Data Sheet

REMERON

Mirtazapine 15mg, 30mg & 45mg

Presentation

REMERON 15mg: Each tablet consists of 15mg of mirtazapine. REMERON 15mg tablets are yellow oval, biconvex and marked with 'Organon' on one side and a code (TZ/3) on the other side. The 15mg tablets are scored.

REMERON 30mg: Each tablet consists of 30mg of mirtazapine. REMERON 30mg tablets are red-brown oval, biconvex and marked with 'Organon' on one side and a code (TZ/5) on the other side. The 30mg tablets are scored.

REMERON 45mg: Each tablet consists of 45mg of mirtazapine. REMERON 45mg tablets are white oval, biconvex and marked with 'Organon' on one side and a code (TZ/7) on the other side.

Uses

Actions

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. Mirtazapine is generally well tolerated. It has practically no anticholinergic activity and, at therapeutic doses, has practically no effect on the cardiovascular system.

Pharmacokinetics

After oral administration of REMERON tablets, the active constituent mirtazapine is rapidly and well absorbed (bioavailability ≈ 50%), reaching peak plasma levels after about 2 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 insufficiency.

Indications

Episode of major depression.

Dosage and Administration

Administration

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

The clearance of mirtazapine may be decreased in patients with renal or hepatic insufficiency. This should be taken into account when prescribing REMERON to this category of patients.

Mirtazapine has a half-life of 20-40 hours and, therefore, REMERON is suitable for once-a-day administration. It should be taken preferably as a single night-time dose before going to bed.

REMERON may also be given in sub-doses equally divided over the day (once in the morning and once at night-time).

Treatment should preferably be continued until the patient has been completely symptom-free for 4-6 months. After this, treatment can be gradually discontinued. 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.

Adults

Treatment should begin with 15mg daily. The dosage generally needs to be increased to obtain an optimal clinical response. The effective daily dose is usually between 15 and 45mg.

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

Safety and efficacy have not been established in placebo-controlled trials in this population. Safety and efficacy cannot be extrapolated from data obtained in adults. Consequently, mirtazapine should not be used in patients under 18 years of age.

Contraindications

Hypersensitivity to mirtazapine, or to any of the excipients in the tablet.

Warnings and Precautions

Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with REMERON. This mostly appears after 4-6 weeks of treatment and is in general reversible after termination of treatment. However, in very rare cases agranulocytosis can be fatal. Reversible agranulocytosis has also been reported as a rare occurrence in clinical studies with REMERON. In the postmarketing period with REMERON very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. All fatal cases 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.

Clinical worsening and Suicide Risk

Patients of any age with Major Depressive Disorder may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Patients should be closely monitored, especially at the beginning of therapy or when the dose is changed, until such improvement occurs.

There has been a long-standing concern that some antidepressants may have a role in the emergence of suicidality in some patients. The possible risk of increased suicidality in patients applies to all classes of antidepressant medicines, as available data are not adequate to exclude this risk for any antidepressant. Therefore, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Generally, when stopping an antidepressant, doses should be tapered rather than stopped abruptly.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adult and paediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and non-psychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and non-psychiatric disorders.

Mania and Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with any antidepressant alone may increase the likelihood of a mixed-manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder. It should be noted that mirtazapine is not approved for use in treating bipolar depression.

Information for Patients and Families

Patients and their families should be alerted about the need to monitor for the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient's doctor, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

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

• epilepsy and organic brain syndrome; from clinical experience it appears that insults occur rarely in patients treated with REMERON
• hepatic or renal insufficiency
• cardiac diseases like conduction disturbances, angina pectoris and recent myocardial infarct, where normal precautions should be taken and concomitant medicines carefully administered
• low blood pressure.

Like with other antidepressants care should be taken in patients with:

• micturation disturbances like prostate hypertrophy (although problems are not to be expected because REMERON possesses only very weak anticholinergic activity)
• acute narrow-angle glaucoma and increased intra-ocular pressure (also here little chance of problems with REMERON because of its very weak anticholinergic activity)
• diabetes mellitus

Treatment should be discontinued if jaundice occurs.

Moreover, 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 manic-depressive psychosis is being treated, it can transform into the manic phase
• with regard to the chance of suicide, in particular at the beginning of treatment, only a limited number of REMERON tablets should be given to the patient
• although REMERON 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 underlying disease. As advised above, it is recommended to discontinue treatment with mirtazapine gradually.
• elderly patients are often more sensitive, especially with regard to the side-effects of antidepressants. During clinical research with REMERON, side-effects have not been reported more often in elderly patients than in other age groups
• from post-marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with REMERON alone
• interactions with other serotonergic agents (see Interactions)

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine

The patient has the right to treatment meeting appropriate ethical and professional standards, and the patient need to be fully informed with frank discussion of risk/benefit issues relating to this medicine's efficacy and safety when used in the treatment regimen proposed.

Use in Children and Adolescents Under 18 Years of Age

REMERON 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.

Pregnancy and Lactation

Although studies in animals have not shown any teratogenic effects of toxicological significance, the safety of REMERON in human pregnancy has not been established. REMERON should be used during pregnancy only if it is clearly needed.

Although animal experiments show that mirtazapine is excreted only in very small amounts in the milk, the use of REMERON in nursing mothers is not recommended since no human data in breast milk are available.

Effects on Ability To Drive and Use Machines

REMERON has minor to moderate influence on the ability to drive and use machines. REMERON may impair concentration and alertness. Patients treated with antidepressants should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery.

Adverse 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 REMERON.

* Upon treatment with antidepressants in general, anxiety and insomnia (which may be symptoms of depression) can develop or become aggravated. Under Remeron treatment, development or aggravation of anxiety and insomnia has been reported very rarely.
** Incl. akathisia, hyperkinesia

Interactions

Pharmacokinetic Interactions

• Mirtazapine is extensively metabolized by CYP2D6 and CYP3A4, and to a lesser extent by CYP1A2. An interaction study of healthy volunteers showed that paroxetine, a CYP2D6 inhibitor, has no influence on mirtazapine pharmacokinetics at steady state. Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels and the AUC of mirtazapine by approximately 40% and 50% respectively. Caution should be exercised when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin or nefazodone.
• Carbamazepine and phenytoin, CYP3A4 inducers, increased mirtazapine clearance about two-fold, resulting in a 45 to 60% decrease in plasma mirtazapine concentrations. When carbamazepine or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.
• When cimetidine is co-administered, the bioavailability of mirtazapine may be increased by more than 50%. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started or increased when cimetidine treatment is discontinued.
• In in-vivo interaction studies, mirtazapine did not influence the pharmacokinetics of risperidone or paroxetine (CYP2D6 substrate), carbamazepine and phenytoin (CYP3A4 substrate), amitriptyline and cimetidine.
• No relevant clinical effects or changes in pharmacokinetics have been observed in humans on concurrent treatment with mirtazapine and lithium.

Pharmacodynamic Interactions

• Mirtazapine should not be administered concomitantly with MAO inhibitors or within two weeks after discontinuation of MAO inhibitor therapy.
• Mirtazapine may increase the sedating properties of benzodiazepines and other sedatives. 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.
• If other serotonergic agents (e.g. SSRI and venlafaxine) are used concomitantly with mirtazapine, there is a risk of interaction that could lead to the development of a serotonin syndrome. From post-marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with mirtazapine in combination with SSRIs or venlafaxine. If the combination is considered therapeutically necessary, dosage changes should be made with caution and sufficiently close monitoring for signs of beginning serotonergic overstimulation maintained.
• Mirtazapine dosed at 30mg once daily caused a small but statistically significant increase in the INR in subjects treated with warfarin. As at a higher dose of mirtazapine a more pronounced effect cannot be excluded. It is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.

Overdosage

Present experience concerning overdose with REMERON 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 overdosages. Cases of overdose should receive appropriate symptomatic and supportive therapy for vital functions. Activated charcoal or gastric lavage should also be considered.

Pharmaceutical Precautions

Storage

REMERON should be stored at 2-30°C, dry and in the original package in order to protect from light.

Shelf-life

The shelf-life for REMERON tablets is 3 years. REMERON tablets should not be used after the expiry date on the package.

Nature and contents of containers

REMERON tablets are packed in child-safe, push-through strips made of opaque white polyvinyl chloride film and aluminium foil containing a heat-seal coating on the side in contact with the tablets.

Medicine Classification

Prescription Medicine.

Package Quantities

The following packages are available:

• push-through strips with 10 yellow tablets each containing 15mg mirtazapine (code TZ/3)
• push-through strips with 10 red-brown tablets each containing 30mg mirtazapine (code TZ/5).
• push-through strips with 10 white tablets each containing 45mg mirtazapine (code TZ/7).

Further Information

REMERON 15mg, 30mg and 45mg tablets contain:

Core: maize starch, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose

Coating layer: hypromellose, polyethylene glycol 8000, titanium dioxide (E171)

REMERON 15mg tablets also contain yellow iron oxide (E172). The 30mg tablets contain yellow iron oxide (E172) and red iron oxide (E172).

Preclinical Safety Data

Mirtazapine induced no effects of clinical relevance in chronic safety studies in rats and dogs or in reproductive toxicity studies in rats and rabbits. 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 neoplasm 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.

Name and Address

Schering-Plough
a division of Schering-Plough Animal Health Ltd
36 Kitchener St
Auckland
Telephone: (09) 375 9210

Date Of Preparation

7 October 2008

Version 1

(CCDS 5(50) - 3/5/05)