Molipaxin Tablets 150mg

1. Name Of The Medicinal Product

Molipaxin 150mg Tablets

2. Qualitative And Quantitative Composition

Tablet containing 150mg of trazodone Hydrochloride.

For excipients, see 6.1

3. Pharmaceutical Form

Tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Relief of symptoms in all types of depression including depression accompanied by anxiety.

4.2 Posology And Method Of Administration

Route of administration: Oral.

Depression:

a) Adults:

Initially 150mg/day in divided doses after food or as a single dose on retiring.

This may be increased up to 300mg/day in a single or divided doses. The major portion of a divided dose to be taken on retiring. The dose may be further increased to 600mg/day in divided doses in hospitalised patients.

b) Elderly:

For very elderly or frail patients the recommended initial starting dose is reduced to100mg/day given in divided doses or as a single night-time dose. This may be incrementally increased, under supervision, according to efficacy and tolerance. In general, single doses above 100 mg should be avoided in these patients. It is unlikely that 300mg/day will be exceeded.

Children:

Molipaxin is not recommended for use in children below the age of 18 years due to a lack of data on safety.

Depression accompanied by anxiety:

As for depression.

Anxiety:

75mg/day increasing to 300mg/day as necessary.

A decrease in side-effects (increase of the resorption and decrease of the peak plasma concentration) can be reached by taking Molipaxin after a meal..

Hepatic Impairment:

Molipaxin undergoes extensive hepatic metabolism, see section 5.2, and has also been associated with hepatotoxicity, see sections 4.4 and 4.8. Therefore caution should be exercised when prescribing for patients with hepatic impairment, particularly in cases of severe hepatic impairment. Periodic monitoring of liver function may be considered.

Renal Impairment:

No dosage adjustment is usually necessary, but caution should be exercised when prescribing for patients with severe renal impairment (see also section 4.4 and 5.2).

4.3 Contraindications

Known sensitivity to trazodone and any of the excipients.

Alcohol intoxication and intoxication with hypnotics.

Acute myocardial infarction.

4.4 Special Warnings And Precautions For Use

Use in children and adolescents under 18

Molipaxin should not be used in children and adolescents under 18 years old. Suicidal behaviour (suicidal attempt and suicidal planning) and hostility (essentially aggressiveness, opposing behavior and anger) has been observed in a clinical study on children and adolescents treated with antidepressant more frequently than with placebo. Moreover, long-term safety data on children and adolescents regarding growth, maturation and cognitive and behavioral development are not available.

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.

Other psychiatric conditions for which Molipaxin is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

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 antidepressant drugs 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 drug therapy 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.

To minimise the potential risk of suicide attempts, particularly at therapy initiation, only restricted quantities of Molipaxin should be prescribed at each occasion.

It is recommended that careful dosing and regular monitoring is adopted in patients with the following conditions:

• Epilepsy, specifically abrupt increases or decreases of dosage should be avoided

• Patients with hepatic or renal impairment, particulary if severe

• Patients with cardiac disease, such as angina pectoris, conduction disorders or AV blocks of different degree, recent myocardial infarction

• Hyperthyroidism

• Micturition disorders, such as prostate hypertrophy, although problems would not be anticipated as the anticholinergic effect of Molipaxin is only minor

• Acute narrow angle glaucoma, raised intra-ocular pressure, although major changes would not be anticipated due to the minor anticholinergic effect of Molipaxin.

Should jaundice occur in a patient, Molipaxin therapy must be withdrawn.

Administration of antidepressants in patients with schizophrenia or other psychotic disorders may result in a possible worsening of psychotic symptoms. Paranoid thoughts may be intensified. During therapy with Molipaxin a depressive phase can change from a manic – depressive psychosis into a manic phase. In that case Molipaxin must be stopped.

Interactions in terms of serotonine syndrome/malignant neuroleptic syndrome have been described in case of concomitant use of other serotonergically acting substances like other antidepressants (e.g. tricyclic antidepressants, SSRI's, SNRI's and MAO-inhibitors) and neuroleptics. Malignant neuroleptic syndromes with fatal outcome have been reported in cases of coadministration with neuroleptics, for which this syndrome is a known possible adverse drug reaction. See Sections 4.5 and 4.8 for further information.

Since agranulocytosis may clinically reveal itself with influenza-like symptoms, sore throat, and fever, in these cases it is recommended to check haematology.

Hypotension, including orthostatic hypotension and syncope, has been reported to occur in patients receiving Molipaxin. Concomitant administration of antihypertensive therapy with Molipaxin may require a reduction in the dose of the antihypertensive drug

Elderly patients are often more sensitive to antidepressants, in particular to orthostatic hypotension and other anticholinergic effects.

Following therapy with Molipaxin, particularly for a prolonged period, an incremental dosage reduction to withdrawal is recommended, to minimise the occurrence of withdrawal syptoms, characterised by nausea, headache, and malaise.

There is no evidence that Molipaxin possesses any addictive properties.

As with other antidepressant drugs, cases of QT interval prolongation have been reported with Molipaxin very rarely. Caution is advised when prescribing Molipaxin with medicinal products known to prolong QT interval. Molipaxin should be used with caution in patients with known cardiovascular disease including those associated with prolongation of the QT interval.

Potent CYP3A4 inhibitors may lead to increases in trazodone serum levels. See section 4.5 for further information.

As with other drugs with alpha-adrenolytic activity, Molipaxin has very rarely been associated with priapism. This may be treated with an intracavernosum injection of an alpha-adrenergic agent such as adrenaline or metaraminol. However there are reports of Molipaxin-induced priapism which have required surgical intervention or led to permanent sexual dysfunction. Patients developing this suspected adverse reaction should cease Molipaxin immediately.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

General: The sedative effects of antipsychotics, hypnotics, sedatives, anxiolytics, and antihistaminic drugs may be intensified; dosage reduction is recommended in such instances.

The metabolism of antidepressants is accelerated due to hepatic effects by oral contraceptives, phenytoin, carbamazepine and barbiturates. The metabolism of antidepressants is inhibited by cimetidine and some other antipsychotics.

In vitro drug metabolism studies suggest that there is a potential for drug interactions when Molipaxin is given with potent CYP3A4 inhibitors such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir, and nefazodone. It is likely that potent CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. Exposure to ritonavir during initiation or resumption of treatment in patients receiving Molipaxin will increase the potential for excessive sedation, cardiovascular, and gastrointestinal effects. It has been confirmed in in- vivo-studies in healthy volunteers, that a ritonavir dose of 200 mg BID increased the plasma levels of Molipaxin by greater than two-fold, leading to nausea, syncope and hypotension. If Molipaxin is used with a potent CYP3A4 inhibitor, a lower dose of Molipaxin should be considered. However, the co-administration of Molipaxin and potent CYP3A4 inhibitors should be avoided where possible.

Carbamazepine reduced plasma concentrations of trazodone when coadministered. Concomitant use of carbamazepine 400 mg daily led to a decrease of plasma concentrations of Molipaxin and its active metabolite m-chlorophenylpiperazine of 76 % and 60 %, respectively. Patients should be closely monitored to see if there is a need for an increased dose of Molipaxin when taken with carbamazepine.

Molipaxin may enhance the effects of muscle relaxants and volatile anaesthetics, and caution should be exercised in such instances. Similar considerations apply to combined administration with sedative and anti-depressant drugs, including alcohol. Molipaxin intensifies the sedative effects of alcohol. Alcohol should be avoided during Molipaxin therapy. Molipaxin has been well tolerated in depressed schizophrenic patients receiving standard phenothiazine therapy and also in depressed parkinsonian patients receiving therapy with levodopa. Antidepressants can accelerate the metabolism of levodopa.

Tricyclic antidepressants: Concurrent administration should be avoided due to the risk of interaction. Serotonine syndrome and cardiovascular side effects should be bewared.

Fluoxetine: Rare cases have been reported of elevated Molipaxin plasma levels and adverse effects when Molipaxin had been combined with fluoxetine, a CYP1A2/2D6 inhibitor. The mechanism underlying a pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonine syndrome) could not be excluded.

Possible interactions with monoamine oxidase inhibitors have occasionally been reported. Although some clinicians do give both concurrently, use of Molipaxin with MAOIs, or within two weeks of stopping treatment with these compounds is not recommended. The giving of MAOIs within one week of stopping Molipaxin is also not recommended.

Phenothiazines: Severe orthostatic hypotension has been observed in case of concomitant use of phenothiazines, like e.g. chlorpromazine, fluphenazine, levomepromazine, perphenazine.

Other

Concomitant use of Molipaxin with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias, including torsade de pointes. Caution should be used when these drugs are coadministered with Molipaxin.

Since Molipaxin is only a very weak inhibitor of noradrenaline re-uptake and does not modify the blood pressure response to tyramine, interference with the hypotensive action of guanethidine-like compounds is unlikely. However, studies in laboratory animals suggest that Molipaxin may inhibit most of the acute actions of clonidine. In the case of other types of antihypertensive drug, although no clinical interactions have been reported, the possibility of potentiation should be considered.

Undesirable effects may be more frequent when Molipaxin is administered together with preparations containing Hypericum perforatum (St John's wort).

There have been reports of changes in prothrombin time in patients concomitantly receiving trazodone and warfarin.

Concurrent use with Molipaxin may result in elevated serum levels of digoxin or phenytoin. Monitoring of serum levels should be considered in these patients.

4.6 Pregnancy And Lactation

Pregnancy:

Data on a limited number (< 200) of exposed pregnancies indicate no adverse effects of Molipaxin on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. The safety of Molipaxin in human pregnancy has not been established. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development at therapeutic doses. On basic principles, therefore, its use during the first trimester should be avoided.

Caution should be exercised when prescribing to pregnant women. When Molipaxin is used until delivery, newborns should be monitored for the occurrence of withdrawal symptoms.

Lactation:

Limited data indicate that excretion of Molipaxin in human breast milk is low, but levels of the active metabolite are not known. Due to the paucity of data, a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Molipaxin should be made taking into account the benefit of breast-feeding to the child and the benefit of Molipaxin therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

Molipaxin has minor or moderate influence on the ability to drive and use machines. As with all other drugs acting on the central nervous system, patients should be cautioned against the risks of driving or operating machinery until they are sure they are not affected by drowsiness, sedation, dizziness, confusional states, or blurred vision.

4.8 Undesirable Effects

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

Molipaxin has had no effect on arterial blood pCO₂ or pO₂ levels in patients with severe respiratory insufficiency due to chronic bronchial or pulmonary disease.

The following symptoms, some of which are commonly reported in cases of untreated depression, have also been recorded in patients receiving Molipaxin therapy.

MedDRA System Organ Class	Frequency not known (cannot be estimated from the available data)
Blood and the lymphatic system disorders	Blood dyscrasias (including agranulocytosis, thrombocytopenia, eosinophilia, leucopenia and anaemia)
Immune system disorders	Allergic reactions
Endocrine disorders	Syndrome of Inappropriate Antidiuretic Hormone Secretion
Metabolism and nutrition disorders	Hyponatraemia1, weight loss, anorexia, increased appetite,
Psychiatric disorders	Suicidal ideation or suicidal behaviours2, confusional state, insomnia, disorientation, mania, anxiety, nervousness, agitation (very occasionally exacerbating to delirium), delusion, aggressive reaction, hallucinations, nightmares, libido decreased, withdrawal syndrome
Nervous system disorders	Serotonin syndrome, convulsion, neuroleptic malignant syndrome, dizziness, vertigo, headache, drowsiness3, restlessness, decreased alertness, tremor, blurred vision, memory disturbance, myoclonus, expressive aphasia, paraesthesia, dystonia, taste altered
Cardiac disorders	Cardiac arrhythmias4 (including Torsade de Pointes, palpitations, premature ventricular contractions, ventricular couplets, ventricular tachycardia), bradycardia, tachycardia, ECG abnormalities (QT prolongation)2
Vascular disorders	Ortostatic hypotension, hypertension, syncope
Respiratory, thoracic and mediastinal disorders	Nasal congestion, dyspnoea
Gastrointestinal disorders	Nausea, vomiting, dry mouth, constipation, diarrhoea, dyspepsia, stomach pain, gastroenteritis, increased salivation, paralytic ileus
Hepato-biliary disorders	Hepatic function abnormalities (including jaundice and hepatocellular damage)5 , cholestasis intrahepatic
Skin and subcutaneous tissue disorders	Skin rash, pruritus, hyperhidrosis
Musculoskeletal and connective tissue disorders	Pain in limb, back pain, myalgia, arthralgia
Renal and urinary disorders	Micturition disorderd
Reproductive system and breast disorders	Priapism6
General disorders and administration site conditions	Weakness, oedema, influenza-like symptoms, fatigue, chest pain, fever
Investigations	Elevated liver enzymes

¹ Fluid and electrolyte status should be monitored in symptomatic patients.

² See also Section 4.4.

³ Trazodone is a sedative antidepressant and drowsiness, sometimes experienced during the first days of treatment, usually disappears on continued therapy.

⁴ Studies in animals have shown that trazodone is less cardiotoxic than the tricyclic antidepressants, and clinical studies suggest that the drug may be less likely to cause cardiac arrhythmias in man. Clinical studies in patients with pre-existing cardiac disease indicate that trazodone may be arrhythmogenic in some patients in that population.

⁵ Adverse effects on hepatic function, sometimes severe, have been rarely reported. Should such effects occur, trazodone should be immediately discontinued.

⁶ See also Section 4.4

4.9 Overdose

Features of toxicity

The most frequently reported reactions to overdose have included drowsiness, dizziness, nausea and vomiting. In more serious cases coma, tachycardia, hypotension, hyponatraemia, convulsions and respiratory failure have been reported. Cardiac features may include bradycardia, QT prolongation and torsade de pointes. Symptoms may appear 24 hours or more after overdose.

Overdoses of Molipaxin in combination with other antidepressants may cause serotonin syndrome.

Management

There is no specific antidote to trazodone. Activated charcoal should be considered in adults who have ingested more than 1 g trazodone, or in children who have ingested more than 150 mg trazodone within 1 hour of presentation. Alternatively, in adults, gastric lavage may be considered within 1 hour of ingestion of a potentially life-threatening overdose.

Observe for at least 6 hours after ingestion (or 12 hours if a sustained release preparation has been taken). Monitor BP, pulse and Glasgow Coma Scale (GCS). Monitor oxygen saturation if GCS is reduced. Cardiac monitoring is appropriate in symptomatic patients.

Single brief convulsions do not require treatment. Control frequent or prolonged convulsions with intravenous diazepam (0.1-0.3 mg/kg body weight) or lorazepam (4 mg in an adult and 0.05 mg/kg in a child). If these measures do not control the fits, an intravenous infusion of phenytoin may be useful. Give oxygen and correct acid base and metabolic disturbances as required.

Treatment should be symptomatic and supportive in the case of hypotension and excessive sedation. If severe hypotension persists consider use of inotropes, eg dopamine or dobutamine

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: N06A X05. Other antidepressants.

Molipaxin is a potent antidepressant. It also has anxiety reducing activity. Molipaxin is a triazolopyridine derivative chemically unrelated to known tricyclic, tetracyclic and other antidepressant agents. It has negligible effect on noradrenaline re-uptake mechanisms. Whilst the mode of action of Molipaxin is not known precisely, its antidepressant activity may concern noradrenergic potentiation by mechanisms other than uptake blockade. A central antiserotonin effect may account for the drug's anxiety reducing properties.

5.2 Pharmacokinetic Properties

Trazodone is rapidly absorbed from the gastro-intestinal tract and extensively metabolised. Paths of metabolism of Trazodone include n-oxidation and hydroxylation. The metabolic m-chlorophenylpiperazine is active. Trazodone is excreted in the urine almost entirely in the form of its metabolites, either in free or in conjugated form. The elimination of Trazodone is biphasic, with a terminal elimination half-life of 5 to 13 hours. Trazodone is excreted in breast milk.

There was an approximate two-fold increase in terminal phase half-life and significantly higher plasma concentrations of Trazodone in 10 subjects aged 65 to 74 years compared with 12 subjects aged 23 to 30 years following a 100mg dose of Trazodone. It was suggested that there is an age-related reduction in the hepatic metabolism of Trazodone.

In vitro studies in human liver microsomes show that trazodone is metabolised by cytochrome P4503A4 (CYP3A4) to form m-chlorophenylpiperazine. Whilst significant, the role of this pathway in the total clearance of trazodone in vivo has not been fully determined.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The tablets also contain lactose, calcium hydrogen phosphate, microcrystalline cellulose, maize starch, sodium starch glycollate, povidone and magnesium stearate. The film coating contains hydroxypropyl methyl cellulose, propylene glycol, red iron oxide E172 and titanium dioxide.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Glass bottles: Store below 30 ºC.

Blister packs: Store in a dry place below 30ºC.

6.5 Nature And Contents Of Container

i) Amber glass bottles with jay-caps: pack sizes 28, 30 or 100

ii) Blister packs: pack size 28 or 100 tablets

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0606

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of First Authorisation: 30 January 2010

10. Date Of Revision Of The Text

27/09/2010

LEGAL CLASSIFICATION

POM

Mircera solution for injection in pre-filled syringe

1. Name Of The Medicinal Product

MIRCERA 30 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 50 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 75 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 100 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 120 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 150 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 200 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 250 micrograms/0.3 ml solution for injection in pre-filled syringe

MIRCERA 360 micrograms/0.6 ml solution for injection in pre-filled syringe

2. Qualitative And Quantitative Composition

One pre-filled syringe contains 30 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 100 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 50 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 167 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 75 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 250 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 100 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 333 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 120 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 400 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 150 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 500 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 200 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 667 micgrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 250 micrograms of methoxy polyethylene glycol-epoetin beta* at a concentration of 833 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

One pre-filled syringe contains 360 micrograms of methoxy polyethylene glycol-epoetin beta*at a concentration of 600 micrograms/ml. The strength indicates the quantity of the protein moiety of the methoxy polyethylene glycol-epoetin beta molecule without consideration of the glycosylation.

*Protein produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cells and covalently conjugated to a linear methoxy-polyethylene glycol (PEG).

The potency of methoxy polyethene glycol-epoetin beta should not be compared to the potency of another pegylated or non-pegylated protein of the same therapeutic class. For more information, see section 5.1.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection).

The solution is clear and colourless to slightly yellowish.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of symptomatic anaemia associated with chronic kidney disease (CKD).

The safety and efficacy of MIRCERA therapy in other indications has not been established.

4.2 Posology And Method Of Administration

Treatment of symptomatic anaemia in adult chronic kidney disease patients

Treatment with MIRCERA has to be initiated under the supervision of a physician experienced in the management of patients with renal impairment.

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician's evaluation of the individual patient's clinical course and condition is necessary. MIRCERA should be administered either subcutaneously or intravenously in order to increase haemoglobin to not greater than 12 g/dl (7.45 mmol/l). Subcutaneous use is preferable in patients who are not receiving haemodialysis to avoid puncture of peripheral veins.

MIRCERA can be injected subcutaneously in the abdomen, arm or thigh. All three injection sites are equally suitable.

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.45 mmol/l) should be avoided; guidance for appropriate dose adjustment for when haemoglobin values exceeding 12 g/dl (7.45 mmol/l) are observed are described below.

A rise in haemoglobin of greater than 2 g/dl (1.24 mmol/l) over a four-week period should be avoided. If it occurs, appropriate dose adjustment should be made as provided.

Patients should be monitored closely to ensure that the lowest approved dose of MIRCERA is used to provide adequate control of the symptoms of anaemia.

It is recommended that haemoglobin is monitored every two weeks until stabilized and periodically thereafter.

Patients not currently treated with an erythropoiesis stimulating agent (ESA):

In order to increase haemoglobin levels to greater than 10 g/dl (6.21 mmol/l), the recommended starting dose in patients not on dialysis is 1.2 microgram/kg body weight, administered once every month as a single subcutaneous injection.

Alternatively, a starting dose of 0.6 microgram/kg bodyweight may be administered once every two weeks as a single intravenous or subcutaneous injection in patients on dialysis or not on dialysis.

The dose may be increased by approximately 25% of the previous dose if the rate of rise in haemoglobin is less than 1.0 g/dl (0.621 mmol/l) over a month. Further increases of approximately 25% may be made at monthly intervals until the individual target haemoglobin level is obtained.

If the rate of rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in one month or if the haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25% below the previously administered dose. After dose interruption a haemoglobin decrease of approximately 0.35 g/dl (0.22 mmol/l) per week is expected. Dose adjustments should not be made more frequently than once a month.

Patients treated once every two weeks whose haemoglobin concentration is above 10 g/dl (6.21 mmol/l) may receive MIRCERA administered once-monthly using the dose equal to twice the previous once-every-two-weeks dose.

Patients currently treated with an ESA:

Patients currently treated with an ESA can be switched to MIRCERA administered once a month as a single intravenous or subcutaneous injection. The starting dose of methoxy polyethylene glycol-epoetin beta is based on the calculated previous weekly dose of darbepoetin alfa or epoetin at the time of substitution as described in Table 1. The first injection should start at the next scheduled dose of the previously administered darbepoetin alfa or epoetin.

Table 1: MIRCERA starting doses

Previous weekly darbepoetin alfa intravenous or subcutaneous dose (microgram/week)	Previous weekly epoetin intravenous or subcutaneous dose (IU/week)	Monthly MIRCERA intravenous or subcutaneous dose (microgram/once monthly)
<40	<8000	120
40-80	8000-16000	200
>80	>16000	360

If a dose adjustment is required to maintain the target haemoglobin concentration above 10 g/dl (6.21 mmol/l), the monthly dose may be increased by approximately 25%.

If the rate of rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) over a month or if the haemoglobin level is increasing and approaching 12 g/dl (7.45 mmol/l), the dose is to be reduced by approximately 25%. If the haemoglobin level continues to increase, therapy should be interrupted until the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25% below the previously administered dose. After dose interruption a haemoglobin decrease of approximately 0.35 g/dl (0.22 mmol/l) per week is expected. Dose adjustments should not be made more frequently than once a month.

Since the treatment experience is limited in patients on peritoneal dialysis, regular haemoglobin monitoring and strict adherence to dose adjustment guidance is recommended in these patients.

Treatment interruption

Treatment with MIRCERA is normally long-term. However, it can be interrupted at any time, if necessary.

Missed dose

If one dose of MIRCERA is missed, the missed dose is to be administered as soon as possible and administration of MIRCERA is to be restarted at the prescribed dosing frequency.

Paediatric use

MIRCERA is not recommended for use in children and adolescents below 18 years due to a lack of safety and efficacy data.

Elderly patients

In clinical studies 24% of patients treated with MIRCERA were aged 65 to 74 years, while 20% were aged 75 years and over. No dose adjustment is required in patients aged 65 years or older.

Patients with hepatic impairment

No adjustments of the starting dose nor of the dose modification rules are required in patients with hepatic impairment (see section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Uncontrolled hypertension.

4.4 Special Warnings And Precautions For Use

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 microgram/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, iron status has to be evaluated for all patients prior to and during treatment.

Failure to respond to MIRCERA therapy should prompt for a search for causative factors. Deficiencies of iron, folic acid or vitamin B12 reduce the effectiveness of ESAs and should therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, severe aluminium toxicity, underlying haematologic diseases, or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation. If all the conditions mentioned are excluded and the patient has a sudden drop of haemoglobin associated with reticulocytopenia and anti-erythropoietin antibodies, examination of the bone marrow for the diagnosis of Pure Red Cell Aplasia (PRCA) should be considered. In case PRCA is diagnosed, therapy with MIRCERA must be discontinued and patients should not be switched to another ESA.

Pure Red Cell Aplasia caused by anti-erythropoietin antibodies has been reported in association with all ESAs, including MIRCERA. These antibodies have been shown to cross-react with all ESAs, and patients suspected or confirmed to have antibodies to erythropoietin should not be switched to MIRCERA (see section 4.8).

PRCA in patients with Hepatitis C: A paradoxical decrease in haemoglobin and development of severe anaemia associated with low reticulocyte counts should prompt to discontinue treatment with epoetin and perform anti-erythropoietin antibody testing. Cases have been reported in patients with hepatitis C treated with interferon and ribavirin, when epoetins are used concomitantly. Epoetins are not approved in the management of anaemia associated with hepatitis C.

Haemoglobin concentration: In patients with chronic kidney disease, maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death, serious cardiovascular events, including thrombosis or cerebrovascular events including stroke was observed when erythropoiesis stimulating agents (ESAs) were administered to target a haemoglobin of greater than 12 g/dl (7.5 mmol/l) (see section 4.8).

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Blood pressure monitoring: As with other ESAs, blood pressure may rise during treatment with MIRCERA. Blood pressure should be adequately controlled in all patients before, at initiation of, and during treatment with MIRCERA. If high blood pressure is difficult to control by medical treatment or dietary measures, the dose must be reduced or administration discontinued (see section 4.2).

Effect on tumour growth: MIRCERA, like other ESAs, is a growth factor that primarily stimulates red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that ESAs could stimulate the growth of any type of malignancy. Two controlled clinical studies in which epoetins were administered to patients with various cancers including head and neck cancers, and breast cancer, have shown an unexplained excess mortality.

MIRCERA is not approved for the treatment of anaemia in patients with cancer.

The safety and efficacy of MIRCERA therapy has not been established in patients with haemoglobinopathies, seizures, bleeding or a recent history of bleeding requiring transfusions or with platelet levels greater than 500 x 10⁹/l. Therefore, caution should be used in these patients.

Misuse of MIRCERA by healthy people may lead to an excessive increase in haemoglobin. This may be associated with life-threatening cardiovascular complications.

Traceability of MIRCERA: In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient file.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed. There is no evidence that MIRCERA alters the metabolism of other medicinal products.

4.6 Pregnancy And Lactation

Pregnancy:

There are no data from the use of MIRCERA in pregnant women.

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryofoetal development, parturition or postnatal development but indicate a class-related reversible reduction in foetal weight (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Lactation:

It is unknown whether methoxy polyethylene glycol-epoetin beta is excreted in human breast milk. One animal study has shown excretion of methoxy polyethylene glycol-epoetin beta in maternal milk. A decision on whether to continue or discontinue breast-feeding or to continue or discontinue therapy with MIRCERA should be made taking into account the benefit of breast-feeding to the child and the benefit of MIRCERA therapy to the woman.

4.7 Effects On Ability To Drive And Use Machines

MIRCERA has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

The safety data base from clinical trials comprised 3'042 CKD patients, including 1'939 patients treated with MIRCERA and 1'103 with another ESA. Approximately 6% of patients treated with MIRCERA are expected to experience adverse reactions. The most frequent reported adverse reaction was hypertension (common).

The frequencies are defined as follows:

very common (

Table 2: Adverse reactions attributed to the treatment with MIRCERA in controlled clinical trials in CKD patients

System organ class	Frequency	Adverse reaction
Nervous system disorders	Uncommon	Headache
Nervous system disorders	Rare	Hypertensive encephalopathy
Skin and subcutaneous tissue disorders	Rare	Rash, maculo-papular
Injury, poisoning and procedural complications	Uncommon	Vascular access thrombosis
Vascular disorders	Common	Hypertension
Vascular disorders	Rare	Hot flush
Immune system disorders	Rare	Hypersensitivity

All other events attributed to MIRCERA were reported with rare frequency and the majority were mild to moderate in severity. These events were consistent with comorbidities known in the population.

During treatment with MIRCERA, a slight decrease in platelet counts remaining within the normal range was observed in clinical studies.

Platelet counts below 100 x 10⁹/l were observed in 7% of patients treated with MIRCERA and 4% of patients treated with other ESAs.

Data from a controlled clinical trial with epoetin alfa or darbepoetin alfa reported an incidence of stroke as common (

Postmarketing experience

Hypersensitivity reactions, including cases of anaphylactic reaction, have been spontaneously reported, frequency unknown.

As with other erythropoiesis stimulating agents, cases of thrombosis, including pulmonary embolism, have been reported in the post-marketing setting, frequency unknown (see section 4.4).

Cases of thrombocytopenia have been spontaneously reported, frequency unknown.

Neutralising anti-erythropoietin antibody-mediated pure red cell aplasia (PRCA), frequency unknown. In case PRCA is diagnosed therapy with MIRCERA must be discontinued, and patients should not be switched to another recombinant erythropoietic protein (see section 4.4).

4.9 Overdose

The therapeutic range of MIRCERA is wide. Individual responsiveness must be considered when treatment is initiated. Overdose can result in manifestations of an exaggerated pharmacodynamic effect, e.g. excessive erythropoiesis. In case of excessive haemoglobin levels, treatment with MIRCERA should be temporarily discontinued (see section 4.2). If clinically indicated, phlebotomy may be performed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antianaemic preparations, ATC code: B03XA03

Methoxy polyethylene glycol-epoetin beta, the active substance of MIRCERA, is a continuous erythropoietin receptor activator that shows a different activity at the receptor level characterized by a slower association to and faster dissociation from the receptor, a reduced specific activity in vitro with an increased activity in vivo, as well as an increased half-life, in contrast to erythropoietin. The average molecular mass is approximately 60 kDa of which the protein moiety plus the carbohydrate part constitutes approximately 30 kDa.

MIRCERA stimulates erythropoiesis by interaction with the erythropoietin receptor on progenitor cells in the bone marrow. As primary growth factor for erythroid development, the natural hormone erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, the natural hormone erythropoietin interacts with erythroid progenitor cells to increase red cell production.

Data from correction studies with patients treated once every two weeks and once every four weeks show that the haemoglobin response rates in the MIRCERA group at the end of the correction period were high and comparable to comparators. The median time to response was 43 days in the MIRCERA arm and 29 days in the comparator arm, with increases of haemoglobin within the first 6 weeks of 0.2 g/dl/week and 0.3 g/dl/week, respectively.

Four randomised controlled studies were performed in dialysis patients treated with darbepoetin alfa or epoetin at the time of enrollment. Patients were randomized to stay on their treatment at the time of enrollment or to be switched to MIRCERA in order to maintain stable haemoglobin levels. At the evaluation period (week 29-36), the mean and median level of haemoglobin in patients treated with MIRCERA was virtually identical to their baseline haemoglobin level.

In a randomised, double-blind, placebo-controlled study of 4,038 CRF patients not on dialysis with type 2 diabetes and haemoglobin levels

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.

Survival and tumour progression have been examined in five large controlled studies involving a total of 2'833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy. The target haemoglobin concentration in two studies was >13 g/dl; in the remaining three studies it was 12-14 g/dl. In the open-label study there was no difference in overall survival between patients treated with recombinant human erythropoietin and controls. In the four placebo-controlled studies the hazard ratios for overall survival ranged between 1.25 and 2.47 in favour of controls. These studies have shown a consistent unexplained statistically significant excess mortality in patients who have anaemia associated with various common cancers who received recombinant human erythropoietin compared to controls. Overall survival outcome in the trials could not be satisfactorily explained by differences in the incidence of thrombosis and related complications between those given recombinant human erythropoietin and those in the control group.

A patient-level data analysis has also been performed on more than 13,900 cancer patients (chemo-, radia-, chemoradia-, or no therapy) participating in 53 controlled clinical trials involving several epoetins. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.06 in favour of controls (95% CI: 1.00, 1.12; 53 trials and 13933 patients) and for the cancer patients receiving chemotherapy, the overall survival hazard ratio was 1.04 (95% CI: 0.97, 1.11; 38 trials and 10,441 patients). Meta-analyses also indicate consistently a significantly increased relative risk of thromboembolic events in cancer patients receiving recombinant human erythropoietin (see section 4.4). Mircera is not approved for treatment of patients with chemotherapy induced anaemia (see section 4.1), no patients treated with MIRCERA were part of this data analysis.

5.2 Pharmacokinetic Properties

The pharmacokinetics of methoxy polyethylene glycol-epoetin beta were studied in healthy volunteers and in anaemic patients with CKD including patients on dialysis and not on dialysis.

Following subcutaneous administration to CKD patients not on dialysis, the maximum serum concentrations of methoxy polyethylene glycol-epoetin beta were observed 95 hours (median value) after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after subcutaneous administration was 54%. The observed terminal elimination half-life was 142 hours in CKD patients not on dialysis.

Following subcutaneous administration to CKD patients on dialysis, the maximum serum concentrations of methoxy polyethylene glycol-epoetin beta were observed 72 hours (median value) after administration. The absolute bioavailability of methoxy polyethylene glycol-epoetin beta after subcutaneous administration was 62% and the observed terminal elimination half-life was 139 hours in CKD patients on dialysis.

Following intravenous administration to CKD patients on dialysis, the total systemic clearance was 0.494 ml/h per kg. The elimination half-life after intravenous administration of methoxy polyethylene glycol-epoetin beta is 134 hours.

A comparison of serum concentrations of methoxy polyethylene glycol-epoetin beta measured before and after haemodialysis in 41 CKD patients showed that haemodialysis has no effect on the pharmacokinetics of this medicinal product.

An analysis in 126 CKD patients showed no pharmacokinetic difference between patients on dialysis and patients not on dialysis.

In a single dose study, after intravenous administration, the pharmacokinetics of methoxy polyethylene glycol-epoetin beta are similar in patients with severe hepatic impairment as compared to healthy subjects (see section 4.2).

5.3 Preclinical Safety Data

Non-clinical data show no special hazard for humans based on conventional studies of cardiovascular safety pharmacology, repeat dose toxicity and reproductive toxicity.

The carcinogenic potential of methoxy polyethylene glycol-epoetin beta has not been evaluated in long-term animal studies. It did not induce a proliferative response in non-haematological tumor cell lines in vitro. In a six-month rat toxicity study no tumorigenic or unexpected mitogenic responses were observed in non-haematological tissues. In addition, using a panel of human tissues, the in vitro binding of methoxy polyethylene glycol-epoetin beta was only observed in target cells (bone marrow progenitor cells).

No significant placental transfer of methoxy polyethylene glycol-epoetin beta was observed in the rat, and studies in animals have not shown any harmful effect on pregnancy, embryofoetal development, parturition or postnatal development. There was however a class-related reversible reduction in foetal weight and a decrease in postnatal body-weight gain of offspring at the doses causing exaggerated pharmacodynamic effects in mothers. Physical, cognitive, or sexual developments in the offspring of mothers receiving methoxy polyethylene glycol-epoetin beta during gestation and lactation were not affected. When methoxy polyethylene glycol-epoetin beta was administered subcutaneously to male and female rats prior to and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium dihydrogen phosphate monohydrate

Sodium sulphate

Mannitol (E421)

Methionine

Poloxamer 188

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C)

Do not freeze

Keep the pre-filled syringe in the outer carton in order to protect from light

The end-user may remove the medicinal product from refrigeration for storage at a room temperature not above 30°C for one single period of 1 month. Once removed from the refrigerator the medicinal product must be used within this period.

6.5 Nature And Contents Of Container

Pre-filled syringe (type I glass) with laminated plunger stopper (bromobutyl rubber material) and tip cap (bromobutyl rubber material) and a needle 27G1/2. Pack size of 1.

6.6 Special Precautions For Disposal And Other Handling

The pre-filled syringe is ready for use. The sterile pre-filled syringe does not contain any preservative and is to be used for a single injection only. Only one dose should be administered per syringe. Only solutions which are clear, colourless to slightly yellowish and free of visible particles must be injected.

Do not shake.

Allow the pre-filled syringe to reach room temperature before injecting.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/07/400/008 - MIRCERA 50 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/009 - MIRCERA 75 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/010 - MIRCERA 100 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/011 - MIRCERA 150 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/012 - MIRCERA 200 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/013 - MIRCERA 250 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/017 - MIRCERA 30 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/020 - MIRCERA 120 micrograms/0.3 ml solution for injection in pre-filled syringe.

EU/1/07/400/021 - MIRCERA 360 micrograms/0.6 ml solution for injection in pre-filled syringe.

9. Date Of First Authorisation/Renewal Of The Authorisation

20 July 2007

10. Date Of Revision Of The Text

20^th October 2011

LEGAL STATUS

POM

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/

Mirtazapine 15mg Tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Mirtazapine 15mg Tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 15mg of mirtazapine

Excipient: Lactose monohydrate.

Each tablet contains 101.8mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Yellow, scored on both sides, 10 x 5.2 mm oval, biconvex, film-coated tablets. Marked with I on one side.

The tablet can be divided into equal halves

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of episodes of major depression.

4.2 Posology And Method Of Administration

Adults

The effective daily dose is usually between 15 and 45mg; the starting dose is 15 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.

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.

Children and adolescents under the age of 18 years

Mirtazapine should not be used in children and adolescents under the age of 18 years (see section 4.4).

Renal impairment

The clearance of mirtazapine may be decreased in patients with moderate to severe renal impairment (creatinine clearance <40ml/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).

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.

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).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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

4.4 Special Warnings And Precautions For Use

Use in children and adolescents under 18 years of age

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 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 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 care givers 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.

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 <40ml/min) and severe (creatinine clearance <10ml/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 <80ml/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.

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. 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, 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 (L-tryptophan, triptans, tramadol, linezolid, 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.

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.

4.6 Pregnancy And Lactation

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). 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.

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).

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.

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'.

Table 1. Adverse reactions of mirtazapine

System organ class	Very common (	Common (	Uncommon (	Rare (	Frequency not known
Investigations	Weight increased1
Blood and the lymphatic system disorders					Bone marrow depression (granulocytopenia, agranulocytosis, aplastic anemia thrombocytopenia) Eosinophilia
Nervous system disorders	Somnolence1, 4 Sedation1, 4 Headache2	Lethargy1 Dizziness Tremor	Paraesthesia2 Restless legs Syncope	Myoclonus	Convulsions (insults) Serotonin syndrome Oral paraesthesia
Gastrointestinal disorders	Dry mouth	Nausea3 Diarrhea2 Vomiting2	Oral hypoaesthesia		Mouth oedema
Skin and subcutaneous tissue disorders		Exanthema2
Musculoskeletal and connective tissue disorders		Arthralgia Myalgia Back pain1
Metabolism and nutrition disorders	Increase in appetite1				Hyponatraemia
Vascular disorders		Orthostatic hypotension	Hypotension2
General disorders and administration site conditions		Oedema peripheral1 Fatigue
Hepatobiliary disorders				Elevations in serum transaminase activities
Psychiatric disorders		Abnormal dreams Confusion Anxiety2, 5 Insomnia3, 5	Nightmares2 Mania Agitation2 Hallucinations Psychomotor restlessness (incl. akathisia, hyperkinesia)		Suicidal ideation6 Suicidal behaviour6
Endocrine disorders					Inappropriate antidiuretic hormone secretion

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 gammaglutamyltransferase have been observed (however associated adverse events have not been reported statistically significantly more frequently with mirtazapine than with placebo).

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.

Cases of overdose should receive appropriate symptomatic and supportive therapy for vital functions.

Activated charcoal or gastric lavage should also be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other antidepressants, ATC code: N06AX11

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.

The histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. It has practically no anticholinergic activity and, at therapeutic doses, has practically no effect on the cardiovascular system.

5.2 Pharmacokinetic Properties

After oral administration of mirtazapine, the active substance mirtazapine is rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels after approx. two hours. Binding of mirtazapine to plasma proteins is approx. 85%. 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. Mirtazapine displays linear pharmacokinetics within the recommended dose range. Food intake has no influence on the pharmacokinetics of mirtazapine.

Mirtazapine is extensively metabolized 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.

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

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, carcinogenicity or genotoxicity.

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

Core:

Lactose monohydrate

Pregelatinised maize starch

Anhydrous colloidal silica

Croscarmellose sodium

Magnesium stearate.

Coating:

Hypromellose

Macrogol 8000

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172).

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 polypropylene tablet containers with LDPE/HDPE caps.

The pack size of 500 tablets is intended for hospital use. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

IS-220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0170

9. Date Of First Authorisation/Renewal Of The Authorisation

20/03/2008

10. Date Of Revision Of The Text

20.07.2010