1.NAME OF THE MEDICINAL PRODUCT
a) Mirtazapine Film coated Tablets USP 7.5mg Taj Pharma
b) Mirtazapine Film coated Tablets USP 15mg Taj Pharma
c) Mirtazapine Film coated Tablets USP 30mg Taj Pharma
d) Mirtazapine Film coated Tablets USP 45mg Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
a) Each film coated tablet contains
Mirtazapine USP 7.5mg.
Excipients q.s.

b) Each film coated tablet contains
Mirtazapine USP   15mg
Excipients    q.s.

c) Each film coated tablet contains
Mirtazapine USP     30mg
Excipients q.s.

d) Each film coated tablet contains
Mirtazapine USP      45mg
Excipients q.s.

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM
Film coated Tablet (tablet)
Mirtazapine 30 mg tablets are Reddish Brown, biconvex, capsule shaped, film coated tablets with a score line in between 0 and 9
The tablet can be divided into equal doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Mirtazapine tablets are indicated in adults for the treatment of episodes of major depression.

4.2  Posology and method of administration
Posology
ADULTS
The effective daily dose is usually between 15 and 45 mg; the starting dose is 15 or 30 mg.

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).

OLDER PEOPLE
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.

Paediatric population

Mirtazapine should not be used in children and adolescents under the age of 18 years 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)

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 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 to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated (see section 4.4).

Method of administration
Mirtazapine has an elimination half-life of 20-40 hours and therefore Mirtazapine is suitable for once daily administration. It should be taken preferably as a single night-time dose before going to bed. Mirtazapine 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 and 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 placebocontrolled 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 15 mg 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 15 mg 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 postmarketing use of mirtazapine. The majotity 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).

Older people
Older people 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, the Lapp 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 (Ltryptophan, 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 30 mg 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 twofold, 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 onfertility.

4.7 Effects on ability to drive and use machines
Mirtazapine has 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 60 mg 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’.

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
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 • Increase in appetite1

• Weight increased1

• 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

• Sedation14

• 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 • Constipation1

• Nausea3

• Diarrhea2

• Vomiting2

• 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.

4 N.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 gammaglutamyltransferase 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. 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.

5. 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.

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 45 mg 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
Mirtazapine is extensively metabolised and eliminated via the urine and faeces within a few days. 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
Mirtazapine 30 mg tablets contain
Core:
Lactose monohydrate, Maize starch, Low substituted Hydroxypropyl Cellulose, Magnesium Stearate (E470b) and Silica Colloidal anhydrous

Film Coating:
Hypromellose (E464), Titanium dioxide (E 171) Yellow Iron oxide (E172), Red Iron oxide (E172) and Black Iron oxide (E172).

6.2 Incompatibilities
Not applicable

6.3  Shelf life
4 years.

6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container
Blister packs comprising of 250 µ PVC coated with 60 gsm PVdC & 25 µ aluminium foil.
10/14/28/30/40/50/56/60/70/84/90/100/200/250/500 tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Mirtazapine Film coated Tablets USP 15mg Taj Pharma

Package leaflet: Information for the patient

a) Mirtazapine Film coated Tablets USP 7.5mg Taj Pharma
b) Mirtazapine Film coated Tablets USP 15mg Taj Pharma
c) Mirtazapine Film coated Tablets USP 30mg Taj Pharma
d) Mirtazapine Film coated Tablets USP 45mg Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– 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 only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet (see section 4).

What is in this leaflet
1. What Mirtazapine is and what it is used for
2. What you need to know before you take Mirtazapine
3. How to take Mirtazapine
4. Possible side effects
5. How to store Mirtazapine
6. Contents of the pack and other 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.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE MIRTAZAPINE
Do not take Mirtazapine tablets if you are

  • allergicto mirtazapine or any of the other ingredients of this medicine (listed in section 6). If so, you must talk to your doctor as soon as you can before taking Mirtazapine tablets.
  • taking or have recently taken (within the last two weeks) medicines called monoamine oxidase inhibitors (MAOIs).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Mirtazapine tablets

Children and adolescents
Mirtazapine should normally not be used for children and adolescents under 18 years because efficacy has not been 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 for patients under 18 because he/she decides that this is in their best interests. If your doctor has prescribed Mirtazapine 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. Also, the long-term safety effects concerning growth, maturation and cognitive and behavioural development of Mirtazapine 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 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, if not done previously
    • seizures (epilepsy). If you develop seizures or your seizures become more frequent, stop taking Mirtazapine and contact your doctor immediately
    • liver disease, including jaundice. If jaundice occurs, stop taking Mirtazapine 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 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.
  • develop signs of infectionsuch 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.
  • are an elderly You could be more sensitive to the side-effects of antidepressants.

Other medicines and Mirtazapine tablets

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Do not take Mirtazapine in combination with:

  • monoamine oxidase inhibitors(MAO inhibitors). Also, do not take Mirtazapine during the two weeks after you have stopped taking MAO inhibitors. If you stop taking Mirtazapine, 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 in combination with:

  • antidepressantssuch 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  Johns Wort – Hypericum perforatum preparations (a herbal remedy for depression).
    In very rare cases mirtazapine alone or the combination of mirtazapine 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 needed to lower the dose of mirtazapine, or when use of nefazodone is stopped, to increase the dose of mirtazapine again.
  • medicines for anxietyor 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 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), medicines for HIV/AIDS (such as HIV protease inhibitors)
  • medicine for stomach ulcers (cimetidine). In combination with Mirtazapine these medicines can increase the amount of mirtazapine in your blood. Inform your doctor if you are using these medicines. It might be needed to lower the dose of mirtazapine, or when these medicines are stopped to increase the dose of mirtazapine again.
  • medicines for epilepsysuch as carbamazepine and phenytoin; medicines for tuberculosis such as rifampicin. In combination with Mirtazapine these medicines can reduce the amount of mirtazapine in your blood. Inform your doctor if you are using these medicines. It might be needed to increase the dose of mirtazapine, or when these medicines are stopped to lower the dose of mirtazapine again.
  • medicines to prevent blood clottingsuch as warfarin. Mirtazapine 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.

Mirtazapine tablets with food, drink and alcohol
You may get drowsy if you drink alcohol while you are taking Mirtazapine. You are advised not to drink any alcohol.

You can take Mirtazapine with or without food.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

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

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

Make sure your midwife and/or doctor knows you are on Mirtazapine. 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.

Driving and using machines
Mirtazapine can affect your concentration or alertness. Make sure these abilities are not affected before you drive or operate machinery.

Mirtazapine tablets contain lactose
Mirtazapine tablets contain lactose. If you have been told by your doctor that you have an intolerance for some sugars, contact your doctor before taking this medicinal product.

3. HOW TO TAKE MIRTAZAPINE
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How much to take
The recommended 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 adapt the dose.

When to take Mirtazapine tablets
Take Mirtazapine 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 – 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 without chewing, with some water.

When can you expect to start feeling better
Usually Mirtazapine 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: 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 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 many Mirtazapine tablets, call a doctor straight away.

The most likely signs of an overdose of Mirtazapine (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, 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 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, even when your depression has lifted. If you suddenly stop taking Mirtazpine 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 medicine, ask your doctor, pharmacist or nurse.

4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Mirtazapine tablets and tell your doctor immediately if you experience any of the following side effects:

Uncommon (may affect up to 1 in 100 people):

  • Feeling elated or emotionally ‘high’ (mania).

Rare (may affect up to 1 in 1,000 people):

  • Yellow colouring of eyes or skin; this may suggest disturbance in liver function (jaundice).
  • Severe upper abdominal pain often with nausea and vomiting (pancreatitis)

Not known (frequency cannot be estimated from the available data):

  • Signs of infection such as sudden unexplainable high fever, sore throat and mouth ulcers (agranulocytosis).
  • 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.
  • Thoughts of harming or killing yourself – contact your doctor or go to a hospital straight away.
  • A skin reaction known as ‘erythema multiforme’(itchy reddish purple patches on the skin, especially on the palms of the hands or soles of the feet, ‘hive-like’ raised swollen areas on the skin, tender areas on the surfaces of the mouth, eyes and genitals, which may be accompanied by fever and tiredness.)
  • Severe rash, blistering (bullous dermatitis), peeling or other effects on the skin, eyes, mouth or genitals, itching or high temperature (symptoms of severe skin reactions called Stevens-Johnson syndrome or toxic epidermal necrolysis).
  • Muscle pain or weakness, or swelling caused by abnormal muscle breakdown sometimes accompanied with dark coloured urine (rhabdomyolysis).

Other possible side effects with Mirtazapine are:

Very common (may affect more than 1 in 10 people):

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

Common (may affect up to 1 in 10 people):

  • lethargy
  • dizziness
  • shakiness or tremor
  • nausea
  • diarrhoea
  • vomiting
  • constipation
  • 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

Uncommon (may affect up to 1 in 100 people):

  • 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 (may affect up to 1 in 1,000 people):

  • muscle twitching or contractions (myoclonus)
  • feeling aggressive

Not known (frequency cannot be estimated from the available data):

  • In rare cases mirtazapine can cause disturbances in the production of blood cells (bone marrow depression). Some people become less resistant to infection because mirtazapine can cause a temporary shortage of white blood cells (granulocytopenia). In rare cases mirtazapine can also cause a shortage of red and white blood cells, as well as blood platelets (aplastic anemia), a shortage of blood platelets (thrombocytopenia) or an increase in the number of white blood cells (eosinophilia).
  • abnormal sensations in the mouth (oral paraesthesia)
  • swelling in the mouth (mouth oedema)
  • hyponatraemia
  • inappropriate anti-diuretic hormone secretion
  • increased salivation
  • slurred speech (dysarhtria)
  • sleepwalking
  • difficulty passing urine
  • changes in blood enzymes (shown in blood tests).

In children under 18 years the following side effects have been commonly observed:

  • significant weight gain
  • hives
  • increased blood triglycerides

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE MIRTAZAPINE
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton or foil 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.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. CONTENTS OF THE PACK AND FURTHER INFORMATION

What Mirtazapine contain
The active substance is mirtazapine.
a) Each film coated tablet contains: Mirtazapine USP 7.5mg.
b) Each film coated tablet contains: Mirtazapine USP 15mg
c) Each film coated tablet contains: Mirtazapine USP  30mg
d) Each film coated tablet contains: Mirtazapine USP  45mg
The other ingredients are lactose monohydrate, pregelatinised maize starch anhydrous colloidal silica, croscarmellose sodium and magnesium stearate.
Tablet coating: hypromellose, macrogol 8000, titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E 172) and talc.

What Mirtazapine look like and contents of the pack
Mirtazapine tablets are Brownish, scored on both sides, oval, biconvex, film-coated tablets. The tablets can be divided into equal halves.

Pack size is 28 tablets and packaging is 3×10 tablets.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com