MIRTAZAPINE Drug Interactions: What You Need to Know

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with mirtazapine tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for mirtazapine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking mirtazapine tablets.

Clinical

Worsening and Suicide Risk 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 behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Agranulocytosis

Patients who are to receive mirtazapine tablets should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration, or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection. Interference with Cognitive and Motor Performance Mirtazapine tablets may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient’s ability to drive, use machines, or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that mirtazapine tablet therapy does not adversely affect their ability to engage in such activities.

Completing

Course of Therapy While patients may notice improvement with mirtazapine tablet therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Concomitant Medication

Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs, since there is a potential for mirtazapine tablets to interact with other drugs. Patients should be made aware of a potential increased risk for serotonin syndrome if concomitant use of mirtazapine tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's wort, is clinically warranted, particularly during treatment initiation and dose increases.

Alcohol

The impairment of cognitive and motor skills produced by mirtazapine tablets has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during mirtazapine tablets therapy.

Nursing

Patients should be advised to notify their physician if they are breastfeeding an infant.

Laboratory Tests

There are no routine laboratory tests recommended.

Drug

Interactions As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY).

Monoamine Oxidase

Inhibitors (See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .)

Serotonergic

Drugs (See CONTRAINDICATIONS and WARNINGS .)

Drugs Affecting Hepatic Metabolism

The metabolism and pharmacokinetics of mirtazapine tablets may be affected by the induction or inhibition of drug-metabolizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes CYP Enzyme Inducers (these studies used both drugs at steady state) Phenytoin : In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. Carbamazepine : In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%. When phenytoin, carbamazepine, or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.

Cyp

Enzyme Inhibitors Cimetidine : In healthy male patients (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%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued. Ketoconazole: In healthy, male, Caucasian patients (n=24), coadministration of the potent 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. Caution should be exercised when coadministering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or nefazodone. Paroxetine : In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (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.

Other

Drug-drug Interactions Amitriptyline In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes in the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. Warfarin In healthy male subjects (n=16), mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalized Ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine, a more pronounced effect can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine. Lithium No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of 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 In an in vivo , nonrandomized, interaction study, subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg b.i.d.).

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 tablets were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine tablets.

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 tablets has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking mirtazapine tablets. 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 case of mirtazapine overdose (see ADVERSE REACTIONS and OVERDOSE sections).

Mirtazapine orally disintegrating tablets are contraindicated in patients:

• Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3) , Drug Interactions (7) ].
• With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine orally disintegrating tablets. Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine orally disintegrating tablets [see Warnings and Precautions (5.6) , Adverse Reactions (6.2) ].
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs. ( 2.4 , 4 , 7 )
• Known hypersensitivity to mirtazapine or any of the excipients in mirtazapine orally disintegrating tablets. ( 4 )

AND PRECAUTIONS Agranulocytosis : If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with mirtazapine orally disintegrating tablets should be discontinued and the patient should be closely monitored. ( 5.2 )

Serotonin

Syndrome : Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue mirtazapine orally disintegrating tablets and initiate supportive treatment. ( 2.4 , 4 , 5.3 , 7 ) Angle-Closure Glaucoma : Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.4 ) QT Prolongation : Use mirtazapine orally disintegrating tablets with caution in patients with risk factors for QT prolongation. ( 5.5 , 7 )

Drug

Reaction with Eosinophilia and System Symptoms (DRESS): Discontinue mirtazapine orally disintegrating tablets if DRESS is suspected. ( 5.6 )

Increased Appetite/Weight

Gain : Mirtazapine orally disintegrating tablets have been associated with increased appetite and weight gain. ( 5.7 ) Somnolence : May impair judgment, thinking and/or motor skills. Use with caution when engaging in activities requiring alertness, such as driving or operating machinery. ( 5.8 , 7 ) Activation of Mania/Hypomania : Screen patients for bipolar disorder prior to initiating treatment. ( 2.3 , 5.9 ) Seizures : Use with caution in patients with a seizure disorder. ( 5.10 )

Elevated

Cholesterol/Triglycerides : Has been reported with mirtazapine use. ( 5.11 ) Hyponatremia : May occur as a result of treatment with serotonergic antidepressants, including mirtazapine orally disintegrating tablets. ( 5.12 )

Transaminase

Elevations : Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. ( 5.13 )

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Table

1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing mirtazapine orally disintegrating tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren&apos;s Syndrome) out of 2796 patients treated with mirtazapine developed agranulocytosis [absolute neutrophil count (ANC) &lt;500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC &lt;500/mm 3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively.

All

3 patients recovered after mirtazapine was stopped. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low white blood cell (WBC) count, treatment with mirtazapine orally disintegrating tablets should be discontinued and the patient should be closely monitored.

5.3 Serotonin Syndrome Serotonergic antidepressants, including mirtazapine orally disintegrating tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John&apos;s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications (4) , Drug Interactions (7) ]</span> . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of mirtazapine orally disintegrating tablets with MAOIs is contraindicated. In addition, do not initiate mirtazapine orally disintegrating tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking mirtazapine orally disintegrating tablets, discontinue mirtazapine orally disintegrating tablets before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4) , Drug Interactions (7) ]</span>. Monitor all patients taking mirtazapine orally disintegrating tablets for the emergence of serotonin syndrome. Discontinue treatment with mirtazapine orally disintegrating tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of mirtazapine orally disintegrating tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.4 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including mirtazapine orally disintegrating tablets, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.5 QT Prolongation and Torsades de Pointes The effect of mirtazapine on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45 mg and 75 mg (1.67 times the maximum recommended daily dose) doses of mirtazapine was not at a level generally considered to be clinically meaningful. During postmarketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death, have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 , 6.2 )]</span> . The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc-prolonging medicines <span class="opacity-50 text-xs">[see Drug Interactions (7) and Overdosage (10) ]</span> . Exercise caution when mirtazapine orally disintegrating tablets are prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other drugs thought to prolong the QTc interval.

5.6 Drug Reaction with Eosinophilia and System Symptoms (DRESS)

Drug

Reaction with eosinophilia and systemic symptoms (DRESS) has been reported with postmarketing use of mirtazapine. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue mirtazapine orally disintegrating tablets immediately if DRESS is suspected and institute appropriate treatment [see Contraindications (4) , Adverse Reactions (6.2) ].

5.7 Increased Appetite and Weight Gain In U.S. controlled clinical studies, appetite increase was reported in 17% of patients treated with mirtazapine, compared to 2% for placebo. In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo. In a pool of premarketing U.S. clinical studies, including many patients for long-term, open-label treatment, 8% of patients receiving mirtazapine discontinued for weight gain. In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated pediatric patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The safety and effectiveness of mirtazapine orally disintegrating tablets in pediatric patients with MDD have not been established <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> .

5.8 Somnolence In U.S. controlled studies, somnolence was reported in 54% of patients treated with mirtazapine, compared to 18% for placebo. In these studies, somnolence resulted in discontinuation for 10.4% of mirtazapine-treated patients, compared to 2.2% for placebo. It is unclear whether tolerance develops to the somnolent effect of mirtazapine orally disintegrating tablets. Because of the potentially significant effects of mirtazapine orally disintegrating tablets on impairment of performance, caution patients about engaging in activities that require alertness, including operating hazardous machinery and motor vehicles, until they are reasonably certain that mirtazapine orally disintegrating tablets does not affect them adversely. The concomitant use of benzodiazepines and alcohol with mirtazapine orally disintegrating tablets should be avoided <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> .

5.9 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with mirtazapine orally disintegrating tablets or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.2% of patients treated with mirtazapine. Prior to initiating treatment with mirtazapine orally disintegrating tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.10 Seizures Mirtazapine orally disintegrating tablets have not been systematically evaluated in patients with seizure disorders. In premarketing clinical trials, 1 seizure was reported among the 2796 U.S. and non-U.S. patients treated with mirtazapine. Mirtazapine orally disintegrating tablets should be prescribed with caution in patients with a seizure disorder.

5.11 Elevated Cholesterol and Triglycerides In U.S. controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine, compared to 7% for placebo. In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo.

5.12 Hyponatremia Hyponatremia may occur as a result of treatment with serotonergic antidepressants, including mirtazapine orally disintegrating tablets. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue mirtazapine orally disintegrating tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span> .

5.13 Transaminase Elevations Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with mirtazapine in a pool of short-term, U.S. controlled trials, compared to 0.3% (1/328) of placebo patients. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. Mirtazapine orally disintegrating tablets should be used with caution in patients with impaired hepatic function <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]</span> .

5.14 Discontinuation Syndrome There have been reports of adverse reactions upon the discontinuation of mirtazapine orally disintegrating tablets (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance. A gradual reduction in the dosage, rather than an abrupt cessation, is recommended <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span>.

5.15 Use in Patients with Concomitant Illness Mirtazapine orally disintegrating tablets have not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Mirtazapine orally disintegrating tablets should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).

5.16 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). Mirtazapine orally disintegrating tablets contain phenylalanine, a component of aspartame. Mirtazapine orally disintegrating tablets contain the following amount of phenylalanine: 3.22 mg per 15 mg orally disintegrating tablet, 6.44 mg per 30 mg orally disintegrating tablet, and 9.66 mg per 45 mg orally disintegrating tablet. Before prescribing mirtazapine orally disintegrating tablets to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including mirtazapine orally disintegrating tablets.