INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
REMERON® 15 mg TABLETS
REMERON® 30 mg TABLETS

34346.102
RU M1060.052.105

SCHEDULING STATUS
S5

PROPRIETARY NAME
(and dosage form):

REMERON^® 15 mg TABLETS
REMERON^® 30 mg TABLETS

COMPOSITION
Each Remeron 15 mgtablet contains 15 mg of mirtazapine.
Each Remeron 30 mg tablet contains 30 mg of mirtazapine.

PHARMACOLOGICAL CLASSIFICATION       
A/1.2/Psychoanaleptics (antidepressants)

PHARMACOLOGICAL ACTION
Pharmacodynamic properties
Mirtazapine is a tetracyclic antidepressant, belonging to the piperazino-azepine group of compounds. Mirtazapine is an antagonist of central alpha2-auto and hetero-adrenoceptors which causes an increase in both noradrenaline and serotonin release.
The effect of released serotonin is exerted specifically via 5-HT1 type receptors, because 5-HT2 and 5-HT3 type receptors are specifically blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking alpha2- auto and hetero-adrenoceptors and 5-HT2 receptors and the R(-) enantiomer by blocking alpha₂ hetero-adrenoceptors and 5-HT3 receptors. In one study there was no efficacy difference indicated between the two enantiomers, despite their different receptor affinities.
The potent histamine H1-antagonistic activity of mirtazapine is responsible for its sedative properties. Mirtazapine has modest antagonism on cholinergic activity. Mirtazapine has modest peripheral alpha1-adrenergic antagonist activities and has been associated with acute postural hypotension in healthy volunteer studies but less so in patient studies (see “Side-effects”).
Pharmacokinetic properties
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; (26 hours in males, 37 hours in females); 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 in about 5 days with 50% accumulation, after which there is no further accumulation. Mirtazapine displays linear pharmacokinetics within the recommended dose range.
Mirtazapine is extensively metabolised and eliminated via the urine and faeces within four days. Major pathways of biotransformation are demethylation and oxidation followed by conjugation. The demethyl metabolite is pharmacologically active and appears to have the same pharmacokinetic profile as the parent compound.
In vitro data from human liver microsomes indicate that cytochrome P450 enzymes CYP 2D6 and CYP 1A2 are involved in the formation of the 8-hydroxymetabolite of mirtazapine, whereas CYP 3A4 is considered to be responsible for the formation of the N-demethyl and N-oxide metabolites.
The presentation of mirtazapine is as a racemate. It is not known whether first pass extraction of the drug is stereoselective, but it is known that the clearance of the two enantiomers is by different metabolic processes. It is not known whether food affects the bioavailability of the two enantiomers.
Population subgroups
Liver Disease - Following a single 15 mg oral dose of mirtazapine, the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering Remeron (mirtazapine) to patients with compromised hepatic function (see “Dosage and directions for use”.)
Renal Disease - Following a single 15 mg oral dose of mirtazapine, patients with moderate [glomerular filtration rate (GFR) = 11-39 mL/min/1,73 m²] and severe [GFR <10 mL/min/1,73 m²] renal impairment had reductions in mean oral clearance of mirtazapine of about 30% and 50% respectively, compared to normal subjects. Caution is indicated in administering Remeron to patients with compromised renal function (see “Dosage and directions for use”.)
Elderly Patients - Following oral administration of mirtazapine 20 mg/day for 7 days to subjects of varying ages (range, 25-74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering Remeron to elderly patients (see “Dosage and directions for use”).

INDICATIONS
Treatment of major depression.

CONTRA-INDICATIONS

-	Oversensitivity to Remeron .
-	Pregnancy and lactation, as there is insufficient clinical data available.
-	Children, as insufficient clinical data are available.

WARNINGS

-	Careful dosing as well as regular and close monitoring is necessary in patients with:
-	epilepsy and organic brain symptoms; 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.

Treatment should be discontinued if jaundice occurs.
MAO-Inhibitors
In patients receiving other antidepressants in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued an antidepressant drug and then are started on an MAOI, there have been reports of serious, and sometimes fatal, reactions, e.g., including nausea, vomiting, flushing, dizziness, tremor, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability with rapid fluctuations of vital signs, seizures, and mental status changes ranging from agitation to coma. Although there are no human data pertinent to such an interaction with Remeron (mirtazapine), it is recommended that Remeron not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI.
Neutropenia, Agranulocytosis
Bone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment. The symptoms mostly appear after 2-6 weeks of treatment. The bone marrow depression is, in general, reversible after termination of treatment. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with Remeron. One should therefore be alert for symptoms like fever, sore throat, stomatitis or other signs of infections. If such symptoms occur the treatment should be stopped and blood counts taken.

DOSAGE AND DIRECTIONS FOR USE
The tablets should be taken orally, if necessary with fluid, and swallowed without chewing.
Initial treatment
Adults
The recommended starting dose for Remeron (mirtazapine) is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In clinical trials the effective dose range was generally 15-45 mg/day. While the relationship between dose and antidepressant response for Remeron has not been adequately explained, patients not responding to the initial 15 mg dose may benefit from dose increases up to a maximum of 45 mg/day. Remeron has an elimination half life of approximately 20-40 hours; therefore, dose changes should not be made at intervals of less than one to two weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose.
Elderly and Patients with Renal or Hepatic Impairment
The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment (see Pharmacokinetic properties under the heading “Pharmacological action”).
Maintenance/ long term treatment
There is no body of evidence available from controlled trials to indicate how long the depressed patient should be treated with Remeron (mirtazapine). It is generally agreed, however, that pharmacological treatment for acute episodes of depression should continue for up to six months or longer. Whether the dose of antidepressant needed to induce remission is identical to the dose needed to maintain euthymia is unknown.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side effects that occurred during clinical trials with Remeron , categorised by body system, are as follows:
Common side-effects
Body as a whole:
Increase in appetite and weight gain, asthenia, flu syndrome, increased sweating.
Metabolic and nutritional disorders:
Oedema, peripheral oedema.
Neurological:
Somnolence/ drowsiness, sedation, dizziness, abnormal dreams, paresthesia, tremor, vertigo.
Digestive system:
Dry mouth, increased appetite, constipation, nausea.
Less common:
Liver: elevations of serum transaminase activities.
Uncommon:
Blood: Granulocytopenia, agranulocytosis. See “Warnings”.
Circulation: Orthostatic hypotension.
CNS: Epileptic seizures, tremor, mania, convulsions (insults), myoclonus.
Skin: Exanthema.
Other side-effects noted in clinical studies are:
Digestive system:
Vomiting, anorexia, dyspepsia.
Metabolic and nutritional disorders
Thirst, bitter taste.
Neurological
Thinking abnormal, tremor, confusion, hyperesthesia, apathy, amnesia, abnormal accommodation, agitation, impaired concentration.
Skin and appendages
Rash.
Uncommon side-effects, of which a causal relationship has not been established, include:
Increased (nonfasting) cholesterol and triglycerides, hypertension, vasodilatation.
Myalgia, myasthenia, arthralgia.
Dyspnoea, cough increased, sinusitis.
Urinary frequency, urinary tract infection.
Face oedema, photosensitivity reaction, abdomen enlarged, angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension, eructation, ataxia, delirium, delusions, depersonalisation, dyskinesia, extrapyramidal syndrome, libido increased, co-ordination abnormal, dysarthria, hallucination, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction, eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain, kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, impotence.

Special precautions
Care should be taken in patients with:

-	micturition disturbances like prostate hypertrophy
-	acute narrow-angle glaucoma and increased intra-ocular pressure
-	diabetes mellitus.

The following should also 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 antidepressants are not addictive, the abrupt termination of treatment after long-term administration may result in nausea, headache and malaise
-	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; however experience until now is limited.

Interaction with other medicaments and other forms of interaction:

-	Mirtazapine may potentiate the central nervous dampening action of alcohol; patients should therefore be advised to avoid alcohol during treatment with Remeron.
-	Remeron should not be administered concomitantly with MAO inhibitors or within two weeks of cessation of therapy with these agents.
-	Mirtazapine may potentiate the sedative effects of benzodiazepines, caution should be taken when these drugs are prescribed together with Remeron.
-	In-vitro data suggest that mirtazapine is a very weak inhibitor of CYP 1A2, CYP 2D6 and CYP 3A4 and clinically significant interactions are unlikely with mirtazapine.

There is little information at this time regarding the interaction of Remeron with SSRIs and the possibility of a serotonin syndrome with such a combination has not been fully investigated.
Effects on ability to drive and use machines
Remeron may impair judgement, thinking, and particularly motor skills because of its prominent sedative effects. Patients treated with Remeron should avoid the performance of potentially dangerous tasks, which require alertness and good concentration, such as driving a motor vehicle or operating machinery. This effect may be aggravated by simultaneous intake of alcohol or central nervous system depressants.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Cases of overdose should be treated by gastric lavage with appropriate symptomatic and supportive therapy for vital functions.

IDENTIFICATION
Remeron 15 mg tablets are yellow, coated, oval, biconvex tablets coded TZ over 3 on both sides of a score on one side and ORGANON on the reverse.
Remeron 30 mg tablets are red-brown, coated, oval, biconvex tablets coded TZ over 5 on both sides of a score on one side and ORGANON on the reverse.

PRESENTATION
Remeron 15 mg - tablets are packed in child-resistant push-through strips (10 tablets per strip) made of white opaque polyvinyl chloride film and coloured soft aluminium foil, incorporating a heat-seal coating on the side in contact with the tablets. The tablets are packed in folding cartons. Three strips are packed in a carton, together with the approved package insert.
Remeron 30 mg - tablets are packed in child-resistant push-through strips (10 tablets per strip) made of white opaque polyvinyl chloride film and coloured soft aluminium foil, incorporating a heat-seal coating on the side in contact with the tablets. The tablets are packed in folding cartons. Three strips are packed in a carton, together with the approved package insert.

STORAGE INSTRUCTIONS
Store at room temperature at 2-30°C. Protect from light and moisture.
Keep out of reach of children.

REGISTRATION NUMBER
Remeron 15 mg: 32/1.2/0481
Remeron 30 mg: 32/1.2/ 0482

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Donmed Pharmaceuticals (Pty.) Ltd
Cambridge Place
cnr. Kirkby and Oxford Streets
Bedfordview 2007

DATE OF PUBLICATION OF THIS PACKAGE INSERT       
July 1998

Under license of NV Organon, The Netherlands

Updated on this site: March 2003
Source: Pharmaceutical Industry
Current: May 2004
Source: Community Pharmacy
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