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APO-LEVOMILNACIPRAN is a brand name for Levomilnacipran, supplied as a capsule (extended release). The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: APO-LEVOMILNACIPRAN (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 levomilnacipran extended release capsules in…
Verbatim from this product's HC label. Tap a section to expand.
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 APO-LEVOMILNACIPRAN.
Conversely, at least 14 days should be allowed after stopping APO-LEVOMILNACIPRAN before starting an MAOI antidepressant. 4 Drug-Drug Interactions. • Use of APO-LEVOMILNACIPRAN with Other Drugs that Inhibit Monoamine Oxidase such as Linezolid or Methylene Blue Do not start APO-LEVOMILNACIPRAN 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. 4 Drug-Drug Interactions and 7 WARNINGS AND PRECAUTIONS, Serotonin toxicity / serotonin syndrome.
In some cases, a patient already receiving APO-LEVOMILNACIPRAN 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, APO- LEVOMILNACIPRAN 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 APO- APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 6 of 53 LEVOMILNACIPRAN 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 APO-LEVOMILNACIPRAN is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
See 7 WARNINGS AND PRECAUTIONS, Serotonin toxicity / serotonin syndrome. 2 Recommended Dose and Dosage Adjustment Initiating Treatment Adults: The recommended dose range for APO-LEVOMILNACIPRAN is 40 mg to 120 mg once daily. APO-LEVOMILNACIPRAN should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily.
1 Adverse Reaction Overview The safety of levomilnacipran extended release capsules was evaluated in 3317 patients (18 to 78 years of age) diagnosed with MDD who participated in clinical studies. Among the 3317 levomilnacipran extended release capsules-treated patients, 1,583 were exposed to levomilnacipran extended release capsules in short-term, placebo-controlled studies.
A total of 895 patients were exposed to levomilnacipran extended release capsules for at least 6 months and 367 were exposed for one year. In these studies, levomilnacipran extended release capsules was given at doses ranging from 40 to 120 mg once daily and was given without regard to food.
The most commonly observed adverse events in levomilnacipran extended release capsules -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 levomilnacipran extended release capsules (40 to 120 mg) discontinued treatment due to an adverse event, compared with 3% of the 1,040 placebo- treated patients in those studies.
5%). Blood Pressure and Heart Rate In placebo-controlled clinical studies for change from baseline to endpoint, levomilnacipran extended release capsules treatment was associated with mean increases in blood pressure and heart rate.
See 7 WARNINGS AND PRECAUTIONS, Cardiovascular. The most commonly reported cardiovascular adverse events among levomilnacipran extended release capsules- treated patients in the short-term clinical studies included heart rate increased, tachycardia, palpitations, hypertension, hypotension, and blood pressure increased (see Table 3).
3 Pediatrics. 2 Geriatrics Caution should be exercised in treating the elderly. Clinical studies of levomilnacipran extended release capsules 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. 4 Geriatrics. 2 CONTRAINDICATIONS • Hypersensitivity: APO-LEVOMILNACIPRAN 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): APO- LEVOMILNACIPRAN 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 APO-LEVOMILNACIPRAN 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.
4 Drug-Drug Interactions. • Cardiovascular: APO-LEVOMILNACIPRAN should not be used in patients with: APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 5 of 53 • 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 Serious Warnings and Precautions Increased risk of self-harm, harm to others, suicidal thinking and behavior with antidepressants use.
• Hypersensitivity: APO-LEVOMILNACIPRAN 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): APO- LEVOMILNACIPRAN 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 APO-LEVOMILNACIPRAN 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.
4 Drug-Drug Interactions. • Cardiovascular: APO-LEVOMILNACIPRAN should not be used in patients with: APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 5 of 53 • 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
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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 levomilnacipran extended release capsules 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 APO-LEVOMILNACIPRAN 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. 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 to 89 mL/min). For patients with moderate renal impairment (creatinine clearance of 30 to 59 mL/min), the dose should not exceed 80 mg/day.
For patients with more severe renal impairment (creatinine clearance of 15 to 29 mL/min) the dose should not exceed 40 mg/day. 3 Pharmacokinetics. APO-LEVOMILNACIPRAN 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. 3 Pharmacokinetics. APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 7 of 53 In a multiple-dose clinical pharmacokinetic study, elderly subjects (> 65 years) had a slightly higher exposure (Cmax by 24% and AUC by 26%) of levomilnacipran than younger subjects (18 to 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. 3 Pediatrics.
Sex:
No dose adjustment is required based on sex. 3 Pharmacokinetics. Discontinuing Treatment Discontinuation symptoms have been reported with discontinuation of serotonergic drugs such as levomilnacipran extended release capsules. Gradual dose reduction is recommended, instead of abrupt discontinuation, whenever possible.
Monitor patients for these symptoms when discontinuing APO-LEVOMILNACIPRAN. 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 7 WARNINGS AND PRECAUTIONS, Discontinuation Symptoms. 4 Administration APO-LEVOMILNACIPRAN should be taken at approximately the same time each day. APO- LEVOMILNACIPRAN should be swallowed whole. Do not open, chew or crush the capsule.
APO-LEVOMILNACIPRAN can be taken with or without food. 5 Drug-Food Interactions. 5 Missed Dose In the event that a dose is missed, the patient should take the missed dose as soon as […]
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 APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 20 of 53 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 levomilnacipran extended release capsules-treated MDD patients (and greater than placebo-treated patients) in the short-term, placebo-controlled studies.
Table 3 - Adverse Events Occurring in ≥ 2% of levomilnacipran extended release capsules- Treated Patients and Greater than Placebo Treated Patients in Five, Short-term, Phase 3 Placebo-Controlled Studies Levomilnacipran extended release capsules 40-120 mg/day N = 1583 (%) Placebo N = 1040 (%) Gastrointestinal disorders Nausea Dry mouth Constipation Vomiting Abdominal Pain 17 10 9 5 5 6 7 3 1 3 Nervous system disorders Headachea Dizziness 17 8 14 5 Skin and subcutaneous tissue disorders Hyperhidrosis Rash 9 2 2 <1 Cardiac disorders Tachycardiaa Palpitations 6 5 2 1 Reproductive system and breast disordersb Erectile dysfunctionb Testicular painb Ejaculation disorderb 6 4 5 1 <1 <1 Investigations Heart rate increaseda Blood pressure increaseda 6 3 1 1 Psychiatric disorders Insomniaa Anxiety 6 2 4 1 Infections and infestations Upper respiratory tract infectiona Nasopharyngitis 5 4 4 3 APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 21 of 53 Levomilnacipran extended release capsules 40-120 mg/day N = 1583 (%) Placebo N = 1040 (%) Renal and urinary disorders Urinary hesitation 4 0 Vascular disorders Hot flush Hypertensiona Hypotension 3 3 3 1 1 1 Metabolism and nutrition disorders Decreased appetite 3 1 a Similar adverse event terms were grouped together b Percentage is relative to the number of patients in the associated demographic sex category.
N = number of patients in the Safety Population 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 levomilnacipran extended release capsules across the dose range 40 to 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 Levomilnacipran extended release capsules Placebo N = 362 (%) 40 mg/day N = 366 (%) 80 mg/day N = 367 (%) 120 mg/day N = 180 (%) Urinary hesitation 4 5 6 0 Erectile dysfunctiona 6 8 10 2 a Percentage is relative to the number of patients in the associated demographic sex category.
N = number of patients in the Safety Population 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 levomilnacipran extended release capsules-treated patients in placebo controlled short- term studies.
APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 22 of 53 Table 5 - Adverse Events Associated With Sexual Dysfunction by Sex in Five, Short-term Phase 3 Placebo-Controlled Studies Male Female Preferred Terma Levomilnacipran extended release capsules 40-120 mg/day N = 577 (%) Placebo N = 374 (%) […]
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.
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 APO-LEVOMILNACIPRAN.
Conversely, at least 14 days should be allowed after stopping APO-LEVOMILNACIPRAN before starting an MAOI antidepressant. 4 Drug-Drug Interactions. • Use of APO-LEVOMILNACIPRAN with Other Drugs that Inhibit Monoamine Oxidase such as Linezolid or Methylene Blue Do not start APO-LEVOMILNACIPRAN 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. 4 Drug-Drug Interactions and 7 WARNINGS AND PRECAUTIONS, Serotonin toxicity / serotonin syndrome.
In some cases, a patient already receiving APO-LEVOMILNACIPRAN 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, APO- LEVOMILNACIPRAN 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 APO- APO-LEVOMILNACIPRAN (levomilnacipran extended release capsules) Page 6 of 53 LEVOMILNACIPRAN 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 APO-LEVOMILNACIPRAN is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
See 7 WARNINGS AND PRECAUTIONS, Serotonin toxicity / serotonin syndrome. 2 Recommended Dose and Dosage Adjustment Initiating Treatment Adults: The recommended dose range for APO-LEVOMILNACIPRAN is 40 mg to 120 mg once daily. APO-LEVOMILNACIPRAN should be initiated at 20 mg once daily for 2 days and then increased to 40 mg once daily.
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 levomilnacipran extended release capsules for up to 26 weeks, following response during 20 weeks of acute, open-label treatment, was established in a placebo-controlled trial. […]