rate (0.33 Hz). Levomilnacipran did not significantly affect the cardiac action potential parameters measured at any concentration tested with normal stimulation rate (1 Hz). When tested using the low stimulation rate (0.33 Hz), levomilnacipran

  • produced a statistically significant increase in APD90 (+19 msec; p < 0.05) at a concentration of 1 μM and in both APD70 (+22 msec; p < 0.01) and ADP90 (+37 msec; p < 0.01) at 10 μM compared with the vehicle control.
• Levomilnacipran was also evaluated in conscious telemetry female Beagle dogs. Animals received oral administration of levomilnacipran (10 mg/kg/day) for 5 days in three series of experiments with a 4-day washout period. Cardiovascular measurements (blood pressure, heart rate, ECG) were noted 3 days before the beginning of test article administration, following a single dose (Day 1), and after 5 days of dosing. Levomilnacipran produced a significant increase in heart rate and diastolic blood pressure after both a single dose and after 5 days of dosing compared with the vehicle control.
• The effect of single oral doses of levomilnacipran on cardiovascular function was assessed in vivo in conscious cynomolgus monkeys. Cardiovascular function (arterial blood pressure, heart rate, ECG) was monitored by telemetry for 2 h before test substance administration and for 24 h after test substance administration. Levomilnacipran 5 and 15 mg/kg did not significantly affect the QT or QTc intervals or the QRS complex throughout the testing period, but levomilnacipran 45 mg/kg produced a significant increase in the QT (up to 48 msec from pretest) and QTc (up to 57 and 55 msec from pretest when corrected with Bazett’s and Fridericia’s formula, respectively) intervals. In addition, there was a small increase in the QRS complex duration (up to 6 msec from pretest) for up to 6 h after levomilnacipran administration. When compared with the vehicle group, levomilnacipran (5, 15, and 45 mg/kg) produced moderate, but statistically significant increases in arterial blood pressure (mean, systolic, diastolic), with the maximum increase at 30 min after levomilnacipran administration and returning to predose levels by 4 h. The increase in arterial blood pressure (about 15 – 21 mmHg from pretest) was not dose related. There were no clear drug-related changes in heart rate at doses of levomilnacipran up to 45 mg/kg. Compared to the 120 mg human dose, oral administration of 45 mg/kg levomilnacipran in monkeys produced >20-fold higher drug levels in the plasma.
• At therapeutically relevant concentrations, levomilnacipran is not expected to have an effect on respiratory function, but at concentrations ~26-fold greater than the 120 mg clinical dose, levomilnacipran increases respiratory rate, decreases peak inspiratory flow, decreases inspiration time, decreases expiration time, decreases tidal volume, decreases minute volume, and increases airway resistance index in rat.
• Levomilnacipran decreases motor activity and body temperature in rats at all doses tested after a single oral dose. At high doses (6- to 66- fold the plasma concentration of the 120 mg clinical dose), levomilnacipran also decreases arousal, alters posture and gait and induces palpebral ptosis.

General Toxicology:

The principal toxicology studies included single-dose and repeat-dose studies in rats and monkeys; genetic toxicology studies; 2-year carcinogenicity studies in transgenic mice and rats; and reproductive and developmental toxicology studies in rats and rabbits.

Single-Dose

The toxicological potential of levomilnacipran following single-dose (acute) oral administration was evaluated in rats and mice. Clinical signs of acute toxicity consisted primarily of tremors and convulsions. The approximate lethal dose was determined to be 140 mg/kg in mice and < 215 mg/kg in rats.

Repeat-Dose The toxicological potential of levomilnacipran was evaluated in rats and monkeys for up to 6 months or 12 months, respectively.

Rats In a 4-week toxicity study, rats were administered 0, 10, 35 or 120 mg/kg/day and the no-observed-adverse-effect level (NOAEL) was 10 mg/kg/day based on decreases in body weight and food consumption and treatment-related centrilobular hepatocellular hypertrophy. In a 13-week toxicity study, rats were administered 0, 10, 35 or 120 mg/kg/day and based on centrilobular hepatocellular hypertrophy the NOAEL was determined to be 10 mg/kg/day a dose which represents an animal-to-human exposure margin of 0.4-fold relative to the human exposure from 120 mg/day of levomilnacipran. Following 6-months of dose administration at 0, 10, 30 or 120 (males) or 100 (females) mg/kg/day the NOAEL was determined to be 30 mg/kg/day for males and 100 mg/kg/day for females based on decreased activity, body weight and food consumption and increases in urine volume and liver weight with correlated minimal to mild centrilobular hepatocellular hypertrophy. The NOAELs represent animal-to-human exposure margins of 2-fold (male) and 14-fold (female) relative to the human exposure from 120 mg/day of levomilnacipran.

Monkeys The toxicological potential of levomilnacipran following repeat-dose oral administration for 13 weeks and 12 months was evaluated in cynomolgus monkeys at doses up to 45 mg/kg/day via direct dose or 90 mg/kg/day via dose escalation.

In a 13-week toxicity study, monkeys were administered 0, 5, 15, or 45 mg/kg/day; reversible decreases in body weight and food consumption were noted and the NOAEL was 15 mg/kg/day a dose which represents an animal-to-human exposure margin of 2-fold relative to the human exposure from 120 mg/day of levomilnacipran. In a 12-month toxicity study, monkeys were administered levomilnacipran via dose escalation at 0, 5/10, 15/30 or 45/70/90 mg/kg/day. All escalations were completed within two weeks of dose initiation. The NOAEL was determined to be 15/30 mg/kg/day based on emesis, decreases in activity, changes in clinical chemistry parameters (decreased albumin, albumin:globulin, cholesterol and increased GGT and ALT), and increased liver weights with correlates of minimal panlobular hepatocellular hypertrophy and minimal to mild midzonal vacuolation of hepatocytes. The NOAEL represents an animal-to-human exposure margin of 8-fold relative to the human exposure from 120 mg/day of levomilnacipran.

Genotoxicity:

Levomilnacipran was not mutagenic when evaluated in vitro in a bacterial mutagenicity study (Ames test) and not genotoxic in a mouse lymphoma study. It was not clastogenic in an in vivo micronucleus assay in rats.

Carcinogenicity:

The carcinogenic potential of levomilnacipran was evaluated in a 6-month carcinogenicity study in transgenic Tg.rasH2 mice and in a 2-year carcinogenicity study in rats.

Mice In a 6-month carcinogenicity study, Tg.rasH2 transgenic mice were administered 0, 15, 50, 150 mg/kg/day levomilnacipran daily via oral gavage. With the exception of a small increase in splenic hemangiosarcoma in males which received 150 mg/kg/day (the highest dose tested) there was no increase in incidence of neoplastic lesions due to levomilnacipran. Splenic hemangiosarcomas are one of the most common spontaneous tumor types in the Tg.rasH2 transgenic mouse. Although the incidence observed in this study was slightly beyond the facility historical control values, it is comparable to the spontaneous incidences reported in the literature for this strain of transgenic mouse. In addition, since this slight numerical increase of a common spontaneous tumor occurred in only one gender in this study, and taken together with other assessments of the carcinogenic/mutagenic potential of levomilnacipran, the results are not regarded to represent a biologically-significant signal that would be meaningful for the purposes of carcinogenic risk assessment.

Rats In a 2-year carcinogenicity study, rats were administered 0, 10, 30, or 90 mg/kg/day levomilnacipran daily via oral gavage. Survival incidence was similar across treatment groups and no increase in neoplastic lesions was noted, indicating that levomilnacipran is not carcinogenic.

Reproductive and Developmental Toxicology:

Impairment of Fertility

The potential effects of levomilnacipran on gonadal function, mating behavior, reproductive performance and early pregnancy were evaluated in rats at oral doses of 0, 10, 30, or 100 mg/kg/day. The NOAEL was 100 mg/kg/day based on reductions in body weight gain and food consumption. There were no levomilnacipran effects on male and female fertility parameters.

Teratogenic Effects

The potential effects of levomilnacipran on embryo/fetal development were evaluated in rats and rabbits at oral doses on 0, 10, 30 or 100 mg/kg/day.

In the rat and rabbit embryo/fetal development studies, decreases in maternal body weight gain and food consumption were noted. In the fetuses, increases in the incidence of ossification anomalies were noted but were of no toxicological significance. In both species, the NOAEL was determined to be 100 mg/kg/day, a dose which represents a rat or rabbit animal-to-human exposure margin of 9-fold and 4-fold, respectively relative to the human exposure from 120 mg/day of levomilnacipran.

When levomilnacipran was administered to pregnant rats at an oral dose of 60 mg/kg/day, 5 times the MRHD, during organogenesis and throughout pregnancy and lactation, there was an increase in early postnatal pup mortality; no pup mortality was seen at 20 mg/kg/day, 1.6 times the MRHD on a mg/m² basis. Among the surviving pups, pre- and post-weaning pup weight gain was reduced up to at least 8 weeks of age; however, physical and functional development, including reproductive performance of the progeny, was not affected. The effects on body weight gain were not seen at 7 mg/kg/day, 0.6 times the MRHD on a mg/m² basis.