- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal category
Excipient(s) with known effect:Each Zispin SolTab 15 mg orodispersible tablet contains 4.65 mg aspartame and 28 mg sucrose.Each Zispin SolTab 30 mg orodispersible tablet contains 9.30 mg aspartame and 56 mg sucrose.Each Zispin SolTab 45 mg orodispersible tablet contains 13.95 mg aspartame and 84 mg sucrose.For the full list of excipients, see section 6.1.
AdultsThe effective daily dose is usually between 15 and 45 mg; the starting dose is 15 or 30 mg.Mirtazapine begins to exert its effect in general after 1-2 weeks of treatment. Treatment with an adequate dose should result in a positive response within 2-4 weeks. With an insufficient response, the dose can be increased up to the maximum dose. If there is no response within a further 2-4 weeks, then treatment should be stopped.Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.It is recommended to discontinue treatment with mirtazapine gradually to avoid withdrawal symptoms (see section 4.4).
Older peopleThe recommended dose is the same as that for adults. In elderly patients an increase in dosing should be done under close supervision to elicit a satisfactory and safe response.
Renal impairmentThe clearance of mirtazapine may be decreased in patients with moderate to severe renal impairment (creatinine clearance <40 ml/min). This should be taken into account when prescribing Zispin SolTab to this category of patients (see section 4.4).
Hepatic impairmentThe clearance of mirtazapine may be decreased in patients with hepatic impairment. This should be taken into account when prescribing Zispin SolTab to this category of patients, particularly with severe hepatic impairment, as patients with severe hepatic impairment have not been investigated (see section 4.4).
Paediatric populationZispin SolTab should not be used in children and adolescents under the age of 18 years as efficacy was not demonstrated in two short-term clinical trials (see section 5.1) and because of safety concerns (see sections 4.4, 4.8 and 5.1).
Method of administrationMirtazapine has an elimination half-life of 20-40 hours and therefore Zispin SolTab is suitable for once daily administration. It should be taken preferably as a single night-time dose before going to bed. Zispin SolTab 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. The tablet will rapidly disintegrate and can be swallowed without water.
Paediatric populationZispin SolTab 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 worseningDepression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.Close supervision of patients and in particular those at high risk should accompany therapy with antidepressants especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.With regard to the chance of suicide, in particular at the beginning of treatment, only the smallest amount of Zispin SolTab orodispersible tablets should be given to the patient consistent with good patient management, in order to reduce the risk of overdose.
Bone marrow depressionBone marrow depression, usually presenting as granulocytopenia or agranulocytosis, has been reported during treatment with Zispin SolTab. Reversible agranulocytosis has been reported as a rare occurrence in clinical studies with Zispin SolTab. In the postmarketing period with Zispin SolTab 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.
JaundiceTreatment should be discontinued if jaundice occurs.
Conditions which need supervisionCareful 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, Zispin SolTab should be introduced cautiously in patients who have a history of seizures. Treatment should be discontinued in any patient who develops seizures, or where there is an increase in seizure frequency. hepatic impairment: Following a single 15 mg oral dose of mirtazapine, the clearance of mirtazapine was approximately 35 % decreased in mild to moderate hepatically impaired patients, compared to subjects with normal hepatic function. The average plasma concentration of mirtazapine was about 55 % increased. renal impairment: Following a single 15 mg oral dose of mirtazapine, in patients with moderate (creatinine clearance <40 ml/min) and severe (creatinine clearance ≤ 10 ml/min) renal impairment the clearance of mirtazapine was about 30 % and 50 % decreased respectively, compared to normal subjects. The average plasma concentration of mirtazapine was about 55 % and 115 % increased respectively. No significant differences were found in patients with mild renal impairment (creatinine clearance <80 ml/min) as compared to the control group. cardiac diseases like conduction disturbances, angina pectoris and recent myocardial infarction, where normal precautions should be taken and concomitant medicines carefully administered. low blood pressure. diabetes mellitus: In patients with diabetes, antidepressants may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted and close monitoring is recommended.Like with other antidepressants, the following should be taken into account: Worsening of psychotic symptoms can occur when antidepressants are administered to patients with schizophrenia or other psychotic disturbances; paranoid thoughts can be intensified When the depressive phase of bipolar disorder is being treated, it can transform into the manic phase. Patients with a history of mania/hypomania should be closely monitored. Mirtazapine should be discontinued in any patient entering a manic phase. Although Zispin SolTab 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 Zispin SolTab because of its very weak anticholinergic activity). Akathisia/psychomotor restlessness: The use of antidepressants have been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental. Cases of QT prolongation, Torsade de Pointes, ventricular tachycardia, and sudden death, have been reported during the post-marketing use of mirtazapine. The majotity of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc prolonging medicines (see section 4.5 and section 4.9). Caution should be exercised when Zispin is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QTc interval.
HyponatraemiaHyponatraemia, 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 syndromeInteraction with serotonergic active substances: serotonin syndrome may occur when selective serotonin reuptake inhibitors (SSRIs) are used concomitantly with other serotonergic active substances (see section 4.5). Symptoms of serotonin syndrome may be hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma. Caution should be advised and a closer clinical monitoring is required when these active substances are combined with mirtazapine. Treatment with mirtazapine should be discontinued if such events occur and supportive symptomatic treatment initiated. From post marketing experience it appears that serotonin syndrome occurs very rarely in patients treated with Zispin SolTab alone (see section 4.8).
Older peopleOlder people are often more sensitive, especially with regard to the undesirable effects of antidepressants. During clinical research with Zispin SolTab, undesirable effects have not been reported more often in elderly patients than in other age groups.
SucroseZispin SolTab contains sugar spheres, containing sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
AspartameZispin SolTab contains aspartame, a source of phenylalanine. Each tablet with 15 mg, 30 mg and 45 mg mirtazapine corresponds to 2.6 mg, 5.2 mg and 7.8 mg phenylalanine, respectively. It may be harmful for patients with phenylketonuria.
Pharmacokinetic interactions• Carbamazepine and phenytoin, CYP3A4 inducers, increased mirtazapine clearance about twofold, resulting in a decrease in average plasma mirtazapine concentration of 60 % and 45 %, respectively. When carbamazepine or any other inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.• Co-administration of the potent CYP3A4 inhibitor ketoconazole increased the peak plasma levels and the AUC of mirtazapine by approximately 40% and 50% respectively.• When cimetidine (weak inhibitor of CYP1A2, CYP2D6 and CYP3A4) is administered with mirtazapine, the mean plasma concentration of mirtazapine may increase more than 50 %. Caution should be exercised and the dose may have to be decreased when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, cimetidine or nefazodone.• Interaction studies did not indicate any relevant pharmacokinetic effects on concurrent treatment of mirtazapine with paroxetine, amitriptyline, risperidone or lithium.
Paediatric populationInteraction studies have only been performed in adults.
PregnancyLimited data of the use of mirtazapine in pregnant women do not indicate an increased risk for congenital malformations. Studies in animals have not shown any teratogenic effects of clinical relevance, however developmental toxicity has been observed (see section 5.3).Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN to mirtazapine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).Caution should be exercised when prescribing to pregnant women. If Zispin SolTab is used until, or shortly before birth, postnatal monitoring of the newborn is recommended to account for possible discontinuation effects.
Breast-feedingAnimal 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 Zispin SolTab should be made taking into account the benefit of breast-feeding to the child and the benefit of Zispin SolTab therapy to the woman.
FertilityNon-clinical reproductive toxicity studies in animals did not show any effect on fertility.
|System organ class||Very common (≥1/10)||Common (≥1/100 to <1/10)||Uncommon (≥1/1,000 to <1/100)||Rare (≥1/10,000 to <1/1,000)||Frequency not known (cannot be estimated from the available data)|
|Blood and the lymphatic system disorders||• Bone marrow depression (granulocytopenia, agranulocytosis, aplastic anaemia, thrombocytopenia) • Eosinophilia|
|Endocrine disorders||• Inappropriate antidiuretic hormone secretion|
|Metabolism and nutrition disorders||• Weight increased1• Increase in appetite1||• Hyponatraemia|
|Psychiatric disorders||• Abnormal dreams • Confusion • Anxiety2, 5• Insomnia3, 5||• Nightmares2• Mania • Agitation2• Hallucinations • Psychomotor restlessness (incl. akathisia, hyperkinesia)||• Aggression||• Suicidal ideation6• Suicidal behaviour6|
|Nervous system disorders||• Somnolence1, 4• Sedation1, 4• Headache2||• Lethargy1• Dizziness • Tremor||• Paraesthesia2• Restless legs • Syncope||• Myoclonus||• Convulsions (insults) • Serotonin syndrome • Oral paresthaesia • Dysarthia|
|Vascular disorders||• Orthostatic hypotension||• Hypotension2|
|Gastrointestinal disorders||• Dry mouth||• Nausea3• Diarrhea2• Vomiting2||• Oral hypoaesthesia||• Pancreatitis||• Mouth oedema • Increased salivation|
|Hepatobiliary disorders||• Elevations in serum transaminase activities|
|Skin and subcutaneous tissue disorders||• Exanthema2||• Stevens-Johnson Syndrome • Dermatitis bullous • Erythema multiforme • Toxic epidermal necrolysis|
|Musculoskeletal and connective tissue disorders||• Arthralgia • Myalgia • Back pain1|
|General disorders and administration site conditions||• Oedema peripheral1• Fatigue||• Somnambulism • Generalised oedema • Localised oedema|
Paediatric populationThe following adverse events were observed commonly in clinical trials in children: weight gain, urticaria and hypertriglyceridaemia (see also section 5.1).Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Paediatric populationThe appropriate actions as described for adults should be taken in case of an overdose in paediatrics.
Mechanism of action/pharmacodynamic effectsMirtazapine is a centrally active presynaptic α2-antagonist, which increases central noradrenergic and serotonergic neurotransmission. The enhancement of serotonergic neurotransmission is specifically mediated via 5-HT1 receptors, because 5-HT2 and 5-HT3 receptors are blocked by mirtazapine. Both enantiomers of mirtazapine are presumed to contribute to the antidepressant activity, the S(+) enantiomer by blocking α2 and 5-HT2 receptors and the R(-) enantiomer by blocking 5-HT3 receptors.
Clinical efficacy and safetyThe histamine H1-antagonistic activity of mirtazapine is associated with its sedative properties. It has practically no anticholinergic activity and, at therapeutic doses, has only limited effects (e.g. orthostatic hypotension) on the cardiovascular system.
Paediatric populationTwo randomised, double-blind, placebo-controlled trials in children aged between 7 and 18 years with major depressive disorder (n=259) using a flexible dose for the first 4 weeks (15-45 mg mirtazapine) followed by a fixed dose (15, 30 or 45 mg mirtazapine) for another 4 weeks failed to demonstrate significant differences between mirtazapine and placebo on the primary and all secondary endpoints. Significant weight gain (≥7%) was observed in 48.8% of the Zispin SolTab treated subjects compared to 5.7% in the placebo arm. Urticaria (11.8% vs. 6.8%) and hypertriglyceridaemia (2.9% vs. 0%) were also commonly observed.
AbsorptionAfter oral administration of Zispin SolTab, the active substance mirtazapine is rapidly and well absorbed (bioavailability ≈ 50 %), reaching peak plasma levels after approx. two hours. Food intake has no influence on the pharmacokinetics of mirtazapine.
DistributionBinding of mirtazapine to plasma proteins is approx. 85 %.
BiotransformationMajor 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.
EliminationMirtazapine is extensively metabolized and eliminated via the urine and faeces within a few days. The mean half-life of elimination is 20-40 hours; longer half-lives, up to 65 hours, have occasionally been recorded and shorter half-lives have been seen in young men. The half-life of elimination is sufficient to justify once-a-day dosing. Steady state is reached after 3-4 days, after which there is no further accumulation.
Linearity/non-linearityMirtazapine displays linear pharmacokinetics within the recommended dose range.
Special populationsThe clearance of mirtazapine may be decreased as a result of renal or hepatic impairment.
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