Mirtazapine (Page 7 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and
200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are
approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day,
based on body surface area (mg/m2) in mice and rats, respectively. There was an increased
incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there
was an increase in hepatocellular adenoma in females at the mid and high doses and in
hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the
high dose.
Mutagenesis
Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as
determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese
hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo
bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells.
Impairment of Fertility
In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [20 times the maximum
recommended human dose (MRHD), based on body surface area (mg/m2)]. Mating and conception
were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more
times the MRHD, and pre-implantation losses occurred at 20 times the MRHD.

14 CLINICAL STUDIES

The efficacy of mirtazapine tablets as a treatment for major depressive disorder was established in
4 placebo- controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major
depressive disorder. Patients were titrated with mirtazapine tablets from a dose range of 5 mg to
35 mg/day. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21
to 32 mg/day. Overall, these studies demonstrated mirtazapine tablets to be superior to placebo on
at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total
score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression
Rating Scale (MADRS). Superiority of mirtazapine tablets over placebo was also found for certain
factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor.
Examination of age and gender subsets of the population did not reveal any differential
responsiveness on the basis of these subgroupings.
In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had
responded during an initial 8 to 12 weeks of acute treatment on mirtazapine tablets were
randomized to continuation of mirtazapine tablets or placebo for up to 40 weeks of observation for
relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score
of
≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8
to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was
determined by the individual investigators. Patients receiving continued mirtazapine tablets
treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to
those receiving placebo. This pattern was demonstrated in both male and female patients.

16 HOW SUPPLIED/STORAGE AND HANDLING

Mirtazapine tablets are supplied as:
Mirtazapine Tablets, USP 15 mg are available for oral administration as pale yellow, oval-shaped,
scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “15” on the other side.
They are supplied as follows:
Boxes of 10×10 UD 100 count NDC 63739-098-10
Mirtazapine Tablets, USP 30 mg are available for oral administration as light pink, oval-shaped,
scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “30” on the other side.
They are supplied as follows:
Boxes of 10×10 UD 100 count NDC 63739-099-10
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see
USP Controlled Room Temperature]. Protect from light and moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts and Behaviors
Advise patients and caregivers to look for the emergence of suicidality, especially early during
treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms
to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].
Agranulocytosis
Advise patients to contact their physician if they experience fever, chills, sore throat, mucous
membrane ulceration, flu-like complaints, or other symptoms that might suggest infection [see
Warnings and Precautions (5.2)].
Serotonin Syndrome
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of
mirtazapine tablets with other serotonergic drugs including triptans, tricyclic antidepressants,
fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs
that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric
disorders and also others, such as linezolid). Advise patients to contact their healthcare provider or
report to the emergency room if they experience signs or symptoms of serotonin syndrome [see
Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3), Drug
Interactions (7)].

QT Prolongation and Torsades de Pointes
Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have
heart palpitations [see Warnings and Precautions (5.5), Drug Interactions (7), Overdosage (10)].
Advise patients to inform physicians that they are taking mirtazapine tablets before any new drug is
taken.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
Advise patients to report to their healthcare provider at the earliest onset of fever, rash, swollen
lymph nodes, or other signs and symptoms suggestive of Drug Reaction with Eosinophilia and
Systemic Symptoms (DRESS) [see Contraindications (4), Warnings and Precautions (5.6)].
Somnolence
Advise patients that mirtazapine tablets may impair judgment, thinking, and particularly, motor
skills, because of its prominent sedative effect. Caution patients about performing activities
requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle,
until they are reasonably certain that mirtazapine tablets therapy does not adversely affect their
ability to engage in such activities. [see Warnings and Precautions (5.7)].
Alcohol
Advise patients to avoid alcohol while taking mirtazapine tablets [see Warnings and Precautions
(5.7), Drug Interactions (7)].
Activation of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania and
instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions
(5.8)].

Discontinuation Syndrome
Advise patients not to abruptly discontinue mirtazapine tablets and to discuss any tapering regimen
with their healthcare provider. Adverse reactions can occur when mirtazapine tablets are
discontinued [see Dosage and Administration (2.6), Warnings and Precautions (5.13)].
Allergic Reactions
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash,
hives, swelling, or difficulty breathing [see Contraindications (4), Adverse Reactions (6.2)].
Pregnancy
• Advise patients to notify their physician if they become pregnant or intend to become pregnant
during mirtazapine tablets therapy.
• Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes
in women exposed to mirtazapine tablets during pregnancy [see Use in Specific Populations
(8.2)].
Lactation
Advise patients to notify their physician if they are breastfeeding an infant [see Use in Specific
Populations (8.2)].

Angle-Closure Glaucoma
Patients should be advised that taking mirtazapine can cause mild pupillary dilation, which in
susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is
almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be
treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure
glaucoma. Patients may wish to be examined to determine whether they are susceptible to
angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see
Warnings and Precautions (5.4).]

Dispense with Medication Guide available at www1.apotex.com/products/us

Distributed By:
McKesson Corporation dba SKY Packaging
Memphis, TN 38141


Manufactured by:
Apotex Inc
Toronto, Ontario
Canada M9L 1T9


Revised: May 2022
21495-1

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.