Componenti:
Metodo di azione:
Opzione di trattamento:
Revisione medica di Fedorchenko Olga Valeryevna, Pharmacy Ultimo aggiornamento in data 13.03.2022
Attenzione! Le informazioni sulla pagina sono solo per gli operatori sanitari! Le informazioni sono raccolte in fonti pubbliche e possono contenere errori significativi! Fare attenzione e ricontrollare tutte le informazioni da questa pagina!
Primi 20 medicinali con gli stessi componenti:
I 20 migliori farmaci con gli stessi trattamenti:
PMS-Mirtazapina (mirtazapina) Le compresse sono indicate per il trattamento del disturbo depressivo maggiore.
L'efficacia di PMS-Mirtazapina nel trattamento del disturbo depressivo maggiore è stata stabilita in studi controllati di 6 settimane su pazienti ambulatoriali le cui diagnosi corrispondevano più da vicino al Manuale diagnostico e statistico dei disturbi mentali - categoria di depressivi maggiori della terza edizione (DSM-III) (vedi FARMACOLOGIA CLINICA).
Un episodio depressivo maggiore (DSM-IV) implica un prominente e relativamente persistente (quasi ogni giorno per almeno 2 settimane) umore depresso o disforico che di solito interferisce con il funzionamento quotidiano, e comprende almeno 5 dei seguenti 9 sintomi: umore depresso, perdita di interesse nelle normali attività, cambiamento significativo di peso e / o appetito, insonnia o ipersonnia, agitazione o ritardo psicomotorio, aumento della fatica, sentimenti di colpa o inutilità, pensiero rallentato o concentrazione compromessa, un tentativo di suicidio, o idea suicidaria.
L'efficacia della sindrome premestruale nei pazienti depressi ospedalizzati non è stata adeguatamente studiata.
L'efficacia di PMS-Mirtazapina nel mantenere una risposta nei pazienti con disturbo depressivo maggiore fino a 40 settimane dopo 8-12 settimane di trattamento iniziale in aperto è stata dimostrata in uno studio rannicchiato. Tuttavia, il medico che sceglie di usare PMS-Mirtazapina per lunghi periodi dovrebbe rivalutare periodicamente l'utilità a lungo termine del farmaco per il singolo paziente (vedere FARMACOLOGIA CLINICA).
REMERONSolTab® (mirtazapina) Le compresse per la disintegrazione orale sono indicate per il trattamento del disturbo depressivo maggiore.
L'efficacia delle compresse di REMERON® (mirtazapina) nel trattamento del disturbo depressivo maggiore è stata stabilita in studi controllati di sei settimane su pazienti ambulatoriali le cui diagnosi corrispondevano più da vicino al Manuale diagnostico e statistico dei disturbi mentali - Categoria 3a edizione (DSM-III) di disturbo depressivo maggiore (vedi FARMACOLOGIA CLINICA).
Un episodio depressivo maggiore (DSM-IV) implica un prominente e relativamente persistente (quasi ogni giorno per almeno 2 settimane) umore depresso o disforico che di solito interferisce con il funzionamento quotidiano, e comprende almeno cinque dei seguenti nove sintomi: umore depresso, perdita di interesse nelle normali attività, cambiamento significativo di peso e / o appetito, insonnia o ipersonnia, agitazione o ritardo psicomotorio, aumento della fatica, sentimenti di colpa o inutilità, pensiero rallentato o concentrazione compromessa, un tentativo di suicidio o idea suicidaria.
L'efficacia di REMERONSolTab® (mirtazapina) nei pazienti depressi ricoverati in ospedale non è stata adeguatamente studiata.
L'efficacia di REMERON® nel mantenere una risposta nei pazienti con disturbo depressivo maggiore fino a 40 settimane dopo 8-12 settimane di trattamento iniziale in aperto è stata dimostrata in uno studio controllato con placebo. Tuttavia, il medico che sceglie di utilizzare REMERON® per lunghi periodi dovrebbe rivalutare periodicamente l'utilità a lungo termine del farmaco per il singolo paziente (vedere FARMACOLOGIA CLINICA).
Trattamento iniziale
La dose iniziale raccomandata per le compresse di PMS-Mirtazapina (mirtazapina) è di 15 mg / die, somministrata in dose singola, preferibilmente la sera prima del sonno. Negli studi clinici controllati che stabiliscono l'efficacia della sindrome premestruale nel trattamento del disturbo depressivo maggiore, l'intervallo di dosi efficace era generalmente compreso tra 15 e 45 mg / die. Mentre la relazione tra dose e risposta soddisfacente nel trattamento del disturbo depressivo maggiore per la sindrome premestruale-mirtazapina non è stata adeguatamente esplorata, i pazienti che non rispondono alla dose iniziale di 15 mg possono beneficiare di aumenti della dose fino a un massimo di 45 mg / die. PMS-Mirtazapina ha un'emivita di eliminazione di circa 20-40 ore; pertanto, le variazioni della dose non devono essere apportate ad intervalli inferiori a 1-2 settimane al fine di consentire un tempo sufficiente per la valutazione della risposta terapeutica a una determinata dose.
Anziani e pazienti con compromissione renale o epatica
La clearance della mirtazapina è ridotta nei pazienti anziani e nei pazienti con insufficienza renale o epatica da moderata a grave. Di conseguenza, il medico prescrittore deve essere consapevole che i livelli plasmatici di mirtazapina possono essere aumentati in questi gruppi di pazienti, rispetto ai livelli osservati negli adulti più giovani senza insufficienza renale o epatica (vedere PRECAUZIONI e FARMACOLOGIA CLINICA).
Manutenzione / Trattamento esteso
È generalmente concordato che gli episodi acuti di depressione richiedono diversi mesi o più di terapia farmacologica prolungata oltre la risposta all'episodio acuto. Valutazione sistematica delle compresse di PMS-Mirtazapina (mirtazapina) ha dimostrato che la sua efficacia nel disturbo depressivo maggiore viene mantenuta per periodi fino a 40 settimane dopo 8-12 settimane di trattamento iniziale alla dose da 15 a 45 mg / die (vedere FARMACOLOGIA CLINICA). Sulla base di questi dati limitati, non è noto se la dose di PMS-Mirtazapina necessaria per il trattamento di mantenimento sia identica alla dose necessaria per ottenere una risposta iniziale. I pazienti devono essere periodicamente rivalutati per determinare la necessità di un trattamento di mantenimento e la dose appropriata per tale trattamento.
Passaggio di un paziente da o verso un inibitore dell'ossidasi monoaminica (MAOI) destinato a trattare i disturbi psichiatrici
Dovrebbero trascorrere almeno 14 giorni tra l'interruzione di un MAOI destinato a trattare disturbi psichiatrici e l'inizio della terapia con compresse di PMS-mirtazapina (mirtazapina). Al contrario, dovrebbero essere concessi almeno 14 giorni dopo l'arresto della sindrome premestruale-mirtazapina prima di iniziare un IMAO destinato a trattare disturbi psichiatrici (vedere CONTRAINDICAZIONI).
Uso di PMS-Mirtazapina con altri MAOI, come Linezolid o Blu di metilene
Non iniziare la PMS-Mirtazapina in un paziente in trattamento con linezolid o blu di metilene per via endovenosa perché aumenta il rischio di sindrome serotoninergica. In un paziente che richiede un trattamento più urgente di una condizione psichiatrica, devono essere considerati altri interventi, incluso il ricovero in ospedale (vedere CONTRAINDICAZIONI).
In alcuni casi, un paziente che sta già ricevendo una terapia con PMS-Mirtazapina può richiedere un trattamento urgente con linezolid o blu di metilene per via endovenosa. Se non sono disponibili alternative accettabili al trattamento blu di metilene linezolid o endovenoso e si ritiene che i potenziali benefici del trattamento blu di metilene linezolid o endovenoso siano superiori ai rischi della sindrome serotoninergica in un particolare paziente, PMS-Mirtazapine deve essere arrestato prontamente, e il blu di metilene linezolid o endovenoso può essere somministrato. Il paziente deve essere monitorato per i sintomi della sindrome serotoninergica per 2 settimane o fino a 24 ore dopo l'ultima dose di linezolid o blu di metilene per via endovenosa, a seconda dell'evento che si verifica per primo. La terapia con PMS-Mirtazapina può essere ripresa 24 ore dopo l'ultima dose di linezolid o blu di metilene per via endovenosa (vedere AVVERTENZE).
Non è chiaro il rischio di somministrare blu di metilene per via non endovenosa (come compresse orali o iniezione locale) o in dosi endovenose molto inferiori a 1 mg / kg con PMS-Mirtazapina. Il medico deve tuttavia essere consapevole della possibilità di sintomi emergenti della sindrome serotoninergica con tale uso (vedere AVVERTENZE).
Interruzione del trattamento con sindrome premestruale-mirtazapina
Sono stati segnalati sintomi associati all'interruzione o alla riduzione della dose di compresse di PMS-mirtazapina. I pazienti devono essere monitorati per questi e altri sintomi quando si interrompe il trattamento o durante la riduzione del dosaggio. Si raccomanda una riduzione graduale della dose per diverse settimane, piuttosto che una brusca cessazione, quando possibile. Se si verificano sintomi intollerabili a seguito di una riduzione della dose o all'interruzione del trattamento, la titolazione della dose deve essere gestita sulla base della risposta clinica del paziente (vedere PRECAUZIONI e REAZIONI AVVERSE).
Informazioni per i pazienti
I pazienti devono essere informati che l'assunzione di PMS-Mirtazapina può causare una lieve dilatazione pupillare, che in soggetti sensibili può portare a un episodio di glaucoma ad angolo chiuso. Il glaucoma preesistente è quasi sempre glaucoma ad angolo aperto perché il glaucoma ad angolo chiuso, quando diagnosticato, può essere trattato in modo definitivo con l'iridectomia. Il glaucoma ad angolo aperto non è un fattore di rischio per il glaucoma ad angolo chiuso. I pazienti potrebbero voler essere esaminati per determinare se sono sensibili alla chiusura angolare e hanno una procedura profilattica (ad es., iridectomia), se sono sensibili.
Trattamento iniziale
La dose iniziale raccomandata per le compresse di disintegrazione orale di REMERONSolTab® (mirtazapina) è di 15 mg / die, somministrata in dose singola, preferibilmente la sera prima del sonno. Negli studi clinici controllati che stabiliscono l'efficacia di REMERON® nel trattamento del disturbo depressivo maggiore, l'intervallo di dosi efficace era generalmente di 15-45 mg / die. Sebbene la relazione tra dose e risposta soddisfacente nel trattamento del disturbo depressivo maggiore per REMERON® non sia stata adeguatamente esplorata, i pazienti che non rispondono alla dose iniziale di 15 mg possono beneficiare di aumenti della dose fino a un massimo di 45 mg / die. REMERON® ha un'emivita di eliminazione di circa 20-40 ore; pertanto, le variazioni di dose non devono essere apportate ad intervalli inferiori a una o due settimane al fine di consentire un tempo sufficiente per la valutazione della risposta terapeutica a una determinata dose.
Somministrazione di compresse di disintegrazione orale REMERONSolTab® (mirtazapine)
I pazienti devono essere istruiti ad aprire il blister del tablet con le mani asciutte e posizionare il tablet sulla lingua. Il tablet deve essere usato immediatamente dopo la rimozione dal suo blister; una volta rimosso, non può essere memorizzato. REMERONSolTab® (mirtazapina) Le compresse per la disintegrazione orale si disintegreranno rapidamente sulla lingua e potranno essere deglutite con saliva. Non è necessaria acqua per assumere il tablet. I pazienti non devono tentare di dividere il tablet.
Anziani e pazienti con compromissione renale o epatica
La clearance della mirtazapina è ridotta nei pazienti anziani e nei pazienti con insufficienza renale o epatica da moderata a grave. Di conseguenza, il medico prescrittore deve essere consapevole che i livelli plasmatici di mirtazapina possono essere aumentati in questi gruppi di pazienti, rispetto ai livelli osservati negli adulti più giovani senza insufficienza renale o epatica (vedere PRECAUZIONI e FARMACOLOGIA CLINICA).
Manutenzione / Trattamento esteso
È generalmente concordato che gli episodi acuti di depressione richiedono diversi mesi o più di terapia farmacologica prolungata oltre la risposta all'episodio acuto. La valutazione sistematica di REMERON® (mirtazapina) ha dimostrato che la sua efficacia nel disturbo depressivo maggiore viene mantenuta per periodi fino a 40 settimane dopo 8-12 settimane di trattamento iniziale alla dose di 15-45 mg / die (vedere FARMACOLOGIA CLINICA). Sulla base di questi dati limitati, non è noto se la dose di REMERON® necessaria per il trattamento di mantenimento sia identica alla dose necessaria per ottenere una risposta iniziale. I pazienti devono essere periodicamente rivalutati per determinare la necessità di un trattamento di mantenimento e la dose appropriata per tale trattamento.
Passaggio dei pazienti verso o da un inibitore dell'ossidasi monoaminica
Dovrebbero trascorrere almeno 14 giorni tra l'interruzione di un MAOI e l'inizio della terapia con REMERONSolTab® (mirtazapina) compresse per la disintegrazione orale. Inoltre, dovrebbero essere concessi almeno 14 giorni dopo l'arresto di REMERONSolTab® (mirtazapina) prima di iniziare un MAOI
Ipersensibilità
PMS-mirtazapina (mirtazapina) Le compresse sono controindicate in pazienti con nota ipersensibilità alla mirtazapina o ad uno qualsiasi degli eccipienti.
Inibitori dell'ossidasi monoaminica
L'uso di inibitori delle monoamino ossidasi (MAOI) destinati a trattare disturbi psichiatrici con compresse di PMS-mirtazapina o entro 14 giorni dall'interruzione del trattamento con PMS-mirtazapina è controindicato a causa di un aumentato rischio di sindrome serotoninergica. Anche l'uso di PMS-Mirtazapina entro 14 giorni dall'arresto di un MAOI destinato a trattare disturbi psichiatrici è controindicato (vedere AVVERTENZE e DOSAGGIO E AMMINISTRAZIONE).
Anche l'avvio di PMS-Mirtazapina in un paziente in trattamento con MAOI come linezolid o blu di metilene per via endovenosa è controindicato a causa di un aumentato rischio di sindrome serotoninergica (vedere AVVERTENZE e DOSAGGIO E AMMINISTRAZIONE).
REMERONSolTab® (mirtazapina) Le compresse per la disintegrazione orale sono controindicate nei pazienti con nota ipersensibilità alla mirtazapina.
WARNINGS
Clinical Worsening And Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 - 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
Increases Compared to Placebo | |
< 18 | 14 additional cases |
18-24 | 5 additional cases |
Decreases Compared to Placebo | |
25-64 | 1 fewer case |
≥ 65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for PMS-Mirtazapine (mirtazapine) Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients For Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that PMS-Mirtazapine (mirtazapine) Tablets are not approved for use in treating bipolar depression.
Agranulocytosis
In premarketing clinical trials, 2 (1 with Sjögren's Syndrome) out of 2796 patients treated with PMS-Mirtazapine (mirtazapine) Tablets developed agranulocytosis [absolute neutrophil count (ANC) < 500/mm³ with associated signs and symptoms , e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC < 500/mm³ 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 PMS-Mirtazapine was s topped. These 3 cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low WBC count, treatment with PMS-Mirtazapine should be discontinued and the patient should be closely monitored.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PMS-Mirtazapine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and 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 and intravenous methylene blue).
Serotonin syndrome 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of PMS-Mirtazapine with MAOIs intended to treat psychiatric disorders is contraindicated. PMS-Mirtazapine 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 an MAOI such as linezolid or intravenous methylene blue in a patient taking PMS-Mirtazapine. PMS-Mirtazapine should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of PMS-Mirtazapine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's wort, is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with PMS-Mirtazapine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including PMS-Mirtazapine may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
QT Prolongation And Torsades de Pointes
The effect of PMS-Mirtazapine (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 (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine was not at a level generally considered to be clinically meaningful. During the postmarketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death, have been reported (see ADVERSE REACTIONS). 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 (see DRUG INTERACTIONS and OVERDOSE sections). Caution should be exercised when PMS-Mirtazapine is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QTc interval.
PRECAUTIONS
General
Discontinuation Symptoms
There have been reports of adverse reactions upon the discontinuation of PMS-Mirtazapine (mirtazapine) 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. The majority of the reported cases are mild and self-limiting. Even though these have been reported as adverse reactions, it should be realized that these symptoms may be related to underlying disease.
Patients currently taking PMS-Mirtazapine should NOT discontinue treatment abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue treatment with PMS-Mirtazapine, a gradual reduction in the dose, rather than an abrupt cessation, is recommended.
Akathisia/Psychomotor Restlessness
The use of antidepressants has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Hyponatremia
Hyponatremia has been reported very rarely with the use of mirtazapine. Caution should be exercised in patients at risk, such as elderly patients or patients concomitantly treated with medications known to cause hyponatremia.
Somnolence
In US controlled studies, somnolence was reported in 54% of patients treated with PMS-Mirtazapine (mirtazapine) Tablets, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of PMS-Mirtazapine-treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of PMS-Mirtazapine. Because of the potentially significant effects of PMS-Mirtazapine on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug's effect on their own psychomotor performance (see PATIENT INFORMATION).
Dizziness
In US controlled studies, dizziness was reported in 7% of patients treated with PMS-Mirtazapine, compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of PMS-Mirtazapine.
Increased Appetite/Weight Gain
In US controlled studies, appetite increase was reported in 17% of patients treated with PMS-Mirtazapine, compared to 2% for placebo and 6% for amitriptyline. 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 and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, openlabel treatment, 8% of patients receiving PMS-Mirtazapine discontinued for weight gain. In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of PMS-Mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients (see PRECAUTIONS: Pediatric Use).
Cholesterol/Triglycerides
In US controlled studies, nonfasting cholesterol increases to ≥ 20% above the upper limits of normal were observed in 15% of patients treated with PMS-Mirtazapine, compared to 7% for placebo and 8% for amitriptyline. 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 and 3% for amitriptyline.
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 exposed to PMS-Mirtazapine in a pool of short-term US controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued PMS-Mirtazapine treatment. PMS-Mirtazapine should be used with caution in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Activation Of Mania/Hypomania
Mania/hypomania occurred in approximately 0.2% (3/1299 patients) of PMS-Mirtazapine-treated patients in US studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania.
Seizure
In premarketing clinical trials, only 1 seizure was reported among the 2796 US and non-US patients treated with PMS-Mirtazapine. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients.
Use In Patients With Concomitant Illness
Clinical experience with PMS-Mirtazapine in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with diseases or conditions that affect metabolism or hemodynamic responses.
PMS-Mirtazapine has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. PMS-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. PMS-Mirtazapine 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).
Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR)=11 - 39 mL/min/1.73 m²] and severe [GFR < 10 mL/min/1.73 m²] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering PMS-Mirtazapine to such patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
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 PMS-Mirtazapine (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 PMS-Mirtazapine. 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 PMS-Mirtazapine.
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 PMS-Mirtazapine 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
Completing Course Of Therapy
While patients may notice improvement with PMS-Mirtazapine 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 PMS-Mirtazapine to interact with other drugs.
Patients should be made aware of a potential increased risk for serotonin syndrome if concomitant use of PMS-Mirtazapine 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 PMS-Mirtazapine 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 PMS-Mirtazapine 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.
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 on an mg/m² basis 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. The data suggest that the above effects could possibly be mediated by nongenotoxic mechanisms, the relevance of which to humans is not known.
The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of PMS-Mirtazapine (mirtazapine) Tablets.
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) on an mg/m basis]. 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 preimplantation losses occurred at 20 times the MRHD.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively [20 and 17 times the maximum recommended human dose (MRHD) on an mg/m² basis, respectively], have revealed no evidence of teratogenic effects. However, in rats, there was an increase in postimplantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. The effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on an mg/m² basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
Because some PMS-Mirtazapine may be excreted into breast milk, caution should be exercised when PMS-Mirtazapine (mirtazapine) Tablets are administered to nursing women.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS: Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with PMS-Mirtazapine (mirtazapine) Tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of PMS-Mirtazapine in a child or adolescent must balance the potential risks with the clinical need.
In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of PMS-Mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for PMS-Mirtazapine-treated patients versus 1 kg (2 kg SD) for placebo-treated patients (see PRECAUTIONS: Increased Appetite/Weight Gain).
Geriatric Use
Approximately 190 elderly individuals ( ≥ 65 years of age) participated in clinical studies with PMS-Mirtazapine (mirtazapine) Tablets. This drug is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over-sedation in the elderly. No unusual adverse age-related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering PMS-Mirtazapine to elderly patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short- term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18- 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
Table 1
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
Increases Compared to Placebo | |
< 18 | 14 additional cases |
18 - 24 | 5 additional cases |
Decreases Compared to Placebo | |
25 - 64 | 1 fewer case |
≥ 65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are not approved for use in treating bipolar depression.
Agranulocytosis
In premarketing clinical trials, two (one with Sjogren's Syndrome) out of 2796 patients treated with REMERON® (mirtazapine) Tablets developed agranulocytosis [absolute neutrophil count (ANC) < 500/mm3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC < 500/mm3 without any associated symptoms). For these three patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All three patients recovered after REMERON® was stopped. These three cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval, i.e., 2.2 cases per 10,000 to 3.1 cases per 1000. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets should be discontinued and the patient should be closely monitored.
MAO Inhibitors
In patients receiving other drugs for major depressive disorder in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued a drug for major depressive disorder and then are started on an MAOI, there have been reports of serious, and sometimes fatal reactions, including nausea, vomiting, flushing, dizziness, tremor, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability with rapid fluctuations of vital signs, seizures, and mental status changes ranging from agitation to coma. Although there are no human data pertinent to such an interaction with REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets, it is recommended that REMERONSolTab® (mirtazapine) not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI.
PRECAUTIONS
General
Somnolence
In US controlled studies, somnolence was reported in 54% of patients treated with REMERON® (mirtazapine) Tablets, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of REMERON®-treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of REMERON®. Because of REMERON®'s potentially significant effects on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug's effect on their own psychomotor performance (see Information for Patients).
Dizziness
In US controlled studies, dizziness was reported in 7% of patients treated with REMERON®, compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of REMERON®.
Increased Appetite/Weight Gain
In US controlled studies, appetite increase was reported in 17% of patients treated with REMERON®, compared to 2% for placebo and 6% for amitriptyline. 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 and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON® discontinued for weight gain. In an 8-week long
pediatric clinical trial of doses between 15-45 mg/day, 49% of REMERON®-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients (see PRECAUTIONS: Pediatric Use).
Cholesterol/Triglycerides
In US controlled studies, nonfasting cholesterol increases to ≥ 20% above the upper limits of normal were observed in 15% of patients treated with REMERON®, compared to 7% for placebo and 8% for amitriptyline. 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 and 3% for amitriptyline.
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 exposed to REMERON® in a pool of short-term US controlled trials, compared to 0.3% (1/328) of placebo patients and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT increases did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued REMERON® treatment. REMERONSolTab® (mirtazapine) should be used with caution in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Activation of Mania/Hypomania
Mania/hypomania occurred in approximately 0.2% (3/1299 patients) of REMERON®-treated patients in US studies. Although the incidence of mania/hypomania was very low during treatment with mirtazapine, it should be used carefully in patients with a history of mania/hypomania.
Seizure
In premarketing clinical trials, only one seizure was reported among the 2796 US and non-US patients treated with REMERON®. However, no controlled studies have been carried out in patients with a history of seizures. Therefore, care should be exercised when mirtazapine is used in these patients.
Use in Patients with Concomitant Illness
Clinical experience with REMERONSolTab® (mirtazapine) in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing mirtazapine for patients with diseases or conditions that affect metabolism or hemodynamic responses.
REMERONSolTab® (mirtazapine) has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. REMERON® 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. REMERONSolTab® (mirtazapine) 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).
Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR) = 11-39 mL/min/1.73 m2] and severe [GFR < 10 mL/min/1.73 m2] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering REMERONSolTab® (mirtazapine) to such patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
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 REMERONSolTab® (mirtazapine) Orally Disintegrating 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 REMERONSolTab® (mirtazapine). 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 REMERONSolTab® (mirtazapine).
Clinical Worsening and Suicide Risk
Agranulocytosis
Patients who are to receive REMERONSolTab® (mirtazapine) 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
REMERONSolTab® (mirtazapine) may impair judgement, 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 REMERONSolTab® (mirtazapine) therapy does not adversely affect their ability to engage in such activities.
Completing Course of Therapy
While patients may notice improvement with REMERONSolTab® (mirtazapine) therapy in 1-4 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 REMERONSolTab® (mirtazapine) to interact with other drugs.
Alcohol
The impairment of cognitive and motor skills produced by REMERON® has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking any dosage form of mirtazapine.
Phenylketonurics
Phenylketonuric patients should be informed that REMERONSolTab® (mirtazapine) contains phenylalanine 2.6 mg per 15 mg tablet, 5.2 mg per 30 mg tablet, and 7.8 mg per 45 mg tablet.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during REMERONSolTab® (mirtazapine) therapy.
Nursing
Patients should be advised to notify their physician if they are breast-feeding an infant.
Laboratory Tests
There are no routine laboratory tests recommended.
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 on a mg/m2 basis 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. The data suggest that the above effects could possibly be mediated by non- genotoxic mechanisms, the relevance of which to humans is not known.
The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of REMERON® (mirtazapine) Tablets.
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) on a mg/m2 basis]. 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.
Pregnancy
Teratogenic Effects - Pregnancy Category C
Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively [20 and 17 times the maximum recommended human dose (MRHD) on a mg/m2 basis, respectively], have revealed no evidence of teratogenic effects. However, in rats, there was an increase in post-implantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. The effects occurred at doses that were 20 times the MRHD, but not at 3 times the MRHD, on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether mirtazapine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are administered to nursing women.
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS — Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with REMERON® (mirtazapine) Tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets in a child or adolescent must balance the potential risks with the clinical need.
In an 8-week long pediatric clinical trial of doses between 15-45 mg/day, 49% of REMERON®-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for REMERON®-treated patients versus 1 kg (2 kg SD) for placebo-treated patients (see PRECAUTIONS — Increased Appetite/Weight Gain).
Geriatric Use
Approximately 190 elderly individuals ( ≥ 65 years of age) participated in clinical studies with REMERON® (mirtazapine) Tablets. This drug is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Sedating drugs may cause confusion and over-sedation in the elderly. No unusual adverse age- related phenomena were identified in this group. Pharmacokinetic studies revealed a decreased clearance in the elderly. Caution is indicated in administering REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets to elderly patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Information for Patients
Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's healthcare provider about:
- all risks and benefits of treatment with antidepressant medicines
- all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
- How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
- Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
- Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling very agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.
Associated With Discontinuation Of Treatment
Approximately 16% of the 453 patients who received PMS-Mirtazapine (mirtazapine) Tablets in US 6-week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7% of the 361 placebo-treated patients in those studies. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) are included in Table 2.
Table 2: Common Adverse Events Associated With Discontinuation of Treatment in 6-Week US PMS-Mirtazapine Trials
Adverse Event | Percentage of Patients Discontinuing With Adverse Event | |
PMS-Mirtazapine (n=453) | Placebo (n=361) | |
Somnolence | 10.4% | 2.2% |
Nausea | 1.5% | 0% |
Commonly Observed Adverse Events In US Controlled Clinical Trials
The most commonly observed adverse events associated with the use of PMS-Mirtazapine (mirtazapine) Tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (PMS-Mirtazapine incidence at least twice that for placebo) are listed in Table 3.
Table 3: Common Treatment-Emergent Adverse Events Associated With the Use of PMS-Mirtazapine in 6-Week US Trials
Adverse Event | Percentage of Patients Reporting Adverse Event | |
PMS-Mirtazapine (n=453) | Placebo (n=361) | |
Somnolence | 54% | 18% |
Increased Appetite | 17% | 2% |
Weight Gain | 12% | 2% |
Dizziness | 7% | 3% |
Adverse Events Occurring At An Incidence Of 1% Or More Among PMS-Mirtazapine-Treated Patients
Table 4 enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among PMS-Mirtazapine (mirtazapine) Tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied.
Table 4: Incidence of Adverse Clinical Experiences* ( ≥ 1%) in Short-Term US Controlled Studies
Body System Adverse Clinical Experience | PMS-Mirtazapine (n=453) | Placebo (n=361) |
Body as a Whole | ||
Asthenia | 8% | 5% |
Flu Syndrome | 5% | 3% |
Back Pain | 2% | 1% |
Digestive System | ||
Dry Mouth | 25% | 15% |
Increased Appetite | 17% | 2% |
Constipation | 13% | 7% |
Metabolic and Nutritional Disorders | ||
Weight Gain | 12% | 2% |
Peripheral Edema | 2% | 1% |
Edema | 1% | 0% |
Musculoskeletal System | ||
Myalgia | 2% | 1% |
Nervous System | ||
Somnolence | 54% | 18% |
Dizziness | 7% | 3% |
Abnormal Dreams | 4% | 1% |
Thinking Abnormal | 3% | 1% |
Tremor | 2% | 1% |
Confusion | 2% | 0% |
Respiratory System | ||
Dyspnea | 1% | 0% |
Urogenital System | ||
Urinary Frequency | 2% | 1% |
*Events reported by at least 1% of patients treated with PMS-Mirtazapine are included, except the following events, which had an incidence on placebo greater than or equal to PMS-Mirtazapine: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion. |
ECG Changes
The electrocardiograms for 338 patients who received PMS-Mirtazapine (mirtazapine) Tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥ 500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and - 3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown.
The effect of PMS-Mirtazapine (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 (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine was not at a level generally considered to be clinically meaningful.
Other Adverse Events Observed During The Premarketing Evaluation Of PMS-Mirtazapine
During its premarketing assessment, multiple doses of PMS-Mirtazapine (mirtazapine) Tablets were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of PMS-Mirtazapine who experienced an event of the type cited on at least 1 occasion while receiving PMS-Mirtazapine. All reported events are included except those already listed in Table 4, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote.
It is important to emphasize that, although the events reported occurred during treatment with PMS-Mirtazapine, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in Table 4 appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections.
Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal.
Cardiovascular System: frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure.
Digestive System: frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema.
Endocrine System: rare: goiter, hypothyroidism.
Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.
Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia.
Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis.
Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome.
Respiratory System: frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup.
Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer.
Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia.
Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency.
Other Adverse Events Observed During Postmarketing Evaluation Of PMS-Mirtazapine
Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include cases of the ventricular arrhythmia Torsades de Pointes. In the majority of these cases, however, concomitant drugs were implicated. Cases of severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported. Increased creatine kinase blood levels and rhabdomyolysis have also been reported.
Drug Abuse And Dependence
Controlled Substance Class
PMS-Mirtazapine (mirtazapine) Tablets are not a controlled substance.
Physical And Psychologic Dependence
PMS-Mirtazapine (mirtazapine) Tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of PMS-Mirtazapine misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
Associated with Discontinuation of Treatment
Approximately 16 percent of the 453 patients who received REMERON® (mirtazapine) Tablets in US 6- week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7 percent of the 361 placebo-treated patients in those studies. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) included:
Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US REMERON® Trials
Adverse Event | Percentage of Patients Discontinuing with Adverse Event | |
REMERON® (n=453) | Placebo (n=361) | |
Somnolence | 10.4% | 2.2% |
Nausea | 1.5% | 0% |
Commonly Observed Adverse Events in US Controlled Clinical Trials
The most commonly observed adverse events associated with the use of REMERON® (mirtazapine) Tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (REMERON® incidence at least twice that for placebo) were:
Common Treatment-Emergent Adverse Events Associated with the Use of REMERON® in 6-Week US Trials
Adverse Event | Percentage of Patients Reporting Adverse Event | |
REMERON® (n=453) | Placebo (n=361) | |
Somnolence | 54% | 18% |
Increased Appetite | 17% | 2% |
Weight Gain | 12% | 2% |
Dizziness | 7% | 3% |
Adverse Events Occurring at an Incidence of 1% or More Among REMERON®-Treated Patients
The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among REMERON® (mirtazapine) Tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5-60 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.
INCIDENCE OF ADVERSE CLINICAL EXPERIENCES1 ( ≥ 1%) IN SHORT-TERM US CONTROLLED STUDIES
Body System Adverse Clinical Experience | REMERON® (n=453) | Placebo (n=361) |
Body as a Whole | ||
Asthenia | 8% | 5% |
Flu Syndrome | 5% | 3% |
Back Pain | 2% | 1% |
Digestive System | ||
Dry Mouth | 25% | 15% |
Increased Appetite | 17% | 2% |
Constipation | 13% | 7% |
Metabolic and Nutritional Disorders | ||
Weight Gain | 12% | 2% |
Peripheral Edema | 2% | 1% |
Edema | 1% | 0% |
Musculoskeletal System | ||
Myalgia | 2% | 1% |
Nervous System | ||
Somnolence | 54% | 18% |
Dizziness | 7% | 3% |
Abnormal Dreams | 4% | 1% |
Thinking Abnormal | 3% | 1% |
Tremor | 2% | 1% |
Confusion | 2% | 0% |
Respiratory System | ||
Dyspnea | 1% | 0% |
Urogenital System | ||
Urinary Frequency | 2% | 1% |
1Events reported by at least 1% of patients treated with REMERON® are included, except the following events which had an incidence on placebo ≥ REMERON®: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion.
ECG Changes
The electrocardiograms for 338 patients who received REMERON® (mirtazapine) Tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥ 500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and -3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown.
Other Adverse Events Observed During the Premarketing Evaluation of REMERON®
During its premarketing assessment, multiple doses of REMERON® (mirtazapine) Tablets were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of REMERON® who experienced an event of the type cited on at least one occasion while receiving REMERON®. All reported events are included except those already listed in the previous table, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote.
It is important to emphasize that, although the events reported occurred during treatment with REMERON®, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in the previous table appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections.
Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal.
Cardiovascular System: frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure.
Digestive System: frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema.
Endocrine System: rare: goiter, hypothyroidism.
Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.
Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus.
Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthosis, bursitis.
Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare:
Respiratory System: frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup.
Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer.
Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia.
Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency.
Other Adverse Events Observed During Postmarketing Evaluation of REMERON®
Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include four cases of the ventricular arrhythmia torsades de pointes. In three of the four cases, however, concomitant drugs were implicated. All patients recovered.
Drug Abuse And Dependence
Controlled Substance Class
REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets are not a controlled substance.
Physical and Psychologic Dependence
REMERONSolTab® (mirtazapine) Orally Disintegrating Tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of REMERONSolTab® (mirtazapine) misuse or abuse (e.g., development of tolerance, incrementations of dose, drug- seeking behavior).
Esperienza umana
Esiste un'esperienza molto limitata con il sovradosaggio di compresse di PMS-Mirtazapina (mirtazapina). Negli studi clinici pre-marketing, sono stati segnalati 8 casi di sovradosaggio di PMS-mirtazapina da solo o in combinazione con altri agenti farmacologici. L'unico decesso per overdose di droga riportato durante l'assunzione di PMS-Mirtazapina era in combinazione con amitriptilina e clorprotixene in uno studio clinico non statunitense. Sulla base dei livelli plasmatici, la dose di PMS-mirtazapina assunta era compresa tra 30 e 45 mg, mentre i livelli plasmatici di amitriptilina e clorprotixene erano risultati a livelli tossici. Tutti gli altri casi di sovradosaggio pre-marketing hanno portato al pieno recupero. Segni e sintomi riportati in associazione con sovradosaggio includevano disorientamento, sonnolenza, memoria compromessa e tachicardia. Non sono stati segnalati casi di anomalie ECG, coma o convulsioni a seguito di sovradosaggio con la sola PMS-Mirtazapina.
Tuttavia, sulla base dei rapporti post-marketing, esiste la possibilità di esiti più gravi (inclusi decessi) a dosi molto più elevate della dose terapeutica, in particolare con overdose miste. In questi casi, sono stati segnalati anche il prolungamento dell'intervallo QT e Torsades de Pointes (vedi INTERAZIONI DI FARMACI e REAZIONI AVVERSE sezioni).
Gestione del sovradosaggio
Il trattamento deve consistere in quelle misure generali impiegate nella gestione del sovradosaggio con qualsiasi farmaco efficace nel trattamento del disturbo depressivo maggiore. Garantire un'adeguata via aerea, ossigenazione e ventilazione. Monitorare i parametri ECG (incluso il ritmo cardiaco) e i segni vitali. Si raccomandano anche misure generali di supporto e sintomatiche. L'induzione dell'emesi non è raccomandata. Se necessario, può essere indicato un lavaggio gastrico con un tubo orogastrico a foro grande con adeguata protezione delle vie aeree, se eseguito subito dopo l'ingestione o in pazienti sintomatici. Il carbone attivo deve essere somministrato. Non vi è esperienza con l'uso di diuresi forzata, dialisi, emoperfusione o trasfusione di scambio nel trattamento del sovradosaggio di mirtazapina. Non sono noti antidoti specifici per mirtazapina.
Nella gestione del sovradosaggio, considerare la possibilità di coinvolgimento di più farmaci. Il medico deve prendere in considerazione la possibilità di contattare un centro antiveleni per ulteriori informazioni sul trattamento di qualsiasi sovradosaggio. I numeri di telefono per i centri di controllo del veleno certificati sono elencati nei medici Desk Reference (PDR).
Esperienza umana
Esiste un'esperienza molto limitata con REMERONSolTab® (mirtazapina) Sovradosaggio di compresse per la disintegrazione orale. Negli studi clinici di pre-marketing, sono stati segnalati otto casi di sovradosaggio di REMERON® da solo o in combinazione con altri agenti farmacologici. L'unico decesso per overdose di droga riportato durante l'assunzione di REMERON® era in combinazione con amitriptilina e clorprotixene in uno studio clinico non statunitense. Sulla base dei livelli plasmatici, la dose di REMERON® assunta era di 30-45 mg, mentre i livelli plasmatici di amitriptilina e clorprotixene erano risultati a livelli tossici. Tutti gli altri casi di sovradosaggio pre-marketing hanno portato al pieno recupero. Segni e sintomi riportati in associazione con sovradosaggio includevano disorientamento, sonnolenza, memoria compromessa e tachicardia. Non sono stati segnalati casi di anomalie ECG, coma o convulsioni a seguito di sovradosaggio con REMERON® da solo.
Gestione del sovradosaggio
Il trattamento deve consistere in quelle misure generali impiegate nella gestione del sovradosaggio con qualsiasi farmaco efficace nel trattamento del disturbo depressivo maggiore. Garantire un'adeguata via aerea, ossigenazione e ventilazione. Monitora il ritmo cardiaco e i segni vitali. Si raccomandano anche misure generali di supporto e sintomatiche. L'induzione dell'emesi non è raccomandata. Se necessario, può essere indicato un lavaggio gastrico con un tubo orogastrico a foro grande con adeguata protezione delle vie aeree, se eseguito subito dopo l'ingestione o in pazienti sintomatici. A causa della rapida disintegrazione delle compresse di disintegrazione orale di REMERONSolTab® (mirtazapina), i frammenti di pillola potrebbero non apparire nei contenuti gastrici ottenuti con lavanda.
Il carbone attivo deve essere somministrato. Non vi è esperienza con l'uso di diuresi forzata, dialisi, emoperfusione o trasfusione di scambio nel trattamento del sovradosaggio di mirtazapina. Non sono noti antidoti specifici per mirtazapina.
Nella gestione del sovradosaggio, considerare la possibilità di coinvolgimento di più farmaci. Il medico deve prendere in considerazione la possibilità di contattare un centro antiveleni per ulteriori informazioni sul trattamento di qualsiasi sovradosaggio. I numeri di telefono per i centri di controllo del veleno certificati sono elencati nel Riferimento della scrivania dei medici (PDR).
Il meccanismo d'azione delle compresse di PMS-Mirtazapina (mirtazapina), come con altri farmaci efficaci nel trattamento del disturbo depressivo maggiore, non è noto.
Le prove raccolte in studi preclinici suggeriscono che la mirtazapina migliora l'attività noradrenergica e serotonergica centrale. Questi studi hanno dimostrato che la mirtazapina agisce come antagonista al α2 presinaptico centrale - autoricettori e eterorecettori inibitori adrenergici, un'azione che viene postulata per provocare un aumento dell'attività noradrenergica e serotonergica centrale.
La mirtazapina è un potente antagonista dei recettori 5-HT2 e 5-HT3. La mirtazapina non ha alcuna affinità significativa per i recettori 5-HT1A e 5-HT1B.
La mirtazapina è un potente antagonista dei recettori dell'istamina (H1), una proprietà che può spiegare i suoi importanti effetti sedativi.
La mirtazapina è un antagonista adrenergico periferico moderato, una proprietà che può spiegare l'ipotensione ortostatica occasionale riportata in associazione con il suo uso.
La mirtazapina è un antagonista moderato nei recettori muscarinici, una proprietà che può spiegare l'incidenza relativamente bassa di effetti collaterali anticolinergici associati al suo uso.
Il meccanismo d'azione di REMERONSolTab® (mirtazapina) compresse per la disintegrazione orale, come con altri farmaci efficaci nel trattamento del disturbo depressivo maggiore, non è noto.
Le prove raccolte in studi preclinici suggeriscono che la mirtazapina migliora l'attività noradrenergica e serotonergica centrale. Questi studi hanno dimostrato che la mirtazapina agisce come antagonista negli autoricettori e eterorecettori inibitori adrenergici α2 presinaptici centrali, un'azione che è postulata per provocare un aumento dell'attività noradrenergica e serotonergica centrale.
La mirtazapina è un potente antagonista dei recettori 5-HT2 e 5-HT3. La mirtazapina non ha alcuna affinità significativa per il 5-HT1A e 5-HT1B recettori.
La mirtazapina è un potente antagonista dei recettori dell'istamina (H1), una proprietà che può spiegare i suoi importanti effetti sedativi.
La mirtazapina è un antagonista adrenergico α1 periferico moderato, una proprietà che può spiegare l'ipotensione ortostatica occasionale riportata in associazione con il suo uso.
La mirtazapina è un antagonista moderato nei recettori muscarinici, una proprietà che può spiegare l'incidenza relativamente bassa di effetti collaterali anticolinergici associati al suo uso.
Gara
Non ci sono stati studi clinici per valutare l'effetto della razza sulla farmacocinetica della sindrome premestruale-mirtazapina.
Insufficienza renale
La disposizione della mirtazapina è stata studiata in pazienti con vari gradi di funzionalità renale. L'eliminazione della mirtazapina è correlata alla clearance della creatinina. La clearance corporea totale di mirtazapina è stata ridotta di circa il 30% nei pazienti con insufficienza renale moderata (Clcr = 11 - 39 mL / min / 1,73 m²) e di circa il 50% nei pazienti con insufficienza renale grave (Clcr = <10 mL / min / 1,73 m²) rispetto ai soggetti normali. Si indica cautela nella somministrazione di PMS-Mirtazapina a pazienti con funzionalità renale compromessa (vedere PRECAUZIONI e DOSAGGIO E AMMINISTRAZIONE).
Insufficienza epatica
Dopo una singola dose orale di 15 mg di PMS-Mirtazapina, la clearance orale di mirtazapina è stata ridotta di circa il 30% nei pazienti con compromissione epatica rispetto ai soggetti con normale funzionalità epatica. Si indica cautela nella somministrazione di PMS-Mirtazapina a pazienti con funzionalità epatica compromessa (vedere PRECAUZIONI e DOSAGGIO E AMMINISTRAZIONE).
Prove cliniche che mostrano efficacia
L'efficacia delle compresse di PMS-Mirtazapina (mirtazapina) come trattamento per il disturbo depressivo maggiore è stata stabilita in 4 studi di 6 settimane controllati con placebo su pazienti ambulatoriali adulti che soddisfano i criteri DSM-III per il disturbo depressivo maggiore. I pazienti sono stati titolati con mirtazapina da un intervallo di dosi da 5 mg a 35 mg / die. Complessivamente, questi studi hanno dimostrato che la mirtazapina è superiore al placebo su almeno 3 delle seguenti 4 misure: punteggio totale 21-Item Hamilton Depression Rating Scale (HDRS); HDRS Depress Depress Mood Item; Punteggio di gravità CGI; e Montgomery e Asberg Depression Rating Scale (MADRS). La superiorità della mirtazapina rispetto al placebo è stata trovata anche per alcuni fattori dell'HDRS, tra cui il fattore ansia / somatizzazione e il fattore di disturbo del sonno. La dose media di mirtazapina per i pazienti che hanno completato questi 4 studi variava da 21 a 32 mg / die. Un quinto studio di design simile ha utilizzato una dose più elevata (fino a 50 mg) al giorno e ha anche mostrato efficacia.
L'esame dei sottogruppi di età e di genere della popolazione non ha rivelato alcuna reattività differenziale sulla base di questi sottogruppi.
In uno studio a più lungo termine, i pazienti che soddisfano i criteri (DSM-IV) per il disturbo depressivo maggiore che avevano risposto durante le 8-12 settimane iniziali di trattamento acuto su PMS-Mirtazapina sono stati randomizzati alla continuazione di PMS-Mirtazapina o placebo per fino a 40 settimane di osservazione per ricaduta. La risposta durante la fase aperta è stata definita come aver raggiunto un punteggio totale HAM-D 17 di ≤ 8 e un punteggio CGI-Improvement di 1 o 2 in 2 visite consecutive a partire dalla settimana 6 delle 8-12 settimane in aperto- fase di studio. La ricaduta durante la fase in doppio cieco è stata determinata dai singoli investigatori. I pazienti che hanno ricevuto il trattamento continuato con PMS-Mirtazapina hanno manifestato tassi di ricaduta significativamente più bassi nelle successive 40 settimane rispetto a quelli trattati con placebo. Questo modello è stato dimostrato sia nei pazienti maschi che in quelli femmine.
Gara
Non ci sono stati studi clinici per valutare l'effetto della razza sulla farmacocinetica di REMERONSolTab® (mirtazapina).
Insufficienza renale
La disposizione della mirtazapina è stata studiata in pazienti con vari gradi di funzionalità renale. L'eliminazione della mirtazapina è correlata alla clearance della creatinina. La clearance corporea totale di mirtazapina è stata ridotta di circa il 30% nei pazienti con moderato (Clcr = 11-39 mL / min / 1,73 m2) e circa il 50% nei pazienti con grave (Clcr = <10 ml / min / 1,73 m2) insufficienza renale rispetto ai soggetti normali. Si indica cautela nella somministrazione di REMERONSolTab® (mirtazapina) a pazienti con funzionalità renale compromessa (vedere PRECAUZIONI e DOSAGGIO E AMMINISTRAZIONE).
Insufficienza epatica
Dopo una singola dose orale di 15 mg di REMERON®, la clearance orale di mirtazapina è stata ridotta di circa il 30% nei pazienti con compromissione epatica rispetto ai soggetti con normale funzionalità epatica. Si indica cautela nella somministrazione di REMERONSolTab® (mirtazapina) a pazienti con funzionalità epatica compromessa (vedere PRECAUZIONI e DOSAGGIO E AMMINISTRAZIONE).
Prove cliniche che mostrano efficacia
L'efficacia delle compresse di REMERON® (mirtazapina) come trattamento per il disturbo depressivo maggiore è stata stabilita in quattro studi di 6 settimane controllati con placebo su pazienti ambulatoriali adulti che soddisfano i criteri DSM-III per il disturbo depressivo maggiore. I pazienti sono stati titolati con mirtazapina da un intervallo di dosi da 5 mg a 35 mg / die. Complessivamente, questi studi hanno dimostrato che la mirtazapina è superiore al placebo su almeno tre delle seguenti quattro misure: punteggio totale 21-Item Hamilton Depression Rating Scale (HDRS); HDRS Depress Mood Item; Punteggio di gravità CGI; e Montgomery e Asberg Depression Rating Scale (MADRS). La superiorità della mirtazapina rispetto al placebo è stata trovata anche per alcuni fattori dell'HDRS, tra cui il fattore ansia / somatizzazione e il fattore di disturbo del sonno. La dose media di mirtazapina per i pazienti che hanno completato questi quattro studi variava da 21 a 32 mg / die. Un quinto studio di design simile ha utilizzato una dose più elevata (fino a 50 mg) al giorno e ha anche mostrato efficacia.
L'esame dei sottogruppi di età e di genere della popolazione non ha rivelato alcuna reattività differenziale sulla base di questi sottogruppi.
In uno studio a più lungo termine, i pazienti che soddisfano i criteri (DSM-IV) per il disturbo depressivo maggiore che avevano risposto durante le 8-12 settimane iniziali di trattamento acuto su REMERON® sono stati randomizzati alla continuazione di REMERON® o placebo per un massimo di 40 settimane di osservazione per ricaduta. La risposta durante la fase aperta è stata definita come aver raggiunto un punteggio totale HAM-D 17 di ≤ 8 e un punteggio CGI-Improvement di 1 o 2 in due visite consecutive a partire dalla settimana 6 delle 8-12 settimane in aperto fase dello studio. La ricaduta durante la fase in doppio cieco è stata determinata dai singoli investigatori. I pazienti che hanno ricevuto il trattamento continuo con REMERON® hanno manifestato tassi di ricaduta significativamente più bassi nelle successive 40 settimane rispetto a quelli trattati con placebo. Questo modello è stato dimostrato sia nei pazienti maschi che in quelli femmine.
However, we will provide data for each active ingredient