Mirtazapine Tablets USP 15mg Taj Pharma

Mirtazapine Tablets USP 15mg Taj Pharma

  1. Name of the medicinal product

Mirtazapine 15mg Film coated Tablets

  1. Qualitative and quantitative composition

Each film-coated tablet contains 15mg of mirtazapine

Excipient with known effects: Lactose monohydrate.

Each tablet contains 101.8mg

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Tablet, film-coated.

  1. Clinical particulars

4.1 Therapeutic indications

Treatment of episodes of major depression.

Mirtazapine 15mg Tablets are indicated in adults.

4.2 Posology and method of administration

Posology

Adults

The effective daily dose is usually between 15mg and 45mg; the starting dose is 15mg or 30mg. Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks. With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment should be stopped.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.

It is recommended to discontinue treatment with mirtazapine gradually to avoid withdrawal symptoms (see section 4.4).

Elderly

The recommended dose is the same as that for adults. In elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response.

Renal impairment

The clearance of mirtazapine may be decreased in patients with moderate to severe renal impairment (creatinine clearance <40 ml/min). This should be taken into account when prescribing Mirtazapine tablets to this category of patients (see section 4.4).

Hepatic impairment

The clearance of mirtazapine may be decreased in patients with hepatic impairment. This should be taken into account when prescribing Mirtazapine tablets to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated (see section 4.4).

Paediatric population

Mirtazapine tablets should not be used in children and adolescents under the age of 18 years (see section 4.4) as efficacy was not demonstrated in two short-term clinical trials (see section 5.1) and because of safety concerns (see sections 4.4, 4.8 and 5.1).

Method of administration

Mirtazapine has an elimination half-life of 20-40 hours and therefore Mirtazapine tablets are suitable for once daily administration. It should be taken preferably as a single night-time dose before going to bed. Mirtazapine tablets may also be given in two divided doses (once in the morning and once at night-time, the higher dose should be taken at night).

The tablets should be taken orally, with fluid, and swallowed without chewing.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant use of mirtazapine with monoamine oxidase (MAO) inhibitors (see section 4.5).

4.4 Special warnings and precautions for use

Paediatric population

Mirtazapine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive behavioural development are lacking.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany therapy with antidepressants especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

With regard to the chance of suicide, in particular at the beginning of treatment, only a limited number of Mirtazapine film-coated tablets should be given to the patient consistent with good patient management, in order to reduce the risk of overdose.

Bone marrow depression

Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with mirtazapine. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with mirtazapine. In the postmarketing period with mirtazapine very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. Fatal cases mostly concerned patients with an age above 65. The physician should be alert for symptoms like fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, treatment should be stopped and blood counts taken.

Jaundice

Treatment should be discontinued if jaundice occurs.

Conditions which need supervision

Careful dosing as well as regular and close monitoring is necessary in patients with:

  • epilepsy and organic brain syndrome: Although clinical experience indicates that epileptic seizures are rare during mirtazapine treatment, as with other antidepressants, mirtazapine should be introduced cautiously in patients who have a history of seizures. Treatment should be discontinued in any patient who develops seizures, or where there is an increase in seizure frequency.
  • hepatic impairment: Following a single 15mg oral dose of mirtazapine, the clearance of mirtazapine was approximately 35% decreased in mild to moderate hepatically impaired patients, compared to subjects with normal hepatic function. The average plasma concentration of mirtazapine was about 55% increased.
  • renal impairment: Following a single 15mg oral dose of mirtazapine, in patients with moderate (creatinine clearance <40 ml/min) and severe (creatinine clearance ≤10 ml/min) renal impairment the clearance of mirtazapine was about 30% and 50% decreased respectively, compared to normal subjects. The average plasma concentration of mirtazapine was about 55% and 115% increased respectively. No significant differences were found in patients with mild renal impairment (creatinine clearance <80 ml/min) as compared to the control group.
  • cardiac diseases like conduction disturbances, angina pectoris and recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered.
  • low blood pressure.
  • diabetes mellitus: In patients with diabetes, antidepressants may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted and close monitoring is recommended.

Like with other antidepressants, the following should be taken into account:

  • Worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified
  • When the depressive phase of bipolar disorder is being treated, it can transform into the manic phase. Patients with a history of mania/hypomania should be closely monitored. Mirtazapine should be discontinued in any patient entering a manic phase.
  • Although mirtazapine is not addictive, post-marketing experience shows that abrupt termination of treatment after long term administration may sometimes result in withdrawal symptoms. The majority of withdrawal reactions are mild and self-limiting. Among the various reported withdrawal symptoms, dizziness, agitation, anxiety, headache and nausea are the most frequently reported. Even though they have been reported as withdrawal symptoms, it should be realized that these symptoms may be related to the underlying disease. As advised in section 4.2, it is recommended to discontinue treatment with mirtazapine gradually.
  • Care should be taken in patients with micturition disturbances like prostate hypertrophy and in patients with acute narrow-angle glaucoma and increased intra-ocular pressure (although there is little chance of problems with mirtazapine because of its very weak anticholinergic activity).
  • Akathisia/psychomotor restlessness: The use of antidepressants have been associated with the development of akathisia, characterised 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.
  • Cases of QT prolongation, Torsade de Pointes, ventricular tachycardia, and sudden death, have been reported during the post-marketing use of mirtazapine. 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 section 4.5 and section 4.9). Caution should be exercised when 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.

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), 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 hyponatraemia.

Serotonin syndrome

Interaction with serotonergic active substances: serotonin syndrome may occur when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic active substances (see section 4.5). Symptoms of serotonin syndrome may be hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma. Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine. Treatment with mirtazapine should be discontinued if such events occur and supportive symptomatic treatment initiated. From post marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with mirtazapine alone (see section 4.8).

Elderly patients

Elderly patients are often more sensitive, especially with regard to the undesirable effects of antidepressants. During clinical research with mirtazapine, undesirable effects have not been reported more often in elderly patients than in other age groups.

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Mirtazapine should not be administered concomitantly with MAO inhibitors or within two weeks after discontinuation of MAO inhibitor therapy. In the opposite way about two weeks should pass before patients treated with mirtazapine should be treated with MAO inhibitors (see section 4.3).

In addition, as with SSRIs, co-administration with other serotonergic active substances (L-tryptophan, triptans, tramadol, linezolid, methylene blue, SSRIs, venlafaxine, lithium and St. John’s Wort – Hypericum perforatum – preparations) may lead to an incidence of serotonin associated effects (serotonin syndrome: see section 4.4). Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine.

Mirtazapine may increase the sedating properties of benzodiazepines and other sedatives (notably most antipsychotics, antihistamine H1 antagonists, opioids). Caution should be exercised when these medicinal products are prescribed together with mirtazapine.

Mirtazapine may increase the CNS depressant effect of alcohol. Patients should therefore be advised to avoid alcoholic beverages while taking mirtazapine.

Mirtazapine dosed at 30mg once daily caused a small but statistically significant increase in the international normalized ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine a more pronounced effect can not be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.

The risk of QT prolongation and/or ventricular arrhythmias (e.g. Torsade de Pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g. some antipsychotics and antibiotics).

Pharmacokinetic interactions

Carbamazepine and phenytoin, CYP3A4 inducers, increased mirtazapine clearance about two-fold, resulting in a decrease in average plasma mirtazapine concentration of 60% and 45%, respectively. When carbamazepine or any other inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.

Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels and the AUC of mirtazapine by approximately 40 % and 50 % respectively.

When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is administered with mirtazapine, the mean plasma concentration of mirtazapine may increase more than 50%. Caution should be exercised and the dose may have to be decreased when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, cimetidine or nefazodone.

Interaction studies did not indicate any relevant pharmacokinetic effects on concurrent treatment of mirtazapine with paroxetine, amitriptyline, risperidone or lithium.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Limited data of the use of mirtazapine in pregnant women do not indicate an increased risk for congenital malformations. Studies in animals have not shown any teratogenic effects of clinical relevance, however developmental toxicity has been observed (see section 5.3).

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to mirtazapine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Caution should be exercised when prescribing to pregnant women. If mirtazapine is used until, or shortly before birth, postnatal monitoring of the newborn is recommended to account for possible discontinuation effects.

Breast-feeding

Animal studies and limited human data have shown excretion of mirtazapine in breast milk only in very small amounts. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with mirtazapine should be made taking into account the benefit of breastfeeding to the child and the benefit of mirtazapine therapy to the woman.

Fertility

Non-clinical reproductive toxicity studies in animals did not show any effect on fertility.

4.7 Effects on ability to drive and use machines

Mirtazapine has a minor or moderate influence on the ability to drive and use machines. Mirtazapine may impair concentration and alertness (particularly in the initial phase of treatment). Patients should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery, at any time when affected.

4.8 Undesirable effects

Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with mirtazapine.

The most commonly reported adverse reactions, occurring in more than 5% of patients treated with mirtazapine in randomized placebo-controlled trials (see below) are somnolence, sedation, dry mouth, weight increased, increase in appetite, dizziness and fatigue.

All randomized placebo-controlled trials in patients (including indications other than major depressive disorder) have been evaluated for adverse reactions of mirtazapine. The meta-analysis considered 20 trials, with a planned duration of treatment up to 12 weeks, with 1501 patients (134 person years) receiving doses of mirtazapine up to 60mg and 850 patients (79 person years) receiving placebo. Extension phases of these trials have been excluded to maintain comparability to placebo treatment.

Table 1 shows the categorized incidence of the adverse reactions, which occurred in the clinical trials statistically significantly more frequently during treatment with mirtazapine than with placebo, added with adverse reactions from spontaneous reporting. The frequencies of the adverse reactions from spontaneous reporting are based on the reporting rate of these events in the clinical trials. The frequency of adverse reactions from spontaneous reporting for which no cases in the randomized placebo-controlled patient trials were observed with mirtazapine has been classified as ‘not known’.

Table 1. Adverse reactions of mirtazapine

System organ class Very common

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1,000 to <1/100)

Rare

(≥1/10,000 to <1/1,000)

Frequency not known (cannot be estimated from the available data)
Blood and the lymphatic system disorders Bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia thrombocytopenia)

Eosinophilia

Endocrine disorders Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders Weight Increased1

Increase in appetite1

Hyponatraemia
Psychiatric disorders Abnormal dreams

Confusion

Anxiety2, 5

Insomnia3, 5

Nightmares2

Mania

Agitation2

Hallucinations

Psychomotor restlessness (incl. akathisia, hyperkinesia)

Aggression Suicidal ideation6

Suicidal behaviour6

Nervous system disorders Somnolence1, 4

Sedation1, 4

Headache2

Lethargy1

Dizziness

Tremor

Paraesthesia2

Restless legs

Syncope

Myoclonus Convulsions (insults)

Serotonin syndrome

Oral paraesthesia

Dysarthria

Vascular disorders Orthostatic hypotension Hypotension2
Gastrointestinal disorders Dry mouth Nausea3

Diarrhea2

Vomiting2

Constipation1

Oral hypoaesthesia Pancreatitis Mouth oedema

Increased salivation

Hepatobiliary disorders Elevations in serum transaminase activities
Skin and subcutaneous tissue disorders Exanthema2 Stevens- Johnson Syndrome

Dermatitis bullous

Erythema multiforme

Toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders Arthralgia

Myalgia

Back pain1

Rhabdomyolysis
Renal and urinary disorders Urinary retention
General disorders and administration site conditions Oedema peripheral1

Fatigue

Somnambulism

Generalised oedema

Localised oedema

Investigations Increased creatinine kinase

1 In clinical trials these events occurred statistically significantly more frequently during treatment with mirtazapine than with placebo.

2 In clinical trials these events occurred more frequently during treatment with placebo than with mirtazapine, however not statistically significantly more frequently.

3 In clinical trials these events occurred statistically significantly more frequently during treatment with placebo than with mirtazapine.

4N.B. dose reduction generally does not lead to less somnolence/sedation but can jeopardize antidepressant efficacy.

5 Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under mirtazapine treatment, development or aggravation of anxiety and insomnia has been reported.

6 Cases of suicidal ideation and suicidal behaviours have been reported during mirtazapine therapy or early after treatment discontinuation (see section 4.4).

In laboratory evaluations, in clinical trials, transient increases in transaminases and gamma-glutamyltransferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with mirtazapine than with placebo).

Paediatric population

The following adverse events were observed commonly in clinical trials in children: weight gain, urticaria and hypertriglyceridaemia (see also section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Present experience concerning overdose with mirtazapine alone indicates that symptoms are usually mild. Depression of the central nervous system with disorientation and prolonged sedation have been reported, together with tachycardia and mild hyper- or hypotension. However, there is a possibility of more serious outcomes (including fatalities) at dosages much higher than the therapeutic dose, especially with mixed overdoses. In these cases QT prolongation and Torsade de Pointes have also been reported.

Cases of overdose should receive appropriate symptomatic and supportive therapy for vital functions. ECG monitoring should be undertaken.

Activated charcoal or gastric lavage should also be considered.

Paediatric population

The appropriate actions as described for adults should be taken in case of an overdose in paediatrics.

  1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other antidepressants,

Mechanism of action/pharmacodynamic effects

Mirtazapine is a centrally active presynaptic α2-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors, because 5-HT2 and 5-HT3 receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking α2 and 5-HT2 receptors and the R(-) enantiomer by blocking 5-HT3 receptors.

Clinical efficacy and safety

The histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. It has practically no anticholinergic activity and, at therapeutic doses, has only limited effects (e.g. orthostatic hypotension) on the cardiovascular system.

The effect of mirtazapine on QTc interval was assessed in a randomized, placebo and moxifloxacin controlled clinical trial involving 54 healthy volunteers using a regular dose of 45mg and a supra-therapeutic dose of 75mg. Linear e-max modelling suggested that prolongation of QTc intervals remained below the threshold for clinically meaningful prolongation (see section 4.4).

Paediatric population

Two randomised, double-blind, placebo-controlled trials in children aged between 7 and 18 years with major depressive disorder (n=259) using a flexible dose for the first 4 weeks (15-45mg mirtazapine) followed by a fixed dose (15, 30 or 45mg mirtazapine) for another 4 weeks failed to demonstrate significant differences between mirtazapine and placebo on the primary and all secondary endpoints. Significant weight gain (≥7%) was observed in 48.8% of the mirtazapine treated subjects compared to 5.7% in the placebo arm. Urticaria (11.8% vs 6.8%) and hypertriglyceridaemia (2.9% vs 0%) were also commonly observed.

5.2 Pharmacokinetic properties

Absorption

After oral administration of mirtazapine, the active substance mirtazapine is rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels after approx. two hours. Food intake has no influence on the pharmacokinetics of mirtazapine.

Distribution

Binding of mirtazapine to plasma proteins is approx. 85%.

Biotransformation

Major pathways of biotransformation are demethylation and oxidation, followed by conjugation. In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A4 is considered to be responsible for the formation of the N-demethyl and N-oxide metabolites. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.

Elimination

Mirtazapine is extensively metabolized and eliminated via the urine and faeces within a few days. The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation.

Linearity/non-linearity

Mirtazapine displays linear pharmacokinetics within the recommended dose range.

Special populations

The clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

In reproductive toxicity studies in rats and rabbits no teratogenic effects were observed. At two-fold systemic exposure compared to maximum human therapeutic exposure, there was an increase in postimplantation loss, decrease in the pup birth weights, and reduction in pup survival during the first three days of lactation in rats.

Mirtazapine was not genotoxic in a series of tests for gene mutation and chromosomal and DNA damage. Thyroid gland tumours found in a rat carcinogenicity study and hepatocellular neoplasms found in a mouse carcinogenicity study are considered to be species-specific, non-genotoxic responses associated with long-term treatment with high doses of hepatic enzyme inducers.

  1. Pharmaceutical particulars

6.1 List of excipients

Core: Lactose monohydrate, Pregelatinised maize starch, Anhydrous colloidal silica, Croscarmellose sodium, Magnesium stearate.

Film-Coating:

Hypromellose, Macrogol 8000, Titanium dioxide Yellow iron oxide, Red iron oxide, Talc.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Pack sizes

10, 14, 20, 28, 30, 50, 56 and 100 tablets in clear PVC/Al blister.

30, 100 and 500 tablets in white HDPE (Duma) tablet containers with LDPE caps.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

Manufactured By:
Taj Pharmaceuticals Ltd.
at: Plot. No. 220, Mahagujarat
Industrial Estate, At & Post-Moraiya,
Tal-Sanand, Dist- Ahmedabad Gujarat (India)

 

PACKAGE LEAFLET: INFORMATION FOR THE USER

Mirtazapine Tablets USP 15mg Taj Pharma

 (Mirtazapine)

Read all of this leaflet carefully before you start taking this medicine.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you. Do NOT pass it on to others. It may harm them, even if their symptoms are the same as yours.
  • If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

  1. What Mirtazapine is and what it is used for
    2. Before you take Mirtazapine Film-coated Tablets
    3. How to take Mirtazapine Film-coated Tablets
    4. Possible side effects
    5. How to store Mirtazapine Film-coated Tablets
    6. Further information

1.WHAT MIRTAZAPINE IS AND WHAT IT IS USED FOR

Mirtazapine is one of a group of medicines called antidepressants.

Mirtazapine Tablets are used to treat depressive illness.

  1. BEFORE YOU TAKE MIRTAZAPINE FILM-COATED TABLETS

Do not take Mirtazapine Tablets:

  • If you are allergic (hypersensitive) to mirtazapine or any of the other ingredients of Mirtazapine Tablets. If so, you must talk to your doctor as soon as you can before taking Mirtazapine Tablets.
  • if you are taking or have recently taken (within the last two weeks) medicines called monoamine oxidase inhibitors (MAO-Is).

Take special care with Mirtazapine Tablets:

Use in children and adolescents under 18 years of age

Mirtazapine Tablets should normally not be used for children and adolescents under 18 years because efficacy was not demonstrated. Also, you should know that patients under 18 have an increased risk of side-effects such as suicide attempt, suicidal thoughts and hostility (predominantly aggression, oppositional behaviour and anger) when they take this class of medicines. Despite this, your doctor may prescribe Mirtazapine Tablets for patients under 18 because he/she decides that this is in their best interests.

If your doctor has prescribed Mirtazapine Tablets for a patient under 18 and you want to discuss this, please go back to your doctor.

You should inform your doctor if any of the symptoms listed above develop or worsen when patients under 18 are taking Mirtazapine Tablets. The long term safety effects related to growth and development in this age group have not yet been demonstrated. In addition, significant weight gain has been observed in this age category more often when treated with Mirtazapine Tablets compared with adults.

Thoughts of suicide and worsening of your depression

If you are depressed you can sometimes have thoughts of harming or killing yourself. These may be increased when first starting antidepressants, since these medicines all take time to work, usually about two weeks but sometimes longer.

You may be more likely to think like this:

  • if you have previously had thoughts about killing or harming yourself.
  • if you are a young adult. Information from clinical trials has shown an increased risk of suicidal behaviour in adults aged less than 25 years with psychiatric conditions who were treated with an antidepressant.
  • If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital straight away.
    You may find it helpful to tell a relative or close friend that you are depressed, and ask them to read this leaflet. You might ask them to tell you if they think your depression is getting worse, or if they are worried about changes in your behaviour.

Also take special care with Mirtazapine Tablets

  • if you have, or have ever had one of the following conditions.
    • Tell your doctor about these conditions before taking Mirtazapine Tablets, if not done previously
  • seizures(epilepsy). If you develop seizures or your seizures become more frequent, stop taking Mirtazapine Tablets and contact your doctor immediately;
  • liver disease, including jaundice. If jaundice occurs, stop taking Mirtazapine Tablets and contact your doctor immediately;
  • kidney disease;
  • heart disease, or low blood pressure;
  • schizophrenia. If psychotic symptoms, such as paranoid thoughts become more frequent or severe, contact your doctor straight away;
  • manic depression(alternating periods of feeling elated/overactivity and depressed mood). If you start feeling elated or over-excited, stop taking Mirtazapine Tablets and contact your doctor immediately;
  • diabetes(you may need to adjust your dose of insulin or other antidiabetic medicines);
  • eye disease, such as increased pressure in the eye (glaucoma);
  • difficulty in passing water(urinating), which might be caused by an enlarged prostate.
  • if you develop signs of infection such as inexplicable high fever, sore throat and mouth ulcers.
    • Stop taking Mirtazapine Tablets and consult your doctor immediately for a blood test.
      In rare cases these symptoms can be signs of disturbances in blood cell production in the bone marrow. While rare, these symptoms most commonly appear after 4-6 weeks of treatment.
  • if you are an elderly person. You could be more sensitive to the side-effects of antidepressants.

Taking other medicines

Tell your doctor or pharmacist if you are taking (or plan to take) any of the medicines in the following list.

Please also tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Do not take Mirtazapine Tablets in combination with:

  • monoamine oxidase inhibitors (MAO inhibitors). Also, do not take Mirtazapine Tablets during the two weeks after you have stopped taking MAO inhibitors. If you stop taking Mirtazapine Tablets, do not take MAO inhibitors during the next two weeks either. Examples of MAO inhibitors are moclobemide, tranylcypromine (both are antidepressants) and selegiline (used for Parkinson’s disease).

Take care when taking Mirtazapine Tablets in combination with:

  • antidepressants such as SSRIs, venlafaxine and L-tryptophan or triptans (used to treat migraine), tramadol (a pain-killer), linezolid (an antibiotic), lithium (used to treat some psychiatric conditions) and St. Johns Wort – Hypericum perforatum preparations (a herbal remedy for depression). In very rare cases Mirtazapine Tablets alone or the combination of Mirtazapine Tablets with these medicines, can lead to a so-called serotonin syndrome. Some of the symptoms of this syndrome are: inexplicable fever, sweating, increased heart rate, diarrhoea, (uncontrollable) muscle contractions, shivering, overactive reflexes, restlessness, mood changes and unconsciousness. If you get a combination of these symptoms, talk to your doctor immediately.
  • the antidepressant nefazodone. It can increase the amount of mirtazapine in your blood. Inform your doctor if you are using this medicine. It might be necessary to lower the dose of Mirtazapine Tablets, or when use of nefazodone is stopped, to increase the dose of Mirtazapine Tablets again.
  • medicines for anxiety or insomnia such as benzodiazepines;
  • medicines for schizophrenia such as olanzapine;
  • medicines for allergies such as cetirizine;
  • medicines for severe pain such as morphine.
    In combination with these medicines Mirtazapine Tablets can increase the drowsiness caused by these medicines.
  • medicines for infections; medicines for bacterial infections (such as erythromycin, medicines for fungal infections (such as ketoconazole) and medicines for HIV/AIDS (such as HIV-protease inhibitors). In combination with Mirtazapine Tablets these medicines can increase the amount of mirtazapine in your blood. Inform your doctor if you are using these medicines. It might be necessary to lower the dose of Mirtazapine Tablets, or when these medicines are stopped, to increase the dose of Mirtazapine Tablets again.
  • medicines for epilepsy such as carbamazepine and phenytoin;
  • medicines for tuberculosis such as rifampicin.
    In combination with Mirtazapine Tablets these medicines can reduce the amount of mirtazapine in your blood. Inform your doctor if you are using these medicines. It might be necessary to increase the dose of Mirtazapine Tablets, or when these medicines are stopped to lower the dose of Mirtazapine Tablets again.
  • medicines to prevent blood clotting such as warfarin. Mirtazapine Tablets can increase the effects of warfarin on the blood. Inform your doctor if you are using this medicine. In case of combination it is advised that a doctor monitors your blood carefully.

Taking Mirtazapine Tablets with food and drink

You may get drowsy if you drink alcohol while you are taking Mirtazapine Tablets. You are advised not to drink any alcohol.

You can take Mirtazapine Tablets with or without food.

Pregnancy and breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Limited experience with mirtazapine administration to pregnant women does not indicate an increased risk. However, caution should be exercised when used during pregnancy.

Make sure your midwife and/or doctor knows you are on Mirtazapine Tablets. When taken during pregnancy, similar drugs (SSRIs) may increase the risk of a serious condition in babies, called persistent pulmonary hypertension of the newborn (PPHN), making the baby breathe faster and appear bluish. These symptoms usually begin during the first 24 hours after the baby is born. If this happens to your baby you should contact your midwife and/or doctor immediately.

If you are taking Mirtazapine Tablets and you become pregnant or you plan to get pregnant, ask your doctor whether you may continue taking Mirtazapine Tablets.

If you use Mirtazapine Tablets until, or shortly before birth, your baby should be supervised for possible adverse effects.

Ask your doctor whether you can breast-feed, while taking Mirtazapine Tablets.

Driving and using machines

Mirtazapine Tablets can affect your concentration or alertness.

Make sure these abilities are not affected before you drive or operate machinery.

Important information about some of the ingredients of Mirtazapine Tablets

Mirtazapine Tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Mirtazapine 15mg tablets also contain sunset yellow FCF which can cause allergic reactions including asthma.

  1. HOW TO TAKE MIRTAZAPINE FILM-COATED TABLETS

Always take mirtazapine exactly as your doctor has told you.

You should check with your doctor or pharmacist if you are not sure.

How much to take

The usual starting dose is 15 or 30mg every day.

Your doctor may advise you to increase your dose after a few days to the amount that is best for you (between 15 and 45mg per day). The dose is usually the same for all ages.

However, if you are an elderly person or if you have renal or liver disease, your doctor may prescribe a lower dose.

When to take Mirtazapine Tablets

  • Take Mirtazapine Tablets at the same time each day. It is best to take Mirtazapine Tablets as a single dose before you go to bed. However your doctor may suggest you to split your dose of Mirtazapine Tablets – once in the morning and once at night-time before you go to bed. The higher dose should be taken before you go to bed. Take your tablets orally. Swallow your prescribed dose of Mirtazapine Tablets without chewing, with some water or juice.

When can you expect to start feeling better

Usually Mirtazapine Tablets will start working after 1 to 2 weeks and after 2 to 4 weeks you may start to feel better.

It is important that, during the first few weeks of the treatment, you talk with your doctor about the effects of Mirtazapine Tablets:

  • 2 to 4 weeks after you have started taking Mirtazapine Tablets, talk to your doctor about how this medicine has affected you.

If you still don’t feel better, your doctor may prescribe a higher dose. In that case, talk to your doctor again after another 2 to 4 weeks.

Usually you will need to take Mirtazapine Tablets until your symptoms of depression have disappeared for 4 to 6 months.

If you take more Mirtazapine Tablets than you should

  • If you or someone else have taken too much Mirtazapine Tablets, call a doctor straight away.

The most likely signs of an overdose of Mirtazapine Tablets (without other medicines or alcohol) are drowsiness, disorientation and increased heart rate.

If you forget to take Mirtazapine Tablets

If you are supposed to take your dose once a day

  • If you have forgotten to take your dose of Mirtazapine Tablets, do not take the missed dose. Just skip it. Take your next dose at the normal time.

If you are supposed to take your dose twice a day

  • if you have forgotten to take your morning dose, simply take it together with your evening dose.
  • if you have forgotten to take your evening dose, do not take it with the next morning dose; just skip it and continue with your normal morning and evening doses.
  • if you have forgotten to take both doses, do not attempt to make up for the missed doses. Skip both doses and continue the next day with your normal morning and evening doses.

If you stop taking Mirtazapine Tablets

  • Only stop taking Mirtazapine Tablets in consultation with your doctor.

If you stop too early, your depression might come back.

Once you are feeling better, talk to your doctor. Your doctor will decide when treatment can be stopped.

Do not suddenly stop taking Mirtazapine Tablets, even when your depression has lifted. If you suddenly stop taking Mirtazapine Tablets you may feel sick, dizzy, agitated or anxious, and have headaches. These symptoms can be avoided by stopping gradually. Your doctor will tell you how to decrease the dose gradually.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

  1. POSSIBLE SIDE EFFECTS

Like all medicines, mirtazapine can cause side effects, although not everybody gets them.

Some side effects are more likely to occur than others.

The possible side effects of Mirtazapine Tablets are listed below and can be divided as:

  • Very common: affects more than 1 user in 10
  • Common: affects 1 to 10 users in 100
  • Uncommon: affects 1 to 10 users in 1,000
  • Rare: affects 1 to 10 users in 10,000
  • Very rare: affects less than 1 user in 10,000
  • Not known: cannot be estimated from the available data

Tell your doctor and stop taking mirtazapine immediately if you notice any of the following side effects :

  • Signs of infection such as fever, sore throat, mouth ulcers. These are symptoms of agranulocytosis in which a reduction in the number of white blood cells results in a lower resistance to infection. Other changes to your normal red and white blood cell levels may occur. If you have these symptoms you should tell your doctor who will probably give you a blood test.
  • Feeling elated or emotionally ‘high’ (mania).
  • Yellowing of your skin / eyes (signs of jaundice), this may suggest a disturbance in liver function.
  • Epileptic attack (convulsions).
  • a combination of symptoms such as inexplicable fever, sweating, increased heart rate, diarrhoea, (uncontrollable) muscle contractions, shivering, overactive reflexes, restlessness, mood changes and unconsciousness. In very rare cases these can be signs of serotonin syndrome.

If you have any thoughts of suicide or harming yourself whilst taking this medicine, you should contact your doctor immediately (see also Section 2 – Before you take).

Very common:

  • increase in appetite and weight gain
  • drowsiness or sleepiness
  • headache
  • dry mouth.

Common:

  • lethargy
  • dizziness
  • shakiness or tremor
  • nausea
  • diarrhoea
  • vomiting
  • rash or skin eruptions (exanthema)
  • pain in your joints (arthralgia) or muscles (myalgia)
  • back pain
  • feeling dizzy or faint when you stand up suddenly (orthostatic hypotension)
  • swelling (typically in ankles or feet) caused by fluid retention (oedema)
  • tiredness
  • vivid dreams
  • confusion
  • feeling anxious
  • sleeping problems.

In children under 18 years the following adverse events were observed commonly in clinical trials: significant weight gain, hives and increased blood triglycerides.

Uncommon:

  • abnormal sensation in the skin e.g. burning, stinging, tickling or tingling (paraesthesia)
  • restless legs
  • fainting (syncope)
  • sensations of numbness in the mouth (oral hypoaesthesia)
  • low blood pressure
  • nightmares
  • feeling agitated
  • hallucinations
  • urge to move.

Rare:

  • muscle twitching or contractions (myoclonus)
  • aggression.

Not known:

  • abnormal sensations in the mouth (oral paraesthesia)
  • difficulty in speaking
  • swelling in the mouth (mouth oedema)
  • increased salivation
  • hyponatraemia (low levels of sodium in the blood)
  • inappropriate anti-diuretic hormone secretion
  • sever blistering of the skin/and or mucous membranes of lips, mouth, eyes, nasal passages or genital area, skin eruption. If you develop any of these symptoms, contact your doctor straight away.
  • sleepwalking.

If any of the side effects listed above get serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

  1. HOW TO STORE MIRTAZAPINE FILM-COATED TABLETS:

Keep out of the reach and sight of children.

Do not use Mirtazapine Tablets after the expiry date which is stated on the blister and carton after EXP:. The expiry date refers to the last day of that month.

Store in the original package. Keep the blister in the outer carton.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

  1. FURTHER INFORMATION

What Mirtazapine Tablets contain:

  • The active substance is mirtazapine. Each film-coated tablet contains 15mg,   of mirtazapine.
  • The other ingredients are lactose monohydrate, maize starch, hydroxypropyl cellulose, silica colloidal anhydrous, magnesium stearate, hypromellose, macrogol 8000 and titanium dioxide. The 15mg tablet also contains quinoline yellow, sunset yellow FCF and yellow iron oxide, The tablet also contains yellow iron oxide, red iron oxide and black iron oxide.

What Mirtazapine Tablets look like and contents of the pack:

Your medicine is in the form of film-coated tablets.

  • The 15mg tablets are yellow, oblong, biconvex tablets with a score line on one side.

Mirtazapine Tablets are available in blisters of:
15mg: 14, 28, 30, 56, 60, 70, 90 and 100 tablets.
Not all pack sizes may be marketed.

 

Manufactured By:
Taj Pharmaceuticals Ltd.
at: Plot. No. 220, Mahagujarat
Industrial Estate, At & Post-Moraiya,
Tal-Sanand, Dist- Ahmedabad Gujarat (India)

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Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.