Mirtazapine: Package Insert and Label Information (Page 4 of 5)

12.3 Pharmacokinetics

Plasma levels of mirtazapine are linearly related to dose over a dose range of 15 to 80 mg (1.78 times the maximum recommended dose). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio=1.5). The (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer.

Absorption

Mirtazapine has an absolute bioavailability of about 50% following oral administration. Peak plasma concentrations of mirtazapine are reached within about 2 hours post dose.

Food Effect

The presence of food in the stomach has a minimal effect on both the rate and extent of absorption.

Distribution

Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/mL.

Elimination

Mirtazapine has a half-life of about 20 to 40 hours following oral administration of mirtazapine.

Metabolism

Mirtazapine is extensively metabolized after oral administration. Major pathways of bio-transformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels.

Excretion

Mirtazapine and its metabolites are eliminated predominantly (75%) via urine with 15% in feces.

Specific Populations

Geriatric Patients

Following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range 25 to 74 years old), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The clearance in elderly males was 40% lower compared to younger males, while the clearance was 10% lower in elderly females compared to younger females [see Warnings and Precautions (5.15), Use in Specific Populations (8.5)].

Male and Female Patients

The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males).

Race

There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine.

Patients with Renal Impairment

When compared to subjects with normal renal function, total body clearance of mirtazapine was reduced approximately 30% in renal impaired patients with GFR=11 to 39 mL/min/1.73 m² and approximately 50% in renal impaired patients with GFR=<10 mL/min/1.73 m²) [see Warnings and Precautions (5.15), Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Following a single 15 mg oral dose of mirtazapine, the oral clearance of mirtazapine in patients with hepatic impairment was decreased by approximately 30%, compared to subjects with normal hepatic function [see Warnings and Precautions (5.13, 5.15), Use in Specific Populations (8.6)].

Drug Interactions Studies

Warfarin

Mirtazapine (30 mg daily) at steady state caused a statistically significant increase (0.2) in the International Normalized Ratio (INR) in subjects treated with warfarin [see Drug Interactions (7)].

QTc-Prolonging Drugs

The risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g., some antipsychotics and antibiotics) and in mirtazapine overdose [see Warnings and Precautions (5.5), Adverse Reactions (6.1, 6.2), Drug Interactions (7), and Overdosage (10)].

Phenytoin

In healthy male subjects (n=18), phenytoin (200 mg daily, at steady state) increased mirtazapine (30 mg daily, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45% [see Drug Interactions (7)]. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin.

Carbamazepine

In healthy male subjects (n=24), carbamazepine (400 mg twice a day, at steady state) increased mirtazapine (15 mg twice a day, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60% [see Drug Interactions (7)].

Cimetidine

In healthy male subjects (n=12), when cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50% [see Drug Interactions (7)]. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine.

Ketoconazole

In healthy male Caucasian subjects (n=24), coadministration of the strong CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30 mg dose of mirtazapine by approximately 40% and 50%, respectively [see Drug Interactions (7)].

Amitriptyline

In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes to the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline.

Paroxetine

In healthy CYP2D6 extensive metabolizer subjects (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor.

Lithium

No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with lithium 600 mg/day for 10 days at steady state and a single 30 mg dose of mirtazapine. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown.

Risperidone

Mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg twice a day) in subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug.

Alcohol

Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol.

Diazepam

Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by mirtazapine has been shown to be additive with those caused by diazepam.

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 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 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 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 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 were randomized to continuation of mirtazapine 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 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

Product: 50090-2558

NDC: 50090-2558-2 60 TABLET, FILM COATED in a BOTTLE

NDC: 50090-2558-3 90 TABLET, FILM COATED in a BOTTLE

NDC: 50090-2558-0 30 TABLET, FILM COATED in a BOTTLE

Product: 50090-2800

NDC: 50090-2800-1 90 TABLET, FILM COATED in a BOTTLE

NDC: 50090-2800-0 30 TABLET, FILM COATED in a BOTTLE

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 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 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 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 therapy does not adversely affect their ability to engage in such activities. [see Warnings and Precautions (5.8)].

Alcohol

Advise patients to avoid alcohol while taking mirtazapine [see Warnings and Precautions (5.8), 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 (5.9)].

Discontinuation Syndrome

Advise patients not to abruptly discontinue mirtazapine and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when mirtazapine is discontinued [see Dosage and Administration (2.6), Warnings and Precautions (5.14)].

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 therapy.
• Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mirtazapine during pregnancy [see Use in Specific Populations (8.1)].

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).]

For more information about mirtazapine tablets, call Rising Health, LLC at 1-833-395-6928.

Dispense with medication guide available at : http://www.risingpharma.com/med-guides.html

Distributed by:
Rising Health, LLC
Saddle Brook, NJ 07663

Made in India
Code: TS/DRUGS/19/1993
Revised: 02/2022

MEDICATION GUIDE Mirtazapine Tablets, USP for oral use (mir taz’ a peen)

What is the most important information I should know about mirtazapine tablets? Mirtazapine tablets may cause serious side effects, including: Increased risk of suicidal thoughts or actions in some children and young adults. Mirtazapine tablets, and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. Mirtazapine tablets are not for use in children. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions? Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider or get emergency medical help right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive, being angry or violent thoughts about suicide or dying new or worse depression new or worse anxiety panic attacks feeling very agitated or restless new or worse irritability trouble sleeping an extreme increase in activity or talking (mania) other unusual changes in behavior or mood

What are mirtazapine tablets? Mirtazapine tablets are prescription medicines used to treat a certain type of depression called Major Depressive Disorder (MDD) in adults.It is not known if mirtazapine tablets are safe and effective for use to treat MDD in children.

Who should not take mirtazapine tablets? Do not take mirtazapine tablets if you: take a Monoamine Oxidase Inhibitor (MAOI) have stopped taking an MAOI in the last 14 days are being treated with the antibiotic linezolid or intravenous methylene blue if you are allergic to mirtazapine or any of the ingredients in mirtazapine tablets. See the end of this Medication Guide for a complete list of ingredients in mirtazapine tablets. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue.Do not start taking an MAOI for at least 14 days after you stop treatment with mirtazapine tablets.

Before taking mirtazapine tablets, tell your healthcare provider about all your medical conditions, including if you: have a history of suicide or depression have a history or family history of bipolar disorder, mania or hypomania have a low white blood cell count have glaucoma (high pressure in the eye) have or had heart problems or stroke have an abnormal heart beat called QT prolongation or a family history of QT prolongation have seizures have high cholesterol or triglyceride levels have low sodium levels in your blood have or had kidney or liver problems have low blood pressure are pregnant or plan to become pregnant. It is not known if mirtazapine tablets will harm your unborn baby. Talk to your healthcare provider if you become pregnant or think you may be pregnant during treatment with mirtazapine tablets. If you become pregnant while taking mirtazapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1­-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants/. The purpose of this registry is to monitor the pregnancy outcomes in women who have been treated with mirtazapine at any time during pregnancy. are breastfeeding or plan to breastfeed. Mirtazapine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with mirtazapine tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Mirtazapine tablets and other medicines may affect each other causing possible serious side effects. Mirtazapine tablets may affect the way other medicines work and other medicines may affect the way mirtazapine tablets work.Especially tell your healthcare provider if you take: MAOIs medicines to treat migraine headaches known as triptans tricyclic antidepressants fentanyl lithium tramadol tryptophan buspirone amphetamines benzodiazepines St. John’s Wort medicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) medicines that may affect your heart rhythm (such as certain antibiotics and some antipsychotics) Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take mirtazapine tablets with your other medicines.Do not start or stop any other medicines during treatment with mirtazapine tablets without talking to your healthcare provider first. Stopping mirtazapine tablets suddenly may cause you to have serious side effects. See, “What are the possible side effects of mirtazapine tablets?” Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How should I take mirtazapine tablets? Take mirtazapine tablets exactly as your healthcare provider tells you to. Do not change your dose or stop taking mirtazapine tablets without first talking to your healthcare provider. Your healthcare provider may need to change the dose of mirtazapine tablets until it is the right dose for you. Take mirtazapine tablets 1 time each day, preferably in the evening at bedtime. If you take too much mirtazapine call your healthcare provider or poison control center at 1-800-222-1222 right away or go to the nearest hospital emergency room.

What should I avoid while taking mirtazapine tablets? Do not drive, operate heavy machinery, or do other dangerous activities until you know how mirtazapine tablets affects you. Mirtazapine tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. Avoid drinking alcohol during treatment with mirtazapine tablets. Avoid taking medicines used to treat anxiety, insomnia, and seizures, called benzodiazepines, during treatment with mirtazapine tablets. Ask your healthcare provider if you are not sure if you take one of these medicines.

What are the possible side effects of mirtazapine tablets? Mirtazapine tablets may cause serious side effects, including: See, “What is the most important information I should know about mirtazapine tablets?” Low white blood cell count. Tell your healthcare provider right away if you develop any signs or symptoms of a low white blood cell count, including: fever chills sore throat mouth or nose sores flu-like symptoms infections Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen when you take mirtazapine tablets with certain other medicines. See, “Who should not take mirtazapine tablets?” Stop taking mirtazapine tablets and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome: agitation seeing or hearing things that are not real (hallucinations) confusion coma fast heart beat blood pressure changes dizziness sweating flushing high body temperature (hyperthermia) tremors, stiff muscles, or muscle twitching loss of coordination seizures nausea, vomiting, diarrhea Eye problems (angle-closure glaucoma). Mirtazapine tablets may cause a certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Heart rhythm problems. Severe skin reaction. Mirtazapine tablets may cause a severe skin reaction that may include rash, fever, swollen glands, and other organ involvement such as liver, kidney, lung and heart. The reaction may sometimes be fatal. Tell your healthcare provider right away if you experience any of these signs. Increased appetite and weight gain. Sleepiness. See, “What should I avoid while taking mirtazapine tablets?” Mania or hypomania (manic episodes) in people who have a history of bipolar disorder. Symptoms may include: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual Seizures (convulsions). Increased fat levels (cholesterol and triglycerides) in your blood. Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood may be serious and may cause death. Elderly people may be at greater risk for this. Signs and Symptoms of low sodium levels in your blood may include: headache difficulty concentrating memory changes confusion weakness and unsteadiness on your feet which can lead to falls In severe or more sudden cases, signs and symptoms include: hallucinations (seeing or hearing things that are not real) fainting seizures coma respiratory arrest death Changes in liver function tests. Discontinuation syndrome. Suddenly stopping mirtazapine tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include: dizziness nausea and vomiting headache irritability and agitation problems sleeping abnormal dreams anxiety tiredness changes in your mood sweating confusion hypomania seizures electric shock sensation (paresthesia) ringing in your ears (tinnitus) shaking (tremor) The most common side effects of mirtazapine tablets include: sleepiness increased appetite weight gain dizziness These are not all the possible side effects of mirtazapine tablets.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store mirtazapine tablets? Store mirtazapine tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Keep mirtazapine tablets away from light and moisture. Keep mirtazapine tablets, and all medicines out of the reach of children.

General information about the safe and effective use of mirtazapine tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use mirtazapine tablets for a condition for which it was not prescribed. Do not give mirtazapine tablets to other people, even if they have the same symptoms that you have. They may harm them. You can ask your healthcare provider or pharmacist for information about mirtazapine tablets that is written for healthcare professionals.

What are the ingredients in mirtazapine tablets? Active ingredient: mirtazapineInactive ingredients: colloidal silicon dioxide, corn starch, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, and titanium dioxide. In addition, the 15 mg contains iron oxide yellow and 30 mg contains iron oxide red, iron oxide black, and iron oxide yellow.For more information about mirtazapine tablets, call Rising Health, LLC at 1-833-395-6928.Dispense with medication guide available at: http://www.risingpharma.com/med-guides.html Distributed by: Rising Health, LLC Saddle Brook, NJ 07663 Made in India Code: TS/DRUGS/19/1993

This Medication Guide has been approved by the U.S. Food and Drug Administration

Revised: 02/2022